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Validation Services

Seminar
Morven McAlister & Vanessa
Merefield

SLS Life Sciences Training


May 12, 2006
Presentation Outline
 Overview of validation tests
 Parametric Approach
 Selection of worst case test
parameters
 Product bracketing
 Additional Validation tests
 Trends / Issues

© Pall Corporation 2006


Pall Validation Sites

Validation Laboratory
© Pall Corporation 2006
Validation Definition

“…establishing documented evidence


which provides a high degree of
assurance that a specific process will
consistently produce a product
meeting its predetermined
specifications and quality attributes.”

FDA Guideline on General Principles of Process Validation, 1987

© Pall Corporation 2006


Need for Validation (1)

“ Filtration is a common method of sterilizing


drug product solutions.”
FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing
– Current Good Manufacturing Practice (2004)
Chapter IX – Validation of Aseptic Processing and Sterilization
“ For sterile products, the validation of
sterilising processes should be of the same
standard as for products authorised for
marketing”
European Guide to Good Manufacturing Practices (1998)
Annex 13 - Manufacture of investigational medicinal products

© Pall Corporation 2006


Need for Validation (2)


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© Pall Corporation 2006


Global Consequences
 Growth through mergers and consolidation:
Can larger companies react swiftly enough
to changes?
 Higher complexity and costs of clinical
trials: Delay in bringing new compounds to
market
“…in the last four years (2000-2003) the US FDA on
average has approved 22 new molecular entities (NME)
per year compared to an average annual approval rate of
39 NMEs in the four prior years”
Leslie Platt, Ernst & Young
© Pall Corporation 2006
Need for Validation (3)
“It is particularly critical to validate the
efficacy of the (sterilizing) filtration process.
“…ensure that worst-case formulation and
processing parameters are adequately
studied, evaluated and documented.”
“This data should be available during current
drug pre-approval inspections and for already
marketed products produced by sterile
filtration.”
FDA Human Drug CGMP Notes (1995)
© Pall Corporation 2006
Filter Validation Testing - Overview

 Bacterial Viability
 Establishes bactericidal properties
 Determines suitable flush protocols
 Bacterial Retention
 Confirms sterilizing capability of process
membrane under worst case conditions
 Compatibility
 Confirms maintenance of filter integrity after
exposure to worst case fluid and process

© Pall Corporation 2006


Filter Validation Testing - Overview

 Extractables
 Provides quantitative and qualitative analyses of
filter extractables in model solvent
 Product-specific integrity test values (ITV)
 Establishes filter integrity test values for process
filtration assembly wet with process fluid
 Adsorption Testing
 Determines extent of adsorption of product
components following filtration of product

© Pall Corporation 2006


Product Information Sheet (PINS) /
Process and Product Questionnaire
(PPQ)

© Pall Corporation 2006


PINS / PPQ
 Overview of customer’s fluid & process parameters
 Used to establish fluid / process-specific test
protocols representing worst case test conditions
 All information needed to complete full validation
package
 Requires exact concentration (%) of each
component and carrier solvent in fluid
 Used in determining model solvent for extractables
test
 Allows determination of potential testing issues,
e.g.
– Bactericidal properties, Compatibility issues
© Pall Corporation 2006
Execution of Validation Package (US)
Customer completes Product Information Sheet

Pall writes protocols and sends to customer for approval

Customer contacts Pall project managers directly with any


questions

Customer sends following items to Pall:

-Signed/approved protocols
-Sample product / MSDS / PO

Testing commences at Pall

6-8 weeks
Pall project manager write reports

Reports reviewed and issued to customer


© Pall Corporation 2006
Product Grouping / Selection of Worst
Case Conditions

© Pall Corporation 2006


Selection of Worst-Case Conditions
for Validation Testing
“A set of conditions encompassing upper and
lower processing limits and circumstances,
including those within standard operating
procedures, which pose the greatest chance of
process or product failure when compared to
ideal conditions”
FDA Guideline on Sterile Drug Products Produced by Aseptic Processing, 1987

