A

Seminar
On
Validation Of Membrane Filtration

Shaikh

sem

Presented by :Jenab
Guided by:Pooja patel
M.pharm Q.A 3 rd
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Content
Introduction
Objectives
Why validation needed
Pre-requisites for validation
Validation Study Element(testing parameter of membrane
filtration)
References

Introduction
Unit operation of filtration is the separation of solids from a liquid by
passage through a filter medium
There are two types of filter used in filtration process
Depth filters: It is made of diatomaceous earth, unglazed porcelain
filter, sintered glass or asbestos. These filters are commonly used
when the fluid to be filtered contains a high load of particles.

 Membrane filters: These are porous membrane

about 0.1 mm thick, made of cellulose acetate,
cellulose nitrate, polycarbonate, and polyvinylidene
fluoride, or some other synthetic material.

 Membrane filters are used to sterilize

heat sensitive materials include media ,
special nutrients that might be added to
media , enzymes , vaccines, and
pharmaceutical products such as drugs ,
sera, and vitamins. They are used to
sterilize the things such things as
beverages , intravenous solution and
bacteriological media.
some operating theaters and rooms
occupied by burn patients receive filtere
air to lower the number of air borne
microbes.
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Methods of Sterilization of Products

1. Heat
Moist heat(Autoclave)
Dry heat (oven and tunnel)

2. Gas
Ethylene oxide
Per-acetic acid
Vapor phase hydrogen peroxide
Chlorine dioxide

3. Radiation
Gamma
Beta
Ultraviolet
4.

Membrane filtration

 Validation may be defined as

Establishing

documented evidence which provides a high degree

of assurance that a specific process will consistently
produce a product meeting its

pre-determined

specifications and quality attributes

It has been made mandatory by the regulatory
bodies to prove the safety, efficacy, Purity &
effectiveness of the drug product, medical devices &
biologics in the marketplace & health system

Objectives
To establish documented evidence that the process
employed for validation of membrane filtration method will
produce the desired results consistently when performed as
per the SOP.
For good business practice in which out of control
process increase the amount of cost
To establish quality, safety, and consistency of
product

Why Validation is needed?

Validation is vital for
Safety
Fewer interruptions of work
Lower costs
Elimination of premature replacement
Identification of high maintenance cost
Reduction of variation in results
Greater confidence in the reliability of results

Responsibilities
Sr.
No.

Responsibility

Name of the
Department

Development of Validation protocol

QC

Execution of this protocol

QC

Approval of protocol and of the final report

QA

Final determination of System Acceptability

QA/QC

Review and assembling of data into a final report

QC

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Pre-requisites

In order to efficiently conduct validation of the membrane

filtration method, ensure that the following requirements
are fulfilled
Validated aseptic facility to carry out the validation
All equipments to be used for validation are qualified and
operational SOPs established and followed.
All the equipments and culture media required for the
validation should be sterile.
Sterile 70% IPA solution
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 Membrane filter :- Sterile individually packed

cellulose nitrate or cellulose acetate average pore
size 0.45m
Validation tasks are to be carried out by trained
personnel using techniques and equipment, which
minimize the risk of accidental microbial
contamination of the test and of the testing
environment
Personnel conducting sterility testing or associated
aseptic manipulations should wear sterilized
garments
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Validation study element (testing

parameter of membrane filtration)
Physical
Reproducibility of filter
Sterilization
Integrity test
Operating condition
Shedding
Microbial challenge test
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Chemical
Inertness
Activity/stability
Test for antimicrobial activities
Consistency and reliability
Biological
Endotoxin
Toxicity

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(1) REPRODUCIBILITY OF FILTER

Membrane filters should be routinely discarded
after processing of single lot because there are
chances of contamination or cross contamination of
product
However in those instances when repeated use can
be justified the membrane filtration should
incorporate the maximum number of lots to be
processed
Factor that can affect in filtration process include
viscosity, surface tension of material to be filtered,
ph, flow rates, time, temperature, osmolarity etc.
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(2) STERILIZATION
Validation of sterilization of filter is necessary
because filter it self cause contamination of the
product
To validate use of sterilizing grade filter it is not
only prove that the filter is adequately sterilized but
also method does not damage the filter
Most preferred method is moist heat sterilizing
Variable like heat up, cool down, pressure,
temperature, time, if it is uncontrolled it lead to
filter failure
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(3) INTEGRITY TEST

It should be non destructive and provide an
indication of fitness for use
This include bubble point test, diffusion test,
pressure hold test, water intrusion test
This test of filter should be performed prior to
processing and should be performed routinely
and conducted after filtration to detect any
filter leaks or perforation that might have
occurred during the filtration
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 In bubble point test filter medium wetted with a liquid and

test gas pressure is increase until steady stream of bubble
appears from tube which is immersed in water
The pressure at which the bubble first appear is recorded as
the bubble point
Water bubble point of filter should exceed the greater than
50 psig
The aims of this series of tests were to:
Determine the microbial removal efficiency of filters in
liquid challenge tests using Brevundimonas diminuta
(ATCC 19146)
Determine integrity test parameters
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(4) OPERATING CONDITION

