When Does
Flow Rate Matter?
Criteria for Testing Optimal Filter Flow Rate
Authors:
Maik W. Jornitz is group vice president, global product management,
bioprocess, Sartorius North America Inc., Edgewood, NY, tel. 631.254.4249,
ext. 8309, maik.jornitz@sartorius.com. Theodore H. Meltzer is a principal
at Capitola Consultancy, Bethesda, MD.
Sterilizing grade, 0.2-µm rated membrane filters are used in many
biopharmaceutical processes to ensure the absence of particles and microorganisms
from the filtered fluid (1, 2, 3). These filters must meet particular
performance criteria in specifically defined applications. For this reason,
during filter design, one performance criterion often is enhanced at the
expense of another. Consequently, critical process and flow parameters
must be defined appropriately to identify the optimal flow membrane filter
for a specific application. This paper describes such an evaluation schematic
and tests, as well as some common misconceptions.
When Does
Flow Rate Matter?
Flow rate is critical for membranes used to filter solutions such as buffers,
which have low contamination levels and few fouling components. The prime
objective in such applications is to filter the defined fluid volume as
quickly as possible into a transfer vessel or storage bags to minimize
operational downtime.
Filter flow rate affects equipment scheduling and thus the capacity available
in a production facility. For example, a 0.2-µm
rated filter with a low flow rate (2,500 L/h) would require 48 min to
filter a 2,000-L volume, whereas a high-flow filter (6,000 L/h) would
require only 20 min to filter the same volume. This would reduce the time
for equipment use in half. Alternately, the effective filtration area
could be reduced in half. Either way, filter costs would be reduced.
Because total throughput
is not the focus, filters for filling applications do not contain the
protective layers common in throughput-enhanced filter designs (8, 9).
Instead, high-flow-rate filters have a specific membrane design and single-layer
construction.
Criteria
to Consider
To gain optimal flow rates from membrane filters, many criteria can be
controlled in the filtration process or design. Examples include:
• Differential pressure
• Effective filtration area
• Filter design or membrane configuration, including porosity, pore
structure, and membrane thickness, as well as the diameter of the inner
core, adapter, and connector (4, 5).
Differential
pressure. One way to increase a filter’s flow rate is to
raise the differential pressure over the membrane. Before doing this,
however, maximum operating pressures must be considered. If the operating
pressures are too high—specifically if the filtration process stops
frequently (i.e., in pulsating applications)—the filter membrane
can be damaged. Figure 1 shows such damage on the outer pleat-edge of
a membrane that had instabilities due to its membrane design and pleatability
(8).
Filtration
area. Another way to achieve an optimal flow rate is to increase
the filtration area. Doing so may increase the cost per liter of filtered
volume, however, and increasing the pleat density of a filter often does
not achieve the required filter area. For example, it is generally not
possible to double the flow rate by increasing the filtration area.
.
Membrane
configuration. A membrane’s design determines its porosity,
thickness, and pore structure (6). There is limited flexibility in membrane
configuration, however. For example, flow rate can be enhanced by altering
membrane thickness; the thinner the membrane, the lower the flow resistance
and thus, the higher the flow rate. However, membrane thickness affects
the filter’s retentivity; a membrane that is too thin might allow
organism penetration.
Most
flow-enhanced filters are single-membrane designs. Homogenous double-layer
designs have a higher total membrane thickness and as a result, the flow
rate of such filters is often insufficient (Figure 2) (10).
Process Parameter
Considerations
High-flow
applications that stop and start (e.g., during filling processes) can
create water hammer or pressure pulsation. Therefore, flow-enhanced membrane
filters must be mechanically stable to resist such pressure variations
and flexing of the filter pleat pack. Filter manufacturers routinely test
high-flow filter cartridges to verify that the mechanical resistance defined
will be achieved. Such testing is necessary to ensure appropriate functioning
in the end user’s process, yet not every filter in the high-flow
class achieves such resistivity in practice (Figure 3). For that reason,
we recommend performance qualification trials in the actual filtration
process.
The membrane
configuration is a key element to achieve optimal flow rate conditions.
Figure 2 shows that a single-layer membrane configuration will achieve
higher flow rates than a membrane double-layer combination, especially
of homogenous (e.g., 0.2/0.2 µm) design.
The flow resistivity
of a homogenous double-layer filter can be so high that a single-layer
membrane filter of a smaller pore size (for instance, a 0.1-µm rated
membrane) might reach a comparable flow rate (Figure 4). Furthermore,
the support fleece and pleat densities must be well balanced to avoid
a too-small effective filtration area or uneven flow distribution in the
membrane pleat pack.
Is Testing
47-mm Discs Useful?