“Filter validation should be conducted using the


worst-case conditions, such as maximum filter
use time and pressure”
FDA Guidance for Industry - Sterile Drug Products Produced by Aseptic
Processing – Current Good Manufacturing Practice, 2004
© Pall Corporation 2006
Parametric Validation - Aim

 Determine any effect of the fluid on the filter


and on B. diminuta or suspect bioburden
isolate
 Bacterial viability and retention testing
 Compatibility testing

 Determine any effect of the filter on the


product formulation
 Extractables testing
 Adsorption testing
© Pall Corporation 2006
Parametric Validation - Strategy

 Product attributes
 Process parameters
 Scientific rationale
 Worst-case conditions
 Use of actual products wherever
possible

© Pall Corporation 2006


Selection of Worst Case Conditions for
Validation Testing – Product Grouping
 As per 1987 Aseptic Processing Guideline,
product “families” can be grouped
 “Worst case” models must be justified by scientific
rationale

 Typically, highest concentration of active


under highest operating parameters (maximum
process flow rate, differential pressure,
temperature) represents “worst-case” model

© Pall Corporation 2006


Selection of Worst Case Conditions for
Validation Testing – Product Grouping
 Considerations for product grouping
 Product components
 Test fluid should represent maximum no. components
present, including active

 Concentrations of components
 Highest concentration of components typically tested
 Consider active and other constituents

© Pall Corporation 2006


Selection of Worst Case Conditions for
Validation Testing – Product Grouping
 Ionic Strength
 Affects surface charge of membrane and test
organism and potential adsorptive interactions
 Osmolarity
 High osmolarity may cause shrinking of
microorganisms
 pH
 Affects surface charge of membrane and test
organism and potential adsorptive interactions
 Affects viability of test organism
 Test extremes of pH

© Pall Corporation 2006


Selection of Worst Case Conditions for
Validation Testing – Product Grouping
 Viscosity
 High viscosity fluids usually require higher pressure
and/or elevated temperature processing
 Typically also longer filtration duration
 Surface Tension (incl. surfactants)
 Presence of surfactants (> 0.5%) can reduce
adsorptive capture
 Nutrients
 Low nutrient (oligotrophic) environments may reduce
bacterial cell size / change cell surface characteristics
 Temperature
 Extremes of temperature range typically tested
© Pall Corporation 2006
Bracketing of Products
Process Parameter

Active Volume Time Flow rate Pressure Temperature


concentration
0.25 mg/mL 50 L 45 mins 1.11 L/min 0.8 bar 20ºC

0.5 mg/mL 50 L 45 mins 1.11 L/min 0.8 bar 20ºC

1.0 mg/mL 100 L 60 mins 1.67 L/min 1.2 bar 20ºC

5.0 mg/mL 500 L 420 mins 1.19 L/min 0.5 bar 20ºC

10mg/mL 200 L 90 mins 2.22 L/min 0.7 bar 20ºC

20mg/mL 100 L 60 mins 1.67 L/min 1.2 bar 20ºC

© Pall Corporation 2006


Grouping of Products
Parameter

Product pH Surface Viscosity Osmolarity Ionic


Tension Strength

A 5.83 73.4 1.2 277 0.153

B 6.63 72.4 1.3 233 0.164

C 5.13 71.14 8.4 150 0.083

D 6.47 71.9 1.2 249 0.171

E 5.51 72.6 8.9 138 0.080

F 5.94 71.7 9.6 281 0.177

© Pall Corporation 2006


Bacterial Viability / Flush Testing (1)

 Test bacteria (~106 CFU/mL) inoculated into


customer fluid and control fluid (sterile
deionized (DI) water)

