Overview of Filter Validation

- Sterilizing (Critical) Filter Focus

Michael Payne
Principal Technical Consultant
Merck Millipore
FDA Risk Based Approach
From FDA presentation in June 2003

“When you know your:

 Product
 Flow-path
 Equipment and how it works
 Potential in-process and process impurities
 Validation studies and their weaknesses
 Readily available technologies at your disposal
Then, you can make intelligent, science-based decisions on your process, validations, and
product, and support them during an inspection!
Know the process, equipment and human capabilities.
 System suitability
 Process capabilities
 Personnel and Training
 Clear/detailed SOPs

No matter how hard you try, you cannot inspect quality into a product”
 Filters in a Generic Biological Process
Sterilizing Filters come from their location and classification in the process,
not the regulations or guidelines. This drives process risk

3
Sterilizing Filters Around the Bioreactor

• Service filters not

shown
• Clarifying, prefilters not
shown
• Critical gas filters
• Overlay, sparge,
exhaust
• Critical liquid filters
• Media, additives
• For redundant or serial
filters, furthest away
defines sterile
boundary
4 From ASME BPE-2009 Bioprocessing Equipment
 Focus on Formulation / Filling Suite Drying
filter
Vent filter Vent filter
Washing
Blanket / filters
WFI Transfer Vial
Gas Filter CIP Washing

Vent filter Clean Room Utility

IT gas inlet Depyrogenation
Gas Filters
filter Vent filter IT gas inlet
filter

Protection Protection
filter Gassing Vent filter
filter
API Filter

WFI

Excipient Prefilter Bioburden Sterilizing Sterile Filtration

Filter Filter

Bioburden & Sterile Aseptic Filler

Formulation Filtration Sterile Hold Tank

Stopper
Washer
Dryer
Autoclave Freeze dryer
5
3D System Risk Assessment Tool

Considers
 a system‘s distance from the
process stream
 its location along the process
stream
 the system‘s complexity
Highest score is highest risk
This tool is mainly used to assign
risk level to an overall complex
system

From IVT Autumn 2008, pp70-76, J Oliver Baxter Bioscience

 Examples of Sterilizing Filtration Risk
Risk = process location x operation complexity x product contact

Bioreactor liquid media filter

Risk = 1 x 2 x 2 4
Bioreactor Gas Filter
Risk = 1 x 3 x 2 6
Sterile hold tank gas filter
Risk = 4 x 2 x 5 40
Final POU liquid filter
Risk = 5 x 4 x 5 100

NB: Severity, use time, process condition,

7 defect detection, economics not considered
Who is Responsible for Sterilizing Filter
Validation?
Validation of Filter Performance

Vendor Responsibilities
 Filter Design Qualification
 Filter Fabrication Process Qualification
 Filter Product Quality
User Responsibilities
 Vendor Auditing
 Filter Selection
 Filter/Product Validation Studies
 Process Validation
– System Design
– Validation
– Sterilization
– Cleaning
– Operator Training
Responsibilities of the Filter User

Establish filter/product compatibility

Audit vendor
Validate test methods
Qualify operators
Validate filter sterilization
Validate equipment cleaning
Validate filtration process
Operate within manufacturer’s specifications
Operate within documented and defined conditions
Responsibilities of the Filter User

Ultimately responsible for filter validation

Validate key filter claims
 In your drug product
 Under your “worst-case” process conditions
Outside laboratories are acceptable
 Aseptic Processing Guidelines 2004
– Data may be generated by outside labs, filter suppliers, or the user
 Human Drug cGMP Notes, December 1995
– The drug product manufacturer’s ultimate responsibility is to ensure that “worst-case
forumulation and processing parameters are adequately studied, evaluated, and
documented”.
Audit outside laboratories
Responsibilities of the Filter Manufacturer

Validate filter claims and manufacturing process

Establish specifications and operating limits
 Integrity
 Temperature
 Pressure
 Sterilization
Meet regulatory and compendial requirements
 Non-Fiber releasing
 Endotoxin
 In vivo/In vitro Toxicity
 Sterilizing-grade performance
 Extractables
What Filters Need to be Qualified in a Sterile
Medicinal Products Process
Typical Sterile and Aseptic Process

?Where is the sterilizing filter?