The validation study must ensure that within anticipated
worst case operating condition the filter is not compromised
Time :
Long processing time could allow bacteria which have been
trapped by the filter
Filter manufacturer can provide the data on the retention
tests that have been conducted for specific membrane and
generally suggest that filter should retain bacteria excess of
48hr.
Filter manufacturer decide the time by performing
test
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Temperature :
Manufacture of filter recommended the limit
and these not exceeded
Pressure :
Inlet pressure to the filter must be monitored
to ensure that there is no potential for structure
damage
The differential pressure across the membrane
must comply with the filter manufactures
recommended limits
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(5) SHEDDING
It includes particulates and fiber
Particulates :
It concern for the following reason
Is the filter contributes to particular load of the solution?
Is the filter specified as reducing the particulate load of the
solution?
USP limits when tested by light obscuration method
For LVPs not more than 25 particulates per ml 10 m and
not more than 3 particulates per ml 25 m

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 For SVPs not more than 6000 particulate per container

10 m and 600 25 m
Optical microscopy, light obscuration, light microscopic
image analysis, scanning electron microscope are used in
particulates count
To measure removal of particulates by filter known amount
and size distribution of particulates filtered and amount of
retention is measured

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Fiber :
It concern for 2 reason
Is the filter shedding fiber into the solution?
Is the fiber function to remove fibers
Fiber releasing filter may not be used in filtration
process unless it is not possible to manufacture such
drug product without the use of such filters
If it is not avoidable than use subsequently 0.22 m mean
porosity and 0.45 m NFR filter

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(6) MICROBIAL CHALLENGE TEST

To ensure filter is not undergoing degradation ,deformation
or some change under condition of use
Drug product not cause in organism to shrink
resulting non sterilizing condition
Sterilizing filter one that when challenged with 107
Brevundimonas diminuta per cm2 of filter area will produce
sterile effluent
Care should be taken that drug product should not be
toxic to organism

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(7) FILTER INERTNESS

There may be extraction and adsorption phenomena
occurs
Various technique for determining inertness
like
compatibility, ph, conductivity, gravimetric extractable,
weight change, adsorption, USP oxidizable substance test
etc
Stability of the product should not be affected by the filter
In gravimetric extractable test weight of the extractable are
measured when filtered are shocked in ASTM grade water
for 24 hr.

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 USP oxidizable substance test amount of oxidizable

substance release from the filter in filtrate is measure
(8) A TEST FOR ANTIMICROBIAL ACTIVITY
Objectives

The test is performed to ensure that, any residual of

Antimicrobial Activity is satisfactory eliminated by using
the steps mentioned in this protocol
An inoculums of viable cells of the specific bacteria and
fungi has been passed through the filter, inoculate filter
paper in FTM & incubate at 30 to 350C or in SCDM and
incubate at 20 to 250C

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 If conspicuous growth does not occur within 3 days for

bacteria and 5 days for fungi, the test procedure is not valid
and must be modified
(9) ENDOTOXIN
Validation must address filter does not add endotoxin to
drug product
It depend on quality control process of the filter
manufacturer, water used in manufacturing, choice of filter
vendor, verification are not done properly
Millipak filter unit contain less than 0.5 units of endotoxin
per ml as per USP bacterial endotoxin test

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(10) TOXICITY
A validation study should determine that passage of the
drug product through a filter does not cause any
toxicological effects
Construction material off filtration system should be non
toxic
Manufacture provide relevant test data such a compendial
plastic test similar to USP class 6 test for plastics and USP
mouse safety test for all construction materials

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 In USP class 6 test was performed to conform that filter

are suitable and non-toxic with contact with parenterals
Testing includes systematic and intracutaneous injection as
well as intramuscular implantation
If no toxicity found then filter passes the test
In USP mouse safety test mouse were injected with filter
unit extract, then monitored for sign for toxicity

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Validation Report
Standard format
1. Executive summary
2. Discussion
3. Conclusions & recommendation
4. List of attachment
Topic should be presented in the order in which they appear
in the protocol.
Protocol deviation are fully explained & justified.
The report is signed & dated by designated representatives
of each unit involved in water system validation.
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References
R. A. Nash and A. H. Watcher Pharmaceutical
process validation; Third edition
Agalloco James, Carleton J. Fredric Validation of
Pharmaceutical Processes; Third edition
Pharmaguideline.blogspot.com
www.milipore.com
www.nsdl.niscair.res.in/bitstream

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