 Bacterial concentration monitored in fluid and


control over process time

 Fluid & process established as bactericidal,


moderately bactericidal or non-bactericidal

© Pall Corporation 2006


Test Methodology

© Pall Corporation 2006


Selection of Worst Case Conditions
for Bacterial Viability Testing
 Actual product used
 Viability determined over total contact time of
product with filter
 Maximum process temperature (≤ ≤ 37oC)
 If process temperature >37oC, approach for
moderately bactericidal products may be
required
 Recirculate product at process temperature for
maximum contact time, followed by bacterial
challenge in product at ≤ 37oC

© Pall Corporation 2006


Definition of Bactericidal
 Non-bactericidal
 A decline in viability of less than one log (<90%)
in product over the process time
 Bactericidal
 A decline in viability of greater than 1 log (>90%)
within 60 minutes of exposure in product
 Moderately Bactericidal
 A decline in viability of less than 1 log over 60 minutes,
in conjunction with a decline in viability of 1 log or
more over the process time
 May allow for an in-product challenge after product
recirculation
© Pall Corporation 2006
Bacterial Viability / Flush Testing (2)
 Residual Effects (bactericidal fluid only)
 Removal of bactericidal fluid from test filter
 Fluid passed through test filter then rinsed with
flush fluid (typically DI water)
 Additional volume of DI water passed through
test filter disc, collected and inoculated with low
concentration of test organism
 No. bacteria recovered from fluid must be within
30% of bacterial count recovered from control

© Pall Corporation 2006


Bacterial Viability / Flush Testing (3)
 Recovery Flush (non-bactericidal fluids only)
 Removal of test fluid from recovery (“analysis”)
filters
 Test fluid or control inoculated with a low
concentration of test bacteria
 Vacuum filtered through recovery filter and flush
scheme (typically DI water) applied
 No. bacteria recovered from test fluid must be
within 30% of bacterial count recovered from
control
© Pall Corporation 2006
Options for Bacterial Retention Test
Fluid Type

Non-Bactericidal Moderately Bactericidal


Bactericidal

Challenge Fluid Fluid


performed recirculated recirculated
by inoculating for process for process time
bacteria time followed followed by flush
in fluid by challenge and challenge using
directly (seeded using fluid surrogate solution
challenge) inoculated with inoculated with
test bacteria test bacteria

© Pall Corporation 2006


Microbial Challenge –
Bactericidal Fluids

“In such cases, the fluid should simulate the


product as closely as practical in terms of
viscosity and other physical characteristics
that are not antagonistic towards the
microbial challenge”

FDA Guideline on Sterile Drug Products Produced by Aseptic Processing, 1987

© Pall Corporation 2006


Challenge Fluid Selection for
Bactericidal Products
 Product (short term) with flush
 Modified product (no preservative)
 Modified product (reduced or no active)
 Placebo (where appropriate)
 Surrogate fluid (e.g. saline lactose broth)
 Similar chemical properties

© Pall Corporation 2006


Microbial Challenge
“The (challenge) microorganisms should be small
enough to both challenge the filter's nominal porosity
and simulate the smallest microorganism that may
occur in production.”
FDA Guideline on Sterile Drug Products Produced by Aseptic Processing, 1987

“The microorganism Brevundimonas diminuta (ATCC


19146) when properly grown, harvested and used, is a
common challenge microorganism for 0.2 µm rated
filters because of its small size (0.3 µm mean diameter)”
FDA Guidance for Industry - Sterile Drug Products Produced by Aseptic
Processing – Current Good Manufacturing Practice, 2004

© Pall Corporation 2006


SEM of 0.2 µm Membrane *
Section View
Challenged with 5 x 108
B. diminuta cells per cm2

Osumi et al., PDA J. Pharma. Sci. &


Technol., v. 50: pp. 30-34, (1996)

20 µm

Typical membrane
thickness ~160 µm

* Pall Ultipor® Nylon 6,6 NR Grade


© Pall Corporation 2006
Criteria for Bacterial Retention Testing
of Sterilizing Grade Filters
 Brevundimonas diminuta (ATCC 19146) or other
“worst-case” bioburden isolate
 Controlled culture conditions (ASTM F838-05)
 Minimal size (B. diminuta 0.3 x 0.8 µm)
 Monodispersed
 Demonstrate penetration of 0.45 µm rated
control filter
 Simulate “worst-case" process conditions
 Total challenge ≥ 1 x 107 CFU/cm2
 Analyze total effluent for sterility

