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ISPE Tampa Conference

22-23 February 2010


Tampa, Florida, USA

Current Topics in
Sterilizing Filtration
ISPE Tampa Conference
F b
February
22-23,
22 23 2010
Michael Moussourakis
Technical Manager
Pall Life Sciences

Current Topics in
Sterilizing Filtration
Pre-use Integrity
g y Testing
g
Single Use Filtration Systems
Serial / Double / Redundant Filtration

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Filter Integrity Testing


Pre-use
Pre-sterilization
Post-sterilization

Post-use

Definition of Integrity
Unimpaired, sound
Complete, entire
Whole, undamaged

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Purpose of Integrity Tests


Confirms integrity of filter assembly
Correct grade membrane
Proper installation of element or cartridge(s)
in capsule or housing
Absence of leaks and damage

Confirms process filter is comparable to


filters in core validation study (val
(valn
n guide)
Predicts validated bacterial retention

Integrity Tests do not measure the pore size


of high area filter cartridges
5

Pre-use Integrity Testing


Filter manufacturer
Manufacturing release test (100%)
Confirms integrity prior to shipping,
handling, installation and sterilization

User integrity testing


Pre-sterilization
Confirms integrity after shipping,
shipping
handling, and installation

Post-sterilization
Confirms integrity after sterilization and
immediately prior to use
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

FDA Guidance for Industry


Sterile Drug Products Produced by
Aseptic Processing Current Good
Manufacturing Practice, September, 2004
Integrity testing of the filter(s) can be
performed
f
d prior
i tto processing,
i
and
d
should be routinely performed post-use.

EC Guide to GMP - Revision to


Annex I - Manufacture of
Sterile Medicinal Products
Revised Feb, 2008
Effective March, 2009

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Filtration Of Medicinal Products Which Cannot


Be Sterilised In Their Final Container
113. The integrity of the sterilised filter should be
verified before use and should be confirmed
immediately after use by an appropriate
method such as a bubble point, diffusive flow
or pressure hold test
test.

Rationale for
Post-sterilization / Pre-use IT
Confirms integrity
g y after shipping,
pp g,
handling, installation and sterilization
Risk of loss / rework of product if postuse failure

Recommended by filter
manufacturers
Aids in failure analysis, root cause
determination and corrective and
preventative action (CAPA)
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Rationale against
Post-sterilization / Pre-use IT
Filter manufacturers release integrity
g y test
showed no defects
Users installation test confirms absence of
assembly leaks or damage
Controlled sterilization conditions can be
g filters
validated to not damage
Post-use integrity failure is not a patient safety
risk
Product is rejected or reworked (per SOP)
Manufacturers economic risk only
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Rationale against
Post-sterilization / Pre-use IT
Integrity
g y failure during
g steaming
g is typically
yp
y
detectable by destructive analysis
Directional over-pressurization at elevated
steaming temperature causes

Core collapse
Cage expansion
Other
Ot
e deformations
de o at o s
Membrane rupture

Failure to remove air can cause oxidative


degradation of the membrane and supports
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Pore Enlargement Hypothesis


Enlarged
g p
pore/defect appears
pp
during
g
sterilization
Potentially large enough for bacterial
penetration

Plugs with contaminant during filtration


Undetectable by post-use integrity test
False pass is a patient safety risk

Only a post-sterilization/pre-use integrity


test can detect pore enlargement
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Pore Enlargement Hypothesis


basis in EC
EMEA Inspections - Good Manufacturing Practice
- Questions & Answers
"The filter sterilisation process, maycause the
filter to distort, potentially leading to fluid pathways
that allow the passage of particles greater than
0.2m in size.
For these reasons filters
should be tested both, before use but after
sterilisation, and again after use.
Ref: http://www.ema.europa.eu/Inspections/gmp/q15.htm

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Pore Enlargement Hypothesis is


Contradicted by Data
May
y occur with obsolete or prototype
p
yp R&D
membranes, but
Does not occur with validated commercial
sterilizing grade filter membranes
Filter Validation Guide data
Product-specific validation data
Filter lot release QC test data
Bacterial challenge after autoclaving
Post multiple-autoclaving integrity tests

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Pore Enlargement Hypothesis is


Contradicted by Data
Filters that fail integrity
g y tests after
sterilization do not self-repair
Non-integral filters cannot be masked by
post-use plugging.
Even 0.45 m filters show very high bacterial
retention efficiencies
Formerly considered sterilizing grade

Single defects in process scale filters must be


significantly larger before retention is
compromised and filter integrity tests fail.
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Single-use Filtration Systems

17

FDA Guidance for Industry : INDs


Approaches to Complying with CGMP
During Phase 1
A number of technologies and resources are
available for use that can facilitate conformance
with CGMP and help streamline product
development. Some examples include:

