Current Topics in Sterilizing Filtration

ISPE Tampa Conference 22-23 February 2010Tampa, Florida, USA

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Current Topics in Sterilizing Filtration

ISPE Tampa ConferenceF b 22 23 2010February 22-23, 2010Michael Moussourakis

Technical ManagerPall Life Sciences

Current Topics in Sterilizing Filtration

• Pre-use Integrity Testingg y g• Single Use Filtration Systems• Serial / Double / Redundant Filtration

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Filter Integrity Testing

• Pre-use• Pre-sterilization• Post-sterilization

• Post-use

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Definition of Integrity

• Unimpaired, soundUnimpaired, sound• Complete, entire• Whole, undamaged

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Purpose of Integrity Tests

• Confirms integrity of filter assemblyCorrect grade membrane• 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’n guide)

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

Integrity Tests do not measure the pore size of high area filter cartridges

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

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• Confirms integrity after shipping, handling, and installation

• Post-sterilization• Confirms integrity after sterilization and

immediately prior to use


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FDA Guidance for Industry –Sterile Drug Products Produced bySterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, September, 2004

“Integrity testing of the filter(s) can be f d i t i d

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performed prior to processing, and should be routinely performed post-use.

EC Guide to GMP - Revision to Annex I - Manufacture of Sterile Medicinal ProductsRevised Feb, 2008

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Effective March, 2009


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Filtration Of Medicinal Products Which Cannot Be Sterilised In Their Final Container

113. The integrity of the sterilised filter should be113. 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

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or pressure hold test.

Rationale for Post-sterilization / Pre-use IT

• Confirms integrity after shipping, g y pp g,handling, installation and sterilization• Risk of loss / rework of product if post-

use failure • Recommended by filter

manufacturers

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manufacturers• Aids in failure analysis, root cause

determination and corrective and preventative action (CAPA)


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Rationale againstPost-sterilization / Pre-use IT

• Filter manufacturer’s release integrity test g yshowed no defects

• User’s installation test confirms absence of assembly leaks or damage

• Controlled sterilization conditions can be validated to not damage filters

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g• Post-use integrity failure is not a patient safety

risk• Product is rejected or reworked (per SOP)• Manufacturer’s economic risk only

Rationale againstPost-sterilization / Pre-use IT

• Integrity failure during steaming is typically g y g g yp ydetectable by destructive analysis• Directional over-pressurization at elevated

steaming temperature causes• Core collapse• Cage expansion• Other deformations

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Ot e de o at o s• Membrane rupture

• Failure to remove air can cause oxidative degradation of the membrane and supports


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“Pore Enlargement Hypothesis”

• Enlarged pore/defect appears during g p pp gsterilization• Potentially large enough for bacterial

penetration• Plugs with contaminant during filtration• Undetectable by post-use integrity test

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• “False pass” is a patient safety risk• Only a post-sterilization/pre-use integrity

test can detect “pore enlargement”

“Pore Enlargement Hypothesis” basis in EC

• EMEA Inspections - Good Manufacturing Practice - Questions & Answers

• "The filter sterilisation process, may…cause the filter to distort, potentially leading to fluid pathways that allow the passage of particles greater than 0.2µm in size…. For these reasons filters should be tested both, before use but after

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sterilisation, and again after use.”• Ref: http://www.ema.europa.eu/Inspections/gmp/q15.htm


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“Pore Enlargement Hypothesis” isContradicted by Data

• May occur with obsolete or prototype R&D y p ypmembranes, but

• Does not occur with validated commercial sterilizing grade filter membranes• Filter Validation Guide data• Product-specific validation data

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• Filter lot release QC test data• Bacterial challenge after autoclaving• Post multiple-autoclaving integrity tests

“Pore Enlargement Hypothesis” isContradicted by Data

• Filters that fail integrity tests after g ysterilization do not “self-repair”

• Non-integral filters cannot be masked by post-use plugging.• Even 0.45 µm filters show very high bacterial

retention efficiencies

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• 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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Single-use Filtration Systems

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FDA Guidance for Industry : INDs —Approaches to Complying with CGMPApproaches 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

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with CGMP and help streamline product development. Some examples include:


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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., product not exposed to the environment

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( p pduring processing), which can alleviate the need for stricter room classification for air quality

Single Use Filtration Systems

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Single Use Filtration Systems with Flush Bag for Post-sterilization / Pre-use Integrity Testing

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Flush Bag


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Integrated Disposable Systems (Manifolds)