© Pall Corporation 2006 (Ref: ASTM-F838, PDA TR26)


Selection of Worst Case Conditions
for Bacterial Challenge Testing (1)
 Operating parameters
 Flow rate
 Differential pressure
 Filter throughput per cm2
Typically, maximum
 Total challenge duration
values for each
 Temperature
 No. batches processed per
test parameter
filter assembly
 Filter sterilization conditions

© Pall Corporation 2006


Selection of Worst Case Conditions
for Bacterial Challenge Testing (2)
 Flow rate and pressure are interdependent
 Validate highest flow and highest pressure to
meet or exceed both process parameters
 Hydraulic shock – pulsing can be used
 B.diminuta inoculated into product wherever
possible

© Pall Corporation 2006


Selection of Worst Case Conditions
for Bacterial Challenge Testing (3)
Test Filter
 Same membrane family and pore size rating
 47-mm membrane discs typically used from
standard production
 Minimum production physical QC test limit
 “Low KL” discs
 Pall QBP (quantitative bubble point)

© Pall Corporation 2006


Bacterial Challenge

 Challenge method dependent on fluid properties


 Bactericidal vs. Non-Bactericidal

 Bacterial retention is confirmed if no penetration


of test membrane filter occurs under test
conditions that mimic the full-scale process
conditions

© Pall Corporation 2006


Bacterial Challenge (Non-Bactericidal Fluid)

Recirculation with Seeded Challenge Solution


© Pall Corporation 2006
Product Recirculation (Bactericidal Fluid)

© Pall Corporation 2006


Bacterial Challenge (Bactericidal Fluid)

Seeded Challenge Solution


© Pall Corporation 2006
Adsorption Testing
 To quantify the amount of components adsorbed
from the product onto the filter after passing
through test filters

 Enables calculation of volume of product which


should be flushed through process filter to ensure
saturation of the filter

 Pall collects filtrates and customer performs


analysis

© Pall Corporation 2006


Adsorption Testing
Peristaltic pump

Tubing
Test filter
disc in
housing

Filtrate sample
Product collection vials
Reservoir
© Pall Corporation 2006
Selection of Worst Case Conditions
for Adsorption Testing
 Maximum temperature
 Maximum flow rate

 Small batch size


 Maximum filter throughput
 Maximum contact time

© Pall Corporation 2006


Compatibility Testing
 Demonstrates compatibility of specific
filter with customer process fluid

 Filter exposed to process fluid for


specified period under pre-determined
conditions

 Compatibility determined by performing


integrity tests on filter pre- and post-fluid
exposure and visual examination of filter

© Pall Corporation 2006


Selection of Worst Case Conditions
for Compatibility Testing
 Testing uses actual customer fluid
 Filters sterilized under maximum
conditions (time/temperature) prior to
product exposure
 Testing conducted at maximum
process temperature
 Exposure time must be equal to
process time minimally

© Pall Corporation 2006


Extractables Testing
 Potential sources:
 Hardware, support layers, membranes,
wetting agents, casting additives, etc.

Solvent Additives Oligomer

Polymer
Polymer
Chain
Surface
SURFACE INTERFACE

© Pall Corporation 2006


Extractables Testing

© Pall Corporation 2006


Extractables Assessment

Filter reciprocated in Solvent transferred to


extracting solvent Rotary Evaporator

Pre-weighed
© Pall Corporation 2006
Crucible
Extractables Assessment

Non-Volatile Residue Fourier Transform Infra-red


(NVR) Spectroscopy (FTIR)

