Filter Validation Protocol

Agilent 850-DS Dissolution Sampling Station

Technical Overview

The Agilent 850-DS Dissolution Sampling Station is optionally equipped with a

filtering option that greatly improves dissolution sample processing through the use of
innovatively designed filter plates. The WhatmanTM 850-DS 8-Channel Filter Plates from
GE Healthcare, are consistent with filtration membranes and housing materials currently
used for dissolution sampling. The only differences between traditional luer-type syringe
filters and the filter plates are the absence of the luer fittings, and eight disks are
incorporated on a flat plate. The compact arrangement of the filters on the plate also
make it much easier for the automated equipment to process and filter samples over
traditional automation-ready filters.

To minimize the effort that your laboratory would have to invest to evaluate and
validate the new filter plates, the following is an example of a filter validation. It is a
straightforward procedure and it should be maintained with your method validation
documentation. The filter validation protocol includes filter selection guidance, as well
as three tests to challenge the filter’s efficiency, adsorption and leachability.
Filter Validation Protocol Filter selection Filter tests
Filtration is an essential component of Selecting the correct filter material
Whether a dissolution method is
the dissolution test. The dissolution is quite simple. Depending on your
performed manually or automatically, the
process stops at the moment that a method, you will typically use glass
filter must be challenged in three primary
sample is withdrawn and immediately fiber or membrane filters for HPLC
areas:
filtered. The sample, once clarified of anlaysis. Table 1 provides information
solid particles and excipient material, is on the four types of filters that can be • efficiency
now ready for the second phase of the used with the 850-DS for automated • leachability
test—analysis of the filtered sample. filtration of dissolution samples. The • adsorption
table also cross references the
This analysis is generally performed by corresponding 25 mm luer lock If a filter is being qualified as an
a UV-Vis spectrophotometric or HPLC individual syringe filters that may be equivalent filter for an existing method,
procedure. Additionally, filtration is used for the validation tests mentioned the efficiency challenge may be omitted
needed to alleviate potential blockage below. unless the pore size of the filter has
of HPLC column inlets, caused by changed. If excessive absorption of the
particulates and excipient matter from active drug occurs, excipient interference
sample solutions, that ultimately results is high, or filters become clogged,
in reducing the normal lifetime of the alternative filters may be required.
column.

Table 1. Whatman 25 mm syringe filters, corresponding filter plates, and recommended applications.

Whatman 850-DS
Whatman 25 mm 8-Channel Filter Plate
Individual Puradisc part numbers
Item description Filter part numbers (8 filter disks/plate) Recommended application
PTFE membrane filter, 25 mm, 0.45 μm 6784-2504 (50/pk) 7707-3000 (50/pk) Chemically stable and inert, suitable for acidic aqueous
6785-2504 (200/pk) solutions
Nylon membrane filter, 25 mm, 0.45 μm 6750-2504 (50/pk) 7707-3100 (50/pk) Robust hydrophilic membrane for applications where protein
6751-2504 (200/pk) binding is not critical
Polyethersulfone (PES) membrane filter, 6781-2504 (200/pk) 7707-3200 (50/pk) Hydrophilic, low protein binding membrane recommended
25 mm, 0.45 μm for aqueous samples
Glass fiber (GMF) filter, 25 mm, 0.7 μm* 6825-2517 (50/pk) 7707-3300 (50/pk) The standard for difficult-to-filter samples to retain coarse
6825-2527(200/pk) particles; also, a good filter for gelatinous capsules

*Retention rating rather than pore size.

Efficiency test
Step 3
Filters used in the dissolution method Dispense the samples
must be sufficient to stop the dissolution individually into test tubes
process. The efficiency of the filter is Step 1 Step 2 and analyze according to the
Prepare a sample solution of Filter three sample aliquots analytical method as follows:
its ability to remove undissolved active
approximately 50% of the through separate filters. • Sample 1 - Analyze
pharmaceutical ingredient (API) from a nominal analytical This step should mimic the immediately.
sample solution. See Figure 1. concentration. filtration procedure used for • Sample 2 - Ultrasonicate for
the dissolution test. 5 minutes, mix
well, and analyze.
• Sample 3 - Ultrasonicate for
10 minutes, mix
well, and analyze.
Efficiency acceptance criteria
Ultrasonicated samples should not show more than a 2%
increase in dissolved sample material when compared to the
non-sonicated sample.

Figure 1. Typical efficiency test.