Sterile liquid

Waste flush fluid

xSpare outlet

x

xx

Spare inlet

x x xx xx xx

x x

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flush fluid

Filter

xSample port

Containers to be filled

Sample port

xx x

Sterile storage

container


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Serial / Double / Redundant Filtration

A Short History of Sterilizing Filtration

• Pre-’60’s: Charged depth filters, asbestos filters, porous ceramic filters

• ‘60’s-‘70’s: 0.45 µm membrane filters, cartridges µ , gbubble point testing

• ‘80’s+: 0.2 µm membrane filter cartridges Forward flow (diffusion) testing - 1987 FDA Aseptic Processing Guidelines

• ’90’s+: 0.1 µm membrane filters (enhanced ster’n)Product specific validation

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Product-specific validation - 1998 PDA Technical Report 26

• ’00’s+: Serial / double / redundant filtration - 2003 EC GMP Annex 1 - 2004 FDA Aseptic Processing Guidance


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

What does the dictionary say?

27Ref.s: www.dictionary.com, American Heritage Dictionary


• What do the regulatory agenciesWhat do the regulatory agencies say?

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EMEA Committee for Proprietary p yMedicinal Products (CPMP)Note for Guidance on Manufacture of the Finished Dosage Form (CPMP/QWP/486/95)

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(CPMP/QWP/486/95)

April, 1996

7. Special Items (1/4)

For sterilisation by filtration the maximum yacceptable bioburden prior to the filtration must be stated in the application.

In most situations NMT 10 CFU’s / 100 ml will be acceptable, depending on the volume to be filtered in relation to the diameter* of the

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filter. *sic, filter area


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

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The type of bacteria-retentive filter and ypits pore size should also be described in the application*. Pore sizes (ratings) of 0.22 µm or less are acceptable without further justification, in accordance with

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the Ph. Eur.

* Suggests both bioburden filter and sterilizing filter


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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 pore rated bioburden filter may require

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g p y qadditional bacterial retention validation in addition to validation of the sterilizing filter

EC Guide to GMP - Revision to Annex I - Manufacture of Sterile Medicinal ProductsRevised Feb, 2008

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Effective March, 2009


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Filtration of medicinal products which cannot be sterilised in their final container

110. If the product cannot be sterilised in the110. 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 micro-

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) qorganism retaining properties, into a previously sterilised container.

Filtration of medicinal products which cannot be sterilised in their final container

111. Due to the potential additional risks of pthe filtration method as compared with other sterilisation processes, a second filtration via a further sterilised micro-organism retaining filter, immediately

i t filli b d i bl Th

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prior to filling, may be advisable. The final sterile filtration should be carried out as close as possible to the filling point.


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FDA Guidance for Industry –Sterile Drug Products Produced bySterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, September, 2004

“Use of redundant sterilizing filters

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should be considered in many cases.”

Redundant FiltrationWhat 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*

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* PDA Technical Report 26, Sterilizing Filtration of Liquids (2008 Revision, in press), Glossary


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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

f

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pass integrity testing after use


• It may be difficult to conduct pre-use y pintegrity tests of both filters in a series after sterilization • Sterility downstream of the first filter may

be compromised in testing the second filter

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filter• Contact filter manufacturers for

recommendations


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• 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

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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


• 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

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• Precautions can include add’l 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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• To test the second filterUse valve between the first and 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)

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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

Filtration Configurations

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

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1) Single Filter Upstream of Tank & Filler

• AdvantagesSterilizing

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

T t f t id

Sterile vent filter

Sterile tank

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• Test from upstream side• Reprocess buk if filter fails IT

• If pre-qualified, per SOP Filling line

1) Single Filter Upstream of Tank & Filler

• DisadvantagesSterilizing

filterg• Less secure in long term

filling• Time and distance to filling

line considered sterility risk factors

• Filter integrity failure results in

Sterile vent filter

Sterile tank

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• Filter integrity failure results in loss or reprocessing of batch

• Integrity of vent filter must be confirmed

Filling line


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2) Single Filter Downstream of Tank• Advantages

St ili ti d IT f t filtVent filter

• Sterilization and IT of vent filter may not be required

• Filling can start before tank is full

• Filter sterilizable in situ (SIP) or

Sterilizing filter

Low bioburden

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• Pre-sterilize filter and aseptic or sterile connect

Filling line

• DisadvantagesBioburden may grow in tank

Vent filter

2) Single Filter Downstream of Tank

• Bioburden may grow in tank over long filling times

• Filter should be pre-flushed prior to container filling to reduce leachables and particulates

• or initial filled containers

Sterilizing filter

Low bioburden

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• or initial filled containers may be discarded