Quantity Identity

© Pall Corporation 2006


Extractables Testing
 Qualitative and quantitative analyses of
extractables from process filter
 Non-volatile residue (NVR)
 UV-Vis, FTIR
 Model solvent used based on process
fluid characteristics
 Test conditions reflect process
temperature and time

© Pall Corporation 2006


Advantages of NVR/IR Model System

 Wide range of models available


 NVR detects all nonvolatile material
 Flexible, widely applicable IR
characterization; good for unknown
identification/investigation
 Self-Validating; negative and positive
controls minimize “method validation
blues”

© Pall Corporation 2006


Additional Analytical Methods

 UV-Visible spectroscopy for transparent


solvents
 TOC for aqueous solutions
 GC-MS for volatiles/semi-volatiles
 LC or LC/MS for nonvolatiles or heat-
sensitive compounds
 ICP/MS (Inductively Coupled Plasma/Mass
Spectrometry) analysis for metallic
extractables, if necessary.
© Pall Corporation 2006
Selection of Worst Case Conditions
for Extractables Testing (1)
 Model Solvent Approach
 Determines contribution of filter components to fluid
effluent
 Customer fluid - type and concentration of
components
 Increase solubility & concentration of low MW
weight substances in fluid due to chemical attack?
 Typically, components <10% volume do not exert
significant solubility/compatibility effects
 Fluid pH considered independently

© Pall Corporation 2006


(Ref: Weissman)
Selection of Worst Case Conditions
for Extractables Testing (2)
 Process Parameters
 Temperature
 Testing conducted at temperature equal to or
greater than process temperature
 Filter duration (total contact time)
 Minimum of two extraction cycles
(24 hours per cycle)
 No. extractions completed is equal to or greater
than total contact time of filter with product

© Pall Corporation 2006


Product-wet Integrity Test Values
All three test are
based on the same
physics, the flow of
Gas Source
gas through a
Air, N2 Gauge liquid-wetted
Pressure membrane
Bubbles under
Regulator
Test Filter
applied pressure

 Bubble Point
 Forward Flow
 Pressure Hold
© Pall Corporation 2006
Product-wet Integrity Test Values

 Determine test parameters appropriate for


establishing integrity of a filter when wet with
customer fluid
 Values determined for filter wet with customer
fluid and correlated to reference fluid-wet value
 Reference fluid-wet values correlated to
bacterial retention (published in Filter
Validation Guide).

© Pall Corporation 2006


Membrane Filter Integrity Testing
 Membrane filter wetted with water or product
 Pressurized with air or N2 at validated pressure
 Flow of air through wetted membrane measured
Atmospheric pressure
Low diffusive gas flow
through small wetted
Test Gas pores (integral membrane)
Pressure High convective gas flow
through large pores, e.g.
defective membrane areas

© Pall Corporation 2006 Liquid-wetted Membrane


Multi-point Forward Flow Curve
Flow (ml/min)
25

20

15 •
• “Bubble
Point”
10
• • Transition
5
• • • Region
• •
1 2 3 4
Pressure (bar)

© Pall Corporation 2006


KL Value Determination
Transition from diffusive flow
to open pore flow
Bulk gas
Gas Flow flow
through
Pressure open pores
Diffusive flow
(Q/P)

Pressure KL
KL is the pressure at which the two dotted lines cross
© Pall Corporation 2006
Diffusive Flow Spectrum

Flow Product wet Water wet

1 KL(P) 2 KL(W) 3
© Pall Corporation 2006 Pressure
Product Wetted Integrity Pressure
Determination of test pressure
KL in product KL in water
Product KL Curve

Gas Flow
Pressure
x
(Q/P)
Calculated Water KL Curve
Test Pressure

x
FF test pressure in water

© Pall Corporation 2006 P (mbar)


Selection of Worst Case Conditions
for Product-Wet Integrity Testing
 Product
 Surface Tension
 If surface active agents present in product,
surface-tension derived test pressure used
 Viscosity
 Viscous products may require extended
equilibration or test dwell times
 Process Parameters
 Temperature