18

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

FDA Guidance for Industry: INDs - Approaches


to Complying with CGMP During Phase 1
Use of disposable equipment and process aids,
which can reduce cleaning burden
Use of presterilized containers can eliminate the
need for additional equipment or qualifying
existing equipment
Use of process equipment that is closed
((i.e., p
product not exposed
p
to the environment
during processing), which can alleviate the need
for stricter room classification for air quality

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Single Use Filtration Systems

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Single Use Filtration Systems


with Flush Bag for Post-sterilization
/ Pre-use Integrity Testing

Flush
Bag

21

Single Use Filtration Systems


with Flush Bag for Post-sterilization /
Pre-use Integrity Testing

22

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Single Use Filtration Systems


with Flush Bag for Post-sterilization /
Pre-use Integrity Testing

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Integrated Disposable Systems


(Manifolds)
Sterile
liquid

x
Spare
outlet
Waste
flush fluid

Sample
port

Spare
inlet

x x
x

Sample
port

x
x

Sterile
storage
container

Filter

Containers 24
to be filled

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Serial / Double / Redundant


Filtration

A Short History of Sterilizing Filtration


Pre-60s:
60s-70s:
80s+:

90s+:

00s+:

Charged depth filters, asbestos filters,


porous ceramic filters
0.45
m membrane filters,, cartridges
g
bubble point testing
0.2 m membrane filter cartridges
Forward flow (diffusion) testing
- 1987 FDA Aseptic Processing Guidelines
0.1 m membrane filters (enhanced stern)
Product specific validation
Product-specific
- 1998 PDA Technical Report 26
Serial / double / redundant filtration
- 2003 EC GMP Annex 1
- 2004 FDA Aseptic Processing Guidance
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Serial / Double / Redundant Filtration


What does the dictionary say?
Serial: events occurring sequentially
Double: two together or sequentially
Redundant: Superfluous, not needed

Ref.s: www.dictionary.com, American Heritage Dictionary


27

Serial / Double / Redundant


Filtration
What do the regulatory agencies
say?

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

EMEA Committee for Proprietary


p
y
Medicinal Products (CPMP)
Note for Guidance on Manufacture
of the Finished Dosage Form
(CPMP/QWP/486/95)
April, 1996
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7. Special Items (1/4)


For sterilisation by
y filtration the maximum
acceptable bioburden prior to the filtration
must be stated in the application.
In most situations NMT 10 CFUs / 100 ml will
be acceptable, depending on the volume to
be filtered in relation to the diameter* of the
filter.
*sic, filter area

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

7. Special Items (2/4)


If this requirement
q
is not met,, it is
necessary to use a pre-filtration
through a bacteria-retaining filter to
obtain a sufficiently low bioburden.

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7. Special Items (3/4)


The type
yp of bacteria-retentive filter and
its pore size should also be described in
the application*. Pore sizes (ratings) of
0.22 m or less are acceptable without
further justification, in accordance with
the Ph. Eur.
* Suggests both bioburden filter and sterilizing filter
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

7. Special Items (4/4)


A proposal to use a larger pore size in
combination with an additional sterilisation
step has to be validated and justified in the
application file*.
* Use of a larger
g p
pore rated bioburden filter may
y require
q
additional bacterial retention validation in addition to
validation of the sterilizing filter

33

EC Guide to GMP - Revision to


Annex I - Manufacture of
Sterile Medicinal Products
Revised Feb, 2008
Effective March, 2009

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Filtration of medicinal products which cannot


be sterilised in their final container
110. If the product cannot be sterilised in the
final container, solutions or liquids can
be filtered through a sterile filter of
nominal pore size of 0.22 micron (or
less),
) or with at least equivalent
q
microorganism retaining properties, into a
previously sterilised container.
35

Filtration of medicinal products which cannot


be sterilised in their final container
potential additional risks of
111. Due to the p
the filtration method as compared with
other sterilisation processes, a second
filtration via a further sterilised microorganism retaining filter, immediately
prior
i tto filli
filling, may be
b advisable.
d i bl Th
The
final sterile filtration should be carried
out as close as possible to the filling
point.
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

FDA Guidance for Industry


Sterile Drug Products Produced by
Aseptic Processing Current Good
Manufacturing Practice, September, 2004
Use of redundant sterilizing filters
should be considered in many cases.