• Filter integrity failure results in loss of filled container batch

Filling line


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Bioburden Filter Upstream Single Filter Downstream

• AdvantagesBi b d i t k t ll d V t

Bioburden filter

• Bioburden in tank controlled during long filling times

• Bioburden filter may not need to be sterilized, flushed or integrity tested

Sterilizing filter

Vent filter

Controlledbioburden

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• Bioburden filter can be 0.2 µm or 0.45 µm rated

Filling line

Bioburden Filter Upstream Single Filter Downstream

V t

Bioburden filter

• Disadvantages• Final filter should be pre-flushed

• Or initially filled containers may be discarded

Sterilizing filter

Vent filter

Controlledbioburden

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• Final filter integrity failure results in loss of filled container batch

Filling line


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4) Double Filters Downstream of Tank• Advantages

• Product can be formulationVent filter• Product can be formulation

in tank• Filter B controls bioburden

upstream of sterilizing filter A• Same filter can be used

• Pre use sterility between

AB Sterilizing filter

High bioburden

Bioburden filter

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• Pre-use sterility between double filters not required

• Vent and bioburden filters may not need to be integrity tested

Filling line

• Disadvantages• High bioburden may

Vent filter

4) Double Filters Downstream of Tank

• High bioburden may limit filling time

• Filters should be pre-flushed• or initially filled containers

may be discarded• Both filters may still need to be

AB Sterilizing filter

High bioburden

Bioburden filter

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• Both filters may still need to be integrity tested

• Filter A integrity failure results in loss of filled container batch

Filling line


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5) Redundant Filters Downstream of Tank

• AdvantagesP d t f l t d i t k

Vent filter

• Product formulated in tank• Vent filter testing optional• Post-use integrity failure of

one filter may be allowable • If final filter (A) passes post-

AB

Sterilizing filters

Low bioburden

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use IT, testing of the second filter (B) is not required

• Filled containers can be released

Filling line

• DisadvantagesP t t ili ti / IT

Vent filter

5) Redundant Filters Downstream of Tank

• Post-sterilization/pre-use IT of both filters is complex• Maintain sterility between filters• Additional valve, sterile drain

and air/vent filters required• Difficult to IT add’l filters in situ

AB

Sterilizing filters

Low bioburden

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• Difficult to IT add l filters in situ• Single use system with side bag also

eliminates drain, easier to use Filling line


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• AdvantagesSterile

Sterilizing filter

6) Redundant Filters Upstream/Downstream

• Same filter can be used• High assurance of sterilization

• Entire system can be SIP’d• Suitable for long term• Filter A integrity failure may

Sterilizing filter

Sterile vent filter

Sterile tank

B

A

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g y yallow batch release if Filter B passes integrity

Filling line

• DisadvantagesSterile

Sterilizing filter

6) Redundant Filters Upstream/Downstream

• Separate formulation tank• Sterility of entire system must

be validated• Post-sterilization/pre-use IT

of filter A is complex• Maintain sterility between filters

Sterilizing filter

Sterile vent filter

B

A

Sterile tank

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• Maintain sterility between filters• Additional valve, sterile drain

and air/vent filters required• Difficult to IT add’l filters in situ

Filling line


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7) Double Redundant • Advantages

Fi l filt d d

Sterilizing filter

C Sterile • Final filter redundancy close to filling line

• Meets critical regulatory interpretations

• Suitable for long term use AB

Sterilizing filters

C vent filter

Sterile tank

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• Filter C and vent may not need to be sterilizing or integrity tested (bioburden reduction only) Filling

line

• DisadvantagesSeparate formulation tank

7) Double Redundant Sterilizing

filterC Sterile • Separate formulation tank

• Post-sterilization/pre-use IT is even more complex• Maintain sterility between filters• Additional valve, sterile drain

and air/vent filters requiredAB

Sterilizing filters

C vent filter

Sterile tank

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and air/vent filters required• Difficult to IT add’l filters in situ• Single use system with side bag

also eliminates drain, easier to use

Filling line


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Michael MoussourakisTechnical Manager

Thank YouQuestions?

Technical ManagerPall Life Sciences

25 Harbor Park DrivePort Washington NY 11050

(516) 801 [email protected]

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/pdfs-en/2008 02 12 gmp annex1 pdf

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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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References

• FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing: Good Manufacturing Practice, FDA (2004)

htt // fd / d / id /5882f l hthttp://www.fda.gov/cder/guidance/5882fnl.htm• 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;

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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

Documents

Current Topics in Sterilizing Filtration