Grade C
2nd Filtration

Grade A
1st Filtration LAF

Autoclave
Aseptic filling

Grade B
What Filters need to be Qualified

Sterilising liquid filter

Bioburden reduction filter

Sterilising gas filtration

But not all filters need to be qualified in the same way or in the same depth
Filter Categories

Critical Applications
 Where process fluids “are in direct contact with sterile final product or critical surfaces of the associated
equipment.” (PDA TR40)
 Part of Direct Impact System - equipment or system that will have focused and immediate impact on
product quality (ISPE Commissioning & Qualification Baseline Guide (2001))
 The filter directly affects product quality
– Examples: vent filter on a sterile hold vessel, sterile liquid filter
Moderately critical
 Where process fluids “will not be in direct contact with exposed sterile product or surfaces.” (PDA
TR40)
 Part of an Indirect Impact System - equipment or system expected to have incidental or secondary
impact on product quality (ISPE Commissioning & Qualification Baseline Guide (2001))
 The filter indirectly affects product quality
– Examples: vent filter in a grade D area, bioburden reduction filter
Service
 Where process fluids come from facility-wide systems, are not tailored to a specific process and do not
have contact with the drug substance or potential drug substance.
 Part of a No-Impact System - Where the equipment of system has no impact, direct or indirect, on
product quality (ISPE Commissioning & Qualification Baseline Guide (2001))
 The filter does not affect product quality
– Examples: distribution gas filter, water prefilter
Step-wise Approach to Filter Qualification
Eight Key Elements
Quality System
Chemical compatibility
Duty
Binding / Adsorption
Integrity testing
Sterilisation
Extractables / Leachables
Microbiological Retention
Suggested order of testing – but should be identified in planned validation timeline
Critical Filter Documentation

Suitability for duty

Process definitions
Bacterial retention
Integrity testing
Sterilisation process validation
Adsorption
Leachables / Extractables
Risk analysis approach to processing and product impact GMP ?

Quality by design
Sterilizing Filter Qualification in More Detail
Validation is a Combination of Parameters

Example - factors that can influence filter retention

Size
Shape
Number
Organism
Product Process
pH Differential Pressure
Osmolarity Flow rate
Ionic strength Time
Surfactants Temperature
Viscosity Membrane
Pore size distribution
Surface chemistry
Microporous structure
Impact of Retention Parameters

Product

Membrane

Process

Organism

Consider impact of these when evaluating different operations

Sterile Liquid Filter Qualification & Validation
– Recommendations

PDA TR26 Technical report No.26, Revised 2008, Supplement Volume 62 No. S-5,
Sterilizing Filtration of Liquids
Sterile Gas Filter Qualification & Validation
– Recommendations

PDA TR40 Technical report No.40,

January/February 2005
Supplement
Volume 58 No. S-1
Comments on Sterilizing Gas Filter Validation

 There is no specific standard that defines the retention requirements for a

membrane filter used to sterilize gases

 Liquid bacterial challenge testing represents a worst-case condition for

sterilizing gas filters because the retention efficiency in liquids is much lower
than in gases

 Focus is on evaluation of vendor testing and suitability of documentation

compared with filter duty

 Aerosol testing using bacterial and or viruses is difficult and complicated –

hence vendor testing is logical
Validation of Filter Performance

Qualification data
Vendor
Production controls

Certificate Validation Supplier

of Quality Guide Audit

Drug Define Process

Manufacturer Conditions
 Eight Filter Validation Elements

Integrity Binding
Testing

Duty
Retention VMP, QS &
Documentation

Sterilization
Compatibility
Extractables
/ Leachables

Validation must represent “worst case” process conditions

Feed solution, time, pressure, fluid, volume, sterilization, environment, etc.
Eight Key Elements of Filter Validation

Integrity Binding
Testing

Duty
Quality
System Retention

Sterilization
Compatibility

Extractables

27
Filter Integrity Validation

Goal
-detect any filter failures / housing leaks / bad installation
-Reduce risk of non-sterile product & batch loss

“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. The integrity of critical gas and air vent filters should be confirmed after use. ”
Annex 1; EC Guide to GMP for Sterile Medicinal Products (2008)