37

Redundant Filtration
What does industry say?
Redundant Filtration
A type of serial filtration where a second
sterilizing filter is used as a backup in the
event of an integrity failure of the primary
sterilizing filter*

* PDA Technical Report 26, Sterilizing Filtration of


Liquids (2008 Revision, in press), Glossary
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

PDA TR26 (rev 2008)


7.6.1 Serial Filtration
If one filter has been validated to achieve
sterilization with a specific product
It must satisfactorily pass integrity testing after use

Where serial filtration is required and has been


validated for sterilization of a specific product
The filter train is considered to be the sterilizing unit
All sterilizing grade filters within it must satisfactorily
pass integrity testing after
f use

39

PDA TR26 (rev 2008)


7.6.1 Serial Filtration
It mayy be difficult to conduct pre-use
p
integrity tests of both filters in a series
after sterilization
Sterility downstream of the first filter may
be compromised in testing the second
filter
Contact filter manufacturers for
recommendations
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

PDA TR26 (rev 2008)


7.6.1 Serial Filtration
Redundant filtration
An additional sterilizing-grade filter is placed in
the filter train to ensure against loss of product
Applies if integrity failure of the primary sterilizing filter

The additional filter does not require post-use


integrity testing unless the primary filter fails
Batch can be released as sterile if the second
(redundant) filter passes integrity testing post-use
The primary filter is at the distal end of the filtration
train

41

PDA TR26 (rev 2008)


7.6.1 Serial Filtration
For processes requiring in-series integrity testing
(e.g., where both filters are sterilized in series)
All valves must be completely open during sterilization to
permit steam penetration

Each filter must be tested individually


Sterility of the fluid pathway between the two
filters may need to be maintained
Precautions can include addl sterilizing filters to
Vent the integrity test gas from the first filter
Introduce the test gas for integrity testing the second filter

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

PDA TR26 (rev 2008)


7.6.1 Serial Filtration
To test the second filter
Use valve between the first and second filter
Closing this valve isolates the second filter from the
first

Attach integrity test hose (gas pressure) to the


integrity test port on the second housing
Close the vent valve (open for test of the first
filter)
Test second filter as usual
All steps must be performed aseptically
The gas used must be filter sterilized to prevent
contaminating the connection between the two filters
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Filtration Configurations

Single / Serial
Bioburden Reduction / Sterilizing
Upstream / Downstream
Double / Redundant

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

1) Single Filter Upstream of Tank &


Filler
Sterilizing
filter

Advantages
g

Sterile
vent
filter

Simple to operate
Leachables diluted in bulk
Steamable in place (SIP
Integrity test (IT) pre-use

Sterile
tank

Test
T t from
f
upstream
t
side
id

Reprocess buk if filter fails IT


Filling
line

If pre-qualified, per SOP


45

1) Single Filter Upstream of Tank &


Filler
Sterilizing
filter

Disadvantages
g
Less secure in long term
filling
Time and distance to filling
line considered sterility risk
factors
Filter integrity failure results in
loss or reprocessing of batch
Integrity of vent filter must be
confirmed
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Sterile
vent
filter
Sterile
tank

Filling
line

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

2) Single Filter Downstream of Tank


Advantages
St
Sterilization
ili ti and
d IT off ventt filter
filt
may not be required
Filling can start before tank is
full
Filter sterilizable in situ (SIP) or
Pre-sterilize filter and aseptic or
sterile connect

Vent
filter
Low
bioburden
Sterilizing
filter

Filling
line

47

2) Single Filter Downstream of Tank


Disadvantages
Bioburden may grow in tank
over long filling times
Filter should be pre-flushed prior
to container filling to reduce
leachables and particulates

Vent
filter
Low
bioburden
Sterilizing
filter

or initial filled containers


may be discarded

Filter integrity failure results in


loss of filled container batch
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Filling
line

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Bioburden Filter Upstream


Single Filter Downstream
Bioburden
filter

Advantages

Ventt
V
filter

Bi
Bioburden
b d in
i tank
t k controlled
t ll d
during long filling times
Bioburden filter may not need
to be sterilized, flushed or
integrity tested
Bioburden filter can be 0.2 m or
0.45 m rated

Controlled
bioburden
Sterilizing
filter

Filling
line
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Bioburden Filter Upstream


Single Filter Downstream
Bioburden
filter
Ventt
V
filter

Disadvantages
Final filter should be pre-flushed
Or initially filled containers
may be discarded

Controlled
bioburden
Sterilizing
filter

Final filter integrity failure results


in loss of filled container batch
Filling
line
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

4) Double Filters Downstream of Tank


Advantages
Product can be formulation
in tank
Filter B controls bioburden
upstream of sterilizing filter A

Vent
filter
High bioburden
Bioburden filter

A Sterilizing
filter

Same filter can be used

Pre
Pre-use
use sterility between
double filters not required
Vent and bioburden filters may
not need to be integrity tested

Filling
line

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4) Double Filters Downstream of Tank