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 Step 3
Leachability test
Analyze the solutions on a Filters used to clarify samples must
suitable system as follows:
not contribute to the UV spectra at the
• In triplicate, measure the wavelength of measurement. Additionally,
Step 1 Step 2 100% working standard
Prepare a working standard Filter three solution aliquots according to the analytical leachable substances must not affect the
solution in the intended of the intended dissolution method. Record the quantitative integrity of dissolved active
dissolution media at 100% media through separate filters resulting response values. pharmaceutical ingredient (API). See
nominal concentration of the or filtration systems. This Average the three standard
sample. This solution should step should mimic the measurements.
Figure 2.
not be filtered. filtration procedure used for
the dissolution test. • Measure the three filtered
blank solutions according to
the analytical method and
record the resulting
Leachablilty acceptance criteria response values.
The measurement response values of each of the filtered blank
dissolution media samples should be less than or equal to 0.5% of
the mean response value of the 100% standard solution.

Figure 2. Typical leachability test.

Adsorbance test Table 2. Typical adsorptivity test data.

Filters used to clarify dissolution sample solutions should not adsorb dissolved API Total volume
material onto their surfaces. Membrane technology typically adsorbs drug product onto Aliquot no. filtered (mL) % Recovered
the surface of the membrane. The extent of this adsorbance must be challenged. The 1 1 80*
final method should state that a specific volume be discarded prior to collecting the 2 2 90*
sample for analysis. The unique challenge with dissolution is that the initial sample of 3 3 95*
a typical dissolution profile may only be 20% of the final concentration at 100% of label 4 4 98*
claim (% LC). For this reason, a working standard should be made with the nominal 5 5 100*
concentration of the first timepoint. It will take more of this concentration to condition 6 6 100
the filter with active drug. For example, if you have to flush 3 mL through a filter at 100% 7 7 100
8 8 100
of label claim, you may have to flush 15 mL through the filter to condition it at around
9 9 100
20% of label claim. See Figure 3. 10 10 100

*In this example, the first 5 mL must be discarded

prior to sample collection.

Step 4 Step 5
Analyze the solutions on a For both types of filters used,
suitable system as follows: calculate % recovery of the
API from each filtered
Step 1 Step 2 Step 3 • Measure the unfiltered
standard according to the
Prepare a working In triplicate, Place a syringe standard solution according
following formula. Reference
standard solution withdraw 10 mL of filter on the end of to the analytical method
Table 2 for examples of
in the dissolution the standard the syringe and and record the resulting
expected data from a typical
media at nominal solution outlined in dispense 1.0 mL response value.
adsorptivity test.
concentration of step 1 through a increments into • Measure each of the filtered
the first timepoint syringe and cannula. 10 consecutive Rsam
standard solutions % Recovery = × 100
of the dissolution Separate syringes HPLC vials. according to the analytical Rstd
profile. and cannulas should method and record the
be used for each resulting response values. Rsam = Absorbance of the filtered
replicate test. standard solution
• Measure the unfiltered Rstd = Mean absorbance of the
standard solution again and unfiltered standard
record the resulting 100 = Conversion factor to percent
Adsorbance acceptance criteria response value.
Determine the volume needed to flush the filter so that the resulting
aliquots of standard recover at 98 to 102%. As shown in Table 2, at a
minimum, the final 5 mL of filtered standard should have recovery levels
between 98% and 102%.

Figure 3. Typical adsorptivity test.

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Filter Validation Summary
Although validated dissolution methods
may contain a filter statement such as
“Whatman 25 mm Puradisc filters, or
equivalent,” this generally covers the
use of alternative generic filters that
were originally validated. In the case
of the filter plates with eight individual
filters that were co-developed by Agilent
and GE Healthcare, the filter should
be considered as an equivalent to the
individual 25 mm Puradisc filters outlined
in Table 1.

The decision of equivalence rests solely

with the interpretation of the end user
and in the event further validation is
warranted, Agilent offers this filter
validation to supplement the adoption of
the Whatman filter plates designed for
the 850-DS. The filter plates are designed
to group the filters in a single manageable
plate for ease of use and automation.
Only the outer physical appearance
was modified to a plate design and the
internal product and contact components
of the Puredisc filters remain unchanged.

Whatman filters and filter plates are

supplied by authorized GE Healthcare
representatives worldwide. Each filter
plate consists of eight individual 25 mm
filters configured for use with the Agilent
850-DS filter changer option. Agilent
recommends using each filter plate for
a single timepoint to avoid clogging and
potential carryover issues.

Should you have questions regarding this

protocol or the suitability of these filter
plates in your dissolution testing, please
contact the Agilent Dissolution Hotline at www.agilent.com/lifesciences/
[email protected]. dissolution
This information is subject to change without notice.

Whatman is a registered trademark of GE Healthcare.

© Agilent Technologies, Inc., 2013

Published in the USA, November 14, 2013
5991-3341EN