“Integrity testing of the filter(s) can be performed prior to

processing, and should be routinely performed post-use.”
FDA Aseptic Processing Guidelines (2004)

28
Eight Key Elements of Filter Validation

Integrity Binding
Testing

Duty
Quality
System Retention

Sterilization
Compatibility

Extractables

29
Filter Binding (Adsorption) Validation

Goal
- ensure product consistency as regards composition and concentration
- qualify flushing or rinsing prior to filtration into final container
-avoid product stability issue

Any effects of the filter on the product formulation should be described (e.g.
adsorption of preservative or active or drug substance, or extractable)”
FDA Guidance for Industry

“The filter should not affect the product by removal ingredient from it”
EU GMP, Annex 1

“Adsorption of fluid components and extraction of filter components

shall be evaluated”
ISO 13408-2
30
Eight Key Elements of Filter Validation

Integrity Binding
Testing

Duty
Stability
Retention

Sterilization
Compatibility

Extractables

31
Additional Duty Considerations
- why was this filter device chosen?
Filter physical size
Filter connections
Maximum pressure
Temperature
Flowrate
Required prefiltration
Quality documentation
Operation in required environment
Filter capacity and safety factor

Should be tied back to URS

“Because the filter vendor recommended it” – insufficient justification & ownership
Filter Duty Studies using
Small Scale Equipment
Filter capacity with product – calculates
maximum product volume per filter
Collect data at constant differential
pressure for about 10 minutes
 Cumulative volume (V)

 Time (t)

Calculate and plot t/V vs. t (cumulative

volume at each time)
180
160
140
120
100
80
60
40
20 Also useful for adsorption and
0
filter integrity testing evaluation
0 2 4 6 8 10
Eight Key Elements of Filter Validation

Integrity Binding
Testing

Duty
Quality
System Retention

Sterilization
Compatibility

Extractables
Filter Sterilization Validation

Goal
- Demonstrate the sterilization process
- Employ physical measurements and biological indicators where appropriate

“We recommend placing biological indicator at

appropriate downstream location of the filter”
“Devices that measure cycle parameters should be routinely calibrated”
FDA Aseptic Guideline

“Chemical or biological indicators may also be used,

but should not take the place of physical measurements”
EU GMP, Annex 1
Eight Key Elements of Filter Validation

Integrity Binding
Testing

Duty
Quality
System Retention

Sterilization
Compatibility

Extractables
 Filter Extractables Validation
Goal
 Compounds that can be extracted from product-contacting materials
 Generated in a number of solvents of different polarities under aggressive
conditions

Comments
- generate quantitative/qualitative info
- demonstrate that there is no impact on product safety
HyClone Cflex System @ 14 days NaOH pH 10
0.6
Effects of the filter on the product formulation
Abs

0.4
should be described (e.g. extractable)”
0.2

-0.0 FDA Guideline for Submitting Documentation

2.0
Poly (HPA)
for Sterilization Process Validation
Abs

1.5

1.0 “Use appropriate methods and solvents to obtain

0.4
Sodium salt of poly acrylic acid
the amount of extractable per filter”
0.3

“Show the identity, quantity, and toxicity of the extractable”

Abs

0.2

0.1

-0.0
FDA Human Drug cGMP Notes 9/94
3500 3000 2500 2000 1500 1000
Wavenumbers (cm-1)
Impact of Filter Preparation on Extractables

Filtration system flushed before use

• Testing conditions
• Acceptable levels of process residue

Filtration system not flushed before use

• Dilution calculation
• Risk to product (stability, toxicity, safety)
Eight Key Elements of Filter Validation

Integrity Binding
Testing

Duty
Stability
Retention

Sterilization
Compatibility

Extractables
 Filter Compatibility Validation

Goal
- avoid potential filter damage or alteration
- avoid fluid contamination

Confirmed by filter integrity and also during microbial retention and extractable
testing

“A summary should be provide containing information and data concerning

the validation of the retention of microbes and compatibility of the filter
used for the specific product”
FDA Guidance for Industry

“When considering chemical compatibility, it is important to

include all the filter components under investigation”
PDA Technical report N°26 (2008

“Effects of the filter on the relevant biological, chemical

and physical attributes of the product”
ISO 13408-2
Eight Key Elements of Filter Validation