Disadvantages
High bioburden may
limit filling time
Filters should be pre-flushed

Vent
filter
High bioburden

or initially filled containers


may be discarded

Both filters may still need to be


integrity tested
Filter A integrity failure results in loss
of filled container batch
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Bioburden filter

A Sterilizing
filter

Filling
line

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

5) Redundant Filters Downstream of Tank


Advantages

Vent
filter

P
Product
d t fformulated
l t d in
i ttank
k
Vent filter testing optional
Post-use integrity failure of
one filter may be allowable

Low bioburden
Sterilizing
filters

If final filter (A) passes postuse IT, testing of the second


filter (B) is not required
Filled containers can be
released

Filling
line

53

5) Redundant Filters Downstream of Tank


Disadvantages

Vent
filter

P
Post-sterilization/pre-use
t t ili ti /
IT
of both filters is complex
Maintain sterility between filters
Additional valve, sterile drain
and air/vent filters required
Difficult to IT add
addll filters in situ
Single use system with side bag also
eliminates drain, easier to use

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Low bioburden
Sterilizing
filters

Filling
line

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

6) Redundant Filters Upstream/Downstream


Advantages
Same filter can be used
High assurance of sterilization
Entire system can be SIPd

Suitable for long term


g y failure may
y
Filter A integrity
allow batch release if Filter B
passes integrity

Sterilizing
filter
Sterile
B
vent
filter
Sterile
tank
Sterilizing
filter

Filling
line
55

6) Redundant Filters Upstream/Downstream


Disadvantages
Separate formulation tank
Sterility of entire system must
be validated
Post-sterilization/pre-use IT
of filter A is complex
Maintain sterility between filters
Additional valve, sterile drain
and air/vent filters required
Difficult to IT addl filters in situ

Sterilizing
filter
Sterile
B
vent
filter
Sterile
tank
Sterilizing
filter

Filling
line
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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

7) Double Redundant
Advantages
Fi
Finall filter
filt redundancy
d d
close to filling line
Meets critical regulatory
interpretations
Suitable for long term use
Filter C and vent may not
need to be sterilizing or
integrity tested
(bioburden reduction only)

Sterilizing
filter
Sterile
C
vent
filter
Sterile tank
Sterilizing filters

Filling
line

57

7) Double Redundant
Disadvantages
Separate formulation tank
Post-sterilization/pre-use
IT is even more complex

Sterilizing
filter
Sterile
C
vent
filter

Maintain sterility between filters


Additional valve, sterile drain
and air/vent filters required
Difficult to IT addl filters in situ
Single use system with side bag
also eliminates drain, easier to
use
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Sterile tank
Sterilizing filters

Filling
line

ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

Thank You
Questions?
Michael Moussourakis
Technical Manager
Pall Life Sciences
25 Harbor Park Drive
Port Washington NY 11050
(516) 801 9187
Michael_Moussourakis@pall.com

References
EMEA CPMP Note for Guidance on Manufacture of the Finished
Dosage Form (CPMP/QWP/486/95) (April, 1996)
http://www.emea.europa.eu/pdfs/human/qwp/048695en.pdf

EC Guide to GMP Revision to Annex I - Manufacture of Sterile


Medicinal Products (May, 2003)
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfs-en/revan1vol4_3.pdf

EC Guide to GMP Revision to Annex I - Manufacture of Sterile


Medicinal Products (Rev Feb, 2008, impl. Mar, 2009)
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfsen/2008 02 12 gmp annex1 pdf
en/2008_02_12_gmp_annex1.pdf

Twort, C. et al., GMP and sterile filtration: a review of some practical


and regulatory issues, Eur J Paren. & Pharm. Sciences 13(3): 65-69
(2008)

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ISPE Tampa Conference


22-23 February 2010
Tampa, Florida, USA

References
FDA Guidance for Industry: Sterile Drug Products Produced by
Aseptic Processing: Good Manufacturing Practice, FDA (2004)
htt //
http://www.fda.gov/cder/guidance/5882fnl.htm
fd
/ d / id
/5882f l ht

FDA Guidance for Industry: INDs Approaches to Complying with


CGMP During Phase 1 (2006)
http://www.fda.gov/cber/gdlns/indcgmp.htm

Sterilizing Filtration of Liquids Technical Report No. 26, PDA (2008,


in press)
https://store.pda.org/bookstore/ProductDetails.aspx?productabbreviation=01026

FDA Federal Register Notice: Amendment to the Current Good


Manufacturing Practice Regulations for Finished Pharmaceuticals;
Companion Document to the Direct Final Rule (12/4/2007)
http://www.fda.gov/OHRMS/DOCKETS/98fr/E7-23292.pdf

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