© Pall Corporation 2006


Effect of Area on “Bubble Point”
Flow (ml/min)
250

200

150
High area cartridge Low area disc
100

50

0
Pressure (psi) 40 “BP” 50 “BP” 60
Cartridge “bubble points” are typically lower than
disc
© Pall Corporation 2006 “bubble points” using the same membrane
Critical Testing Parameters

Composition

Sterilization
Throughput

Conditions
Osmolarity

Flow Rate
Viscosity
Strength

Tension
Surface

Temp
Filter
Ionic

Time
pH

∆P
Test Type

Viability

Bacterial
Challenge

Extractables

Compatibility

ITV

Adsorption

© Pall Corporation 2006 Considered for Evaluated for


“worst-case” information only
Additional Validation Testing

© Pall Corporation 2006


Kleenpak Connectors
Soiling Test
 Ability of KPC to produce
sterile connection after
intentional contamination
with bacterial spores
 Male & female connector
soiled with Geobacillus
stearothermophilus
 Challenge level > 105 CFU
per device

© Pall Corporation 2006


Kleenpak Connectors

 Extractables Testing
 Model Solvent Approach

 Compatibility
 Tensile Strength

© Pall Corporation 2006


Disposable Systems
Tubing, bags etc
 Extractables
 FTIR, GCMS, UV
 Bioburden
 14 day incubation period
 2 growth media
 Endotoxin
 If product shelf-life study, qualification of assay
with product required
 Sensitivity 0.005 EU/mL
© Pall Corporation 2006
Pallchek
 Extensive validation required
 Protocols currently under developments
 Various test fluids (water, buffers, media etc)
 Various ATCC bacterial strains
 Potential for product-specific validation
as part of Validation services

© Pall Corporation 2006


Preparation for an audit

© Pall Corporation 2006


Preparation for an Audit (1)
 SLS Labs are not working to GMP
 Audit Hosts
 QA & SLS Lab and project managers present
 SLS procedures must be available and
show documented evidence that they are
followed
 Training Records
 Must be updated with current SOP revisions
 Evidence of competency

© Pall Corporation 2006


Validation Services – Goals / Issues

© Pall Corporation 2006


Trends in Validation Services (US)

 Increase in projects from biotechnology


companies and universities
 Increase in generic drugs
 Increase in projects from S.America
 Increase in extractables projects for pre-filters
 Decrease in project turnaround times

© Pall Corporation 2006


Trends in Validation Services -EU

 Customers requesting PWIT testing performed in


triplicate
Contract manufacturers requesting product
groupings
10-15% increase in filter validations / year
 More interaction with filter manufacturer and
customer
Increased interest in extractables

© Pall Corporation 2006


Goals - Validation Services
PINS/PPQ
 Incomplete PIN sheets frequently submitted
 Customers often lack understanding of process
 PM calls / visits customer to obtain full details
 Illegible handwriting on PIN/PPQ
 Currently PM calls for clarification

 “Typeable” PINS now complete


 PINS/PPQ to be submitted via Pall web site
 Target Date – August 2006

© Pall Corporation 2006


Goals - Validation Services
 During customer routine QC Product Analysis
unidentified peaks reported
 Traced to Pall filter cartridges
 3 recent occurrences
 FDA/PDA recommend all extractables are identified
More detailed analysis required
GCMS installed in PW on May 02, 2006
IQ/OQ currently being performed by manufacturer
Training scheduled immediately after IQ/OQ

Estimated target date for use in customer work – mid


June 2006
Global team needs formed to prioritize testing needs
© Pall Corporation 2006
Goals - Validation Services
Globalization
 Need to standardize test SOPs based on best practise
globally
 Ensure data interpretation same globally
 Review validation testing prices globally
 Ability to easily communicate with global team
 Shared resources (e.g. extractables reports)
 Validation Team Room
 Shared global objectives
 V.Merefield (Europe), M.McAlister (W.Hemisphere),
H. Nomura (Asia)
 First meeting held Jan 2006. Each group working on
action items
© Pall Corporation 2006
Shared Issues - Validation Services

Customers requesting data to support pre-filters


(API)
Compatibility & Extractables Data
SLS UK and US have performed extractables
studies for a range of pre-filters & solvents
How do we confirm compatibility?