Integrity Binding
Testing

Duty
Quality
System Retention

Sterilization
Compatibility

Extractables
Filter Bacterial Retention Validation

Goal
- demonstrate bacterial-retention performance of the filter in a fluid-specific manner
under worst case process conditions
Comments
7
- A challenge concentration of at least 10 cfu/cm2 should generally be used, resulting in NO
passage of the challenge microorganism
- The microorganism should simulate the smallest microorganism that may occur in
production
– Laboratory experiments should address the effect of the extremes of processing factors
– Test filters should be similar to production filters
FDA Guidelines on Filter Retention Testing

“Factors that can affect filter performance generally include

(1) viscosity and surface tension of the material to be filtered,
(2) pH,
(3) compatibility of the material or formulation components with the filter itself,
(4) pressures,
(5) flow rates,
(6) maximum use time,
(7) temperature,
(8) osmolality,
(9) and the effects of hydraulic shock.
When designing the validation protocol, it is important to address the effect of
the extremes of processing factors on the filter capability to produce sterile
effluent.
Filter validation should be conducted using the worst-case conditions, such as
maximum filter use time and pressure”
FDA Guidelines on Product Grouping Rationale
for Filter Retention Testing
“When sufficiently justified, the effects of the product formulation on the
membrane's integrity can be assessed using an appropriate alternate
method. For example, a drug product could be filtered in a manner in
which the worst-case combination of process specifications and conditions
are simulated.
PDA TR26 Retention Testing Approaches
Section 6.0

• “Classification of the filter membrane by means of bacterial challenge using

applicable standardized tests or comparable methodologies.
• Demonstration by the filter user or designated test facility (e.g., filter
manufacturer or contract laboratory) of complete microbial removal from each
product or product family, using a representative challenge microorganism.
Scientific rationale for each product group should be developed and may be
reviewed with the appropriate regulatory agency before validation testing.
These two filter testing concepts are not interchangeable and should be
independently validated.
The goal of these tests is to prove that the production filtration process generates
a sterile effluent.”
PDA Comments on Product Grouping Rationale
for Filter Retention Testing
Primary aim is to reduce variables thereby increasing risk assurance
• Initial grouping should include products with the same formulation and
where the active ingredient concentration varies
• Conduct testing on products with high and low active concentration –
recommended approach
• Secondary grouping approach should consider active ingredient
concentration and concentration of surface tension altering materials
and / or materials that may affect organism morphology (e.g. ionic
strength, pH)
• Difficult to predict these effects without significant additional testing – not
recommended approach
Ensure Retention Testing Documentation is
Complete & Understood
Ensure System Layout is Included in Retention
Testing Documentation & Analysis

?Where is the sterilizing filter?

Grade C
2nd Filtration

Grade A
LAF
1st Filtration

Autoclave
Aseptic filling

Grade B
Eight Key Elements of Filter Validation

Integrity Binding
Testing

Quality Duty
System
Retention

Sterilization
Compatibility

Extractables
Validation Master Plan (VMP)
- Definition
Process Validation is ““the collection and evaluation of data, from the process design
stage throughout production, which establishes scientific evidence that a process is
capable of consistently delivering quality products”
FDA Guidance for Industry Process Validation: General Principles and Practices

A written plan stating how validation will be conducted and defining acceptance
criteria. For example, the protocol for a manufacturing process identifies processing
equipment, critical process parameters/operating ranges, product characteristics,
sampling, test data to be collected, number of validation runs, and acceptable test
results.
ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Validation Master Plan (VMP) - Definition

VMP should;
 contain key elements of a validation programme should
 be clearly defined and documented
 be brief, concise and clear
 contain data on at least the following:
– Validation policy
– Organisational structure of validation activities
– Summary of facilities, systems, equipments and processes to be validated
– Documentation format
– Planning and scheduling
– Change control
– Reference existing documents

EU Guidelines to Good Manufacturing Practice, Volume 4, Annex 15

 Filtration Master Plan should be considered

– Subset of the Validation Master Plan

– Validation of filter performance
• Focus on critical (ie sterilising-grade) filters
• Filter validation philosophy
• Outline specific validation studies