Filter flow rate depends on multiple criteria besides differential pressure,
pore structure, porosity and thickness. The entire design of the filter
and membrane configuration, as well as any connection to the filter element,
influences flow rate performance (7). For example, a membrane can have
an excellent flow rate, but if it is not appropriately pleatable, the
resulting filter cartridge will have a lower effective membrane area,
yielding a low flow rate.
It is insufficient
to test only the membrane, as is commonly done with 47-mm discs. Such
tests will not be able to demonstrate the performance of a filter element
used in the production process. We have conducted tests that show that
initial flow rate comparison trials with 47-mm discs are meaningless (Figure
5).
The 47-mm filter discs
used in a comparison test all have the same theoretical filtration area
of 17.4 cm². When these filters are scaled up, however, the effective
filtration area of the resulting 10-in. filter cartridges varies widely,
from 4,500 to 7,500 cm². Also, the flow rates of these filters at
14.5 psi differential pressure can vary from 2,700 to 8,000 L/h. Testing
just the 47-mm discs does not capture these variations; if it did, the
results would show that one 47-mm disc filter has a flow rate threefold
higher than another 47-mm filter. In addition, the inlet and outlet connectors
of the test device might not be able to cope with such flow.
How to Test for Flow
Performance qualification in a large-scale trial, under real processing
conditions, is the best way to ensure that the filter chosen withstands
the set of process parameters.
Large pleated devices
must be used to evaluate and compare the real flow rates of the filters
used in production. If the ultimate filter is a capsule device, the flow-rate
tests should be conducted with a capsule; similarly, if the filter is
a 10-in. filter element, the tests should be conducted in such a setup
(7). If multiple filters are compared, water can be used in a side-by-side
trial with comparable elements.
Such testing takes
into account the entire design of the filter, the membrane design, the
effective filtration area, flow distribution resulting from pleat densities,
and the fleece thickness. The tests should be performed under the required
or specified process conditions: a set inlet pressure should be established
so that the time to filter a fixed fluid volume can be measured.
In such testing, it
is very important to keep the process parameters constant. If the flow
rate tests are performed to size a filter system, the actual fluid should
be used, under the process conditions found in the production process.
Using the actual fluid also accommodates for specific fluid properties
(such as viscosity) that must be checked. A pleated device should be used,
because only such a device can be scaled to the process size.
To be able to evaluate
the effects of real pressure conditions, possible variations, temperature
influence, and other variables, the filtration conditions during the trial
must mirror production conditions. Only trials conducted in the described
scope will result in appropriate sizing of the necessary filter element.
As Figure 5 shows, the 47-mm flow rate results differ greatly from the
10-in. element flows, and we may conclude that 47-mm test discs are inappropriate
to find an appropriate filter type and scale. Such tests are not only
time consuming, but have no true value.
References
1. American Society for Testing and Materials. Standard
test methods for determining bacterial retention of membrane filters used
for liquid filtration. In: Annual Book of ASTM Standards, Philadelphia,
PA: ASTM. ASTM Committee F-21; 1988. pp. 790–795.
2. FDA, CDER. Guidance for industry, Changes to an approved NDA or ANDA,
CMC 1999.
3. Health Industry Manufacturers Association. Microbial evaluation of
filters for sterilizing liquids. Document No. 3, Volume 4. Washington,
D.C.; 1982.
4. Jornitz MW and Meltzer TH. Flow and pressure, flow decay, and filter
sizing, Chapter 4, and Cartridges, cartridge holders, and their care,
Chapter 8. In: Sterile filtration—a practical approach, Jornitz
MW and Meltzer TH editors. New York: Marcel Dekker; 2001.
5. Levy RV. Sterile filtration of liquids and gases, Chapter 40 In: Disinfection,
sterilization, and preservation. Block SS editor. Philadelphia, PA: Lippincott
Williams & Wilkins; 2001.
6. PDA. Technical Report #26: Sterilizing filtration of liquids, PDA J.
Pharm. Sci. & Tech. Suppl. 1988; 52(S1).
7. Soelkner P and Rupp J. Cartridge filters. Chapter 5 In: Filtration
in the biopharmaceutical industry. Meltzer TH and Jornitz MW editors.
New York: Marcel Dekker; 1998.
8. Priebe PM, Jornitz MW, and Meltzer TH. Making an informed membrane
filter choice—criteria to consider. BioProcess International 2003;
10:64–66.
9. Jornitz MW; Soelkner PG, and Meltzer TH. The economics of modern sterile
filtration. Pharmaceutical Technology US 2003; 27(3):156–166.
10. Karbachsch M. Test methods for integrated filtration systems. Concept
Seminar: Particle-Free and Sterile Filtration of Pharmaceuticals. 1982
Nov. 19–20.
|