© Pall Corporation 2006


Shared Issues - Validation Services
Test Discs
Urgent considerations:
Global sourcing of 47-mm discs
Low spec media – both layers?
Certification of 47-mm discs
 Considered a priority by global validation team
 SOP written by Chris Lewis….under review
List of manufacturing sources for discs underway

© Pall Corporation 2006


Additional Questions?

© Pall Corporation 2006


Reference Documents (1)
1. Bowman, F., M.P. Calhoun and M. White, “Microbiological methods for quality control of
membrane filters”, J. Pharm. Sci., v. 55; p. 818 (1967)
2. Pall, D.B., “Quality Control of Absolute Bacteria Removal Filters,” Bull. Parenteral Drug
Assoc., 29, 392-204 (1975).
3. Howard, G. and R. Duberstein. “A case of penetration of 0.2 µm rated membrane filters by
bacteria.” Journal of the Parenteral Drug Association., v. 34; p. 95 (1980)
4. HIMA (now AdvaMed), “Microbiological Evaluation of Filters for Sterilizing Liquids,” draft
doc. No.3 Vol. 4, April, 1982 (obsolete)
5. ASTM, “Standard Test Method for Determining Bacterial Retention of Membrane Filters
Utilized for Liquid Filtration,” Standard No. F838-83 (1983, No. F838-05, rev. 2005)
6. FDA Guideline on Sterile Drug Products Produced by Aseptic Processing, 1987
7. FDA CDER Perspective on Isolator Technology, ISPE Barrier Technology Conference,
Dec. 1995
8. FDA Guidance for Industry for the Submission Documentation for Sterilization Process
Validation in Applications for Human and Veterinary Drug Products, 1994
9. FDA Human Drug CGMP Notes, Dec. 1995
10. PDA Technical Report No. 26, “Sterilizing Filtration of Liquids,” PDA J. Pharmaceutical
Science and Technology, 52 (3) Supplement, 1-31, 1998

© Pall Corporation 2006


Reference Documents (2)
11. FDA Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing –
current Good Manufacturing Practice, 2004
12. Weitzmann, C. The use of model solvents for evaluating extractables from filters used to
process pharmaceutical products, Pharmaceutical Technology, 21 (#4), 72-99 (1997)
13. Pall Corp., “Determination of product wet integrity test values for Pall filter cartridge,” Publ.
No. USTR 1471(1)
14. Sundaram, S. et al., Considerations in Using "Bubble Point" Type Tests as Filter Integrity
Tests, Part I: Effect of Test Methodology on Filter Cartridge “Bubble Point” Measurements
and Implications for the Use of “Bubble Point” Type Tests as Correlated Tests,
Pharmaceutical Technology, Sept., 2000
15. Sundaram, S. et al., “Considerations in Using "Bubble Point" Type Tests as Filter Integrity
Tests, Part II: Effect of Filter Area on “Bubble Point” Measurements and Implications for the
Use of “Bubble Point” Type Tests as Correlated Tests,” Pharmaceutical Technology, Oct.,
2000
16. Pall Corp., “Validation Guide for Pall 0.2 micron Ultipor N66 and N66 Posidyne Membrane
Cartridges,” (1980)
17. USP General Information Chapter <1227>, Validation of Microbial Recovery from
Pharmacopeial Articles, USP 27, USPC, Inc., Rockville, MD, 2004, p. 2625
18. Osumi, M., N. Yamada and M. Toya, “Bacterial retention mechanisms of membrane filters,”
PDA Journal of Pharmaceutical Science and Technology, v. 50; pp. 30-34, (1996)
© Pall Corporation 2006
Thank you for your
attention!