Filter Validation Training-By PALL

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


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


Need for Validation (2) … …regulations regulationsare are changing changingwhich which result resultin inmore more intensive intensivevalidation validation and andincreased increased clinical clinicalresearch research


… … have haveto to optimize optimizeour our processes processesdue dueto to cost costpressure pressure and andcompetition competition in ingeneric genericmarket market

… … may maynot notoften often have haveresources resources and andexpertise expertise which whichcreates creates bottlenecks bottlenecksin in pipeline pipelinefor forR&D R&D products products

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)


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


Product Grouping / Selection of Worst Case Conditions


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


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


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


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 Volume

Time

Flow rate

Pressure

Temperature

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

Active concentration


Grouping of Products Parameter

Product

pH

Surface Tension

Viscosity

Osmolarity

Ionic 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


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


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


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

Challenge performed by inoculating bacteria in fluid directly (seeded challenge)

Fluid recirculated for process time followed by challenge using fluid inoculated with test bacteria


Bactericidal Fluid recirculated for process time followed by flush and challenge using surrogate solution inoculated with test bacteria

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


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 Total challenge duration Temperature No. batches processed per filter assembly Filter sterilization conditions


Typically, maximum values for each test parameter

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


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)


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


Bacterial Challenge (Non-Bactericidal Fluid)

Recirculation with Seeded Challenge Solution © Pall Corporation 2006

Product Recirculation (Bactericidal Fluid)


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


Adsorption Testing Peristaltic pump

Tubing Test filter disc in housing

Product Reservoir © Pall Corporation 2006

Filtrate sample collection vials

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

Polymer Chain

Polymer Surface SURFACE INTERFACE


Oligomer

Extractables Testing


Extractables Assessment

Filter reciprocated in extracting solvent


Pre-weighed Crucible

Solvent transferred to Rotary Evaporator

Extractables Assessment

Non-Volatile Residue (NVR)

Quantity © Pall Corporation 2006

Fourier Transform Infra-red Spectroscopy (FTIR)

Identity

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”


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 heatsensitive compounds ICP/MS (Inductively Coupled Plasma/Mass Spectrometry) analysis for metallic extractables, if necessary.


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


Product-wet Integrity Test Values

Gas Source Air, N2

Gauge Pressure Regulator Test Filter

Bubble Point Forward Flow Pressure Hold © Pall Corporation 2006

All three test are based on the same physics, the flow of gas through a liquid-wetted Bubbles membrane under applied pressure

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).


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

Test Gas Pressure


Low diffusive gas flow through small wetted pores (integral membrane) High convective gas flow through large pores, e.g. defective membrane areas

Liquid-wetted Membrane

Multi-point Forward Flow Curve Flow (ml/min) 25 20 15 10 5

• • • • • • • 1


2 Pressure (bar)

3

• • • •

“Bubble Point” Transition Region 4

KL Value Determination Transition from diffusive flow to open pore flow

Bulk gas flow through open pores

Gas Flow Pressure

Diffusive flow

(Q/P)

Pressure

KL

KL is the pressure at which the two dotted lines cross © Pall Corporation 2006

Diffusive Flow Spectrum Product wet Water wet

Flow 2

1

1 © Pall Corporation 2006

KL(P) 2 Pressure

KL(W)

3

Product Wetted Integrity Pressure Determination of test pressure KL in product

KL in water

Product KL Curve Gas Flow Pressure

x (Q/P)

Calculated Test Pressure

Water KL Curve x


FF test pressure in water 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 © Pall Corporation 2006 “bubble points” using the same membrane disc

Critical Testing Parameters

Compatibility

ITV

Adsorption


Considered for “worst-case”

Evaluated for information only

Sterilization Conditions

Extractables

Temp

Bacterial Challenge

∆P

Viability

Flow Rate

Time

Filter Throughput

Surface Tension

Osmolarity

Viscosity

Ionic Strength

pH

Composition

Test Type

Additional Validation Testing


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


Kleenpak Connectors Extractables Testing Model Solvent Approach Compatibility Tensile Strength


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


Preparation for an audit


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


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


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


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?


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?


Reference Documents (1) 1.

2. 3. 4. 5. 6. 7. 8. 9.

Bowman, F., M.P. Calhoun and M. White, “Microbiological methods for quality control of membrane filters”, J. Pharm. Sci., v. 55; p. 818 (1967) Pall, D.B., “Quality Control of Absolute Bacteria Removal Filters,” Bull. Parenteral Drug Assoc., 29, 392-204 (1975). 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) HIMA (now AdvaMed), “Microbiological Evaluation of Filters for Sterilizing Liquids,” draft doc. No.3 Vol. 4, April, 1982 (obsolete) 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) FDA Guideline on Sterile Drug Products Produced by Aseptic Processing, 1987 FDA CDER Perspective on Isolator Technology, ISPE Barrier Technology Conference, Dec. 1995 FDA Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products, 1994 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!

Filter Validation Training-By PALL

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