– Filtration process design

• System sizing and engineering
• Standard Operating Procedure

– Validation of filtration process

• Filter sterilisation
• Filter integrity testing
• Process control and monitoring

– Stability studies
– Training and certification
– Part of Quality System
 Filtration Master Plan

A subset of and consistent with site validation master plan

 Should present an overview of the entire filter validation operation, its organisational
structure, its content and planning.
 References the list / inventory of the filter and filter-related to be validated and the
planning schedule.
 Summarises the firm's overall philosophy, intentions and approach to be used for
establishing performance adequacy for filters used on-site that are that are critical in
yielding a consistent quality safe efficacious product
 Should be a summary document and should therefore be brief, concise and clear.
 Multidisciplinary involvement – including external team members
 References authorised standardised working and operating procedures
Aseptic Process Validation

ISO 7 Filter ISO 6

performance

Operators &
Aseptic connections

ISO 5
Integrity
Integrity testing Sterility
testing
Microbial testing
limit tests Product Sterile transfer
Bioburden
Environmental monitoring
Aseptic Process Validation
– Filter System Design P

– Design of filtration system

P

• P&ID and flow schematics

P
• Functional description
T

– Development of SOPs P3

• Filter SIP & autoclaving

T T
• Filter integrity testing
– Installation qualification
– Operational qualification
– Performance qualification

EU Guide to Good Manufacturing Practice, Annex 15 (2009)

FDA Process Validation: General Principles and Practices (Jan 2011)
Validation of the aseptic process
– Critical Equipment
Hardware validation - filter integrity test instrument, sterility test unit, etc.

“Manufacturing equipment should be designed, located and

maintained to suit its intended purpose”
PIC/S (June 2006)

“Facilities, systems and equipment to be used should have been

qualified and analytical testing methods should be validated”
EU GMP, Annex 15

“Instruments, apparatus, gauge and recording devices not meeting

established specifications shall not be used”
FDA cGMP for finished pharmaceuticals
Validation of the aseptic process
- Bioburden monitoring
“The manufacturing process controls should be designed to
minimize the bioburden of the unfiltered product”
“A prefiltration bioburden limit should be established”
FDA Aseptic Guideline

“Since the effectiveness of the filtration process

is also influenced by the microbial burden of the solution
to be filtered, the determination of the microbiological quality
of solutions prior to filtration is an important
aspect of the validation of the filtration process...”
USP <1211> Sterilization & Sterility assurance of compendial acticles

“In most situations, 10 cfu's/100 ml will be acceptable,

depending on the volume to be filtered in relation to the diameter of the filter.
If this requirement is not met, it is necessary to use a pre-filtration
through a bacteria-retaining filter to obtain a sufficiently low bioburden”
EU, Note for Guidance on Manufacture of the finished dosage form
(April 1996)
Validation of the aseptic process
- Process Controls

“The total time for product filtration should be

limited to an established maximum to prevent
microorganism from penetrating the filter”
FDA Aseptic Guideline

“The time taken to filter a known volume of bulk solution and the pressure difference to be used
across the filter should be determined during validation and any significant differences
from this should be noted and investigated”
EU GMP, Annex
Validation of the aseptic process
- Training

ISO 13408-2:2003
“The manufacturer should provide training for all person
el whose duties take them into production area or into
control laboratories … , and for other personnel whose
activities could affect the quality of the product”
EU GMP, PIC/S (2006)

“Each person engaged in the manufacture, processing,

packing, or holding of a drug product shall have
education, training, and experience,
or any combination thereof,
to enable that person to perform the assigned functions”
US GMP, 21 CFR 211.25
 Validation documentation
Validation
Master File
and/or

Validation Summary
Master Plan

Process
Questionnaire Reports

Protocols
Traditional Validation Approach

Adapted from the typical V-model

 Sampling
Equipment
Microbiological
IQ OQ
method validation
PQ
surfaces
Filter
Bacteria
integrity test retention
Bioburden
operator certification
sterility

Steritest school Filter Extractables

performance

Design, SOP Training

validation for Regulatory
filter sterilisation Compliance Compatibility

Sterility
Assurance
Filterability Process
design Adsorption
studies
Filter
Filter integrity test
Engineering sterilisation Product
specific
parameters

Sterilization
Tester
validation
IQ OQ