Quality by Design Principles Applied to Sterilizing Filtration by Michael Payne

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Quality by Design
Principles Applied
to Sterilizing
Filtration
Michael Payne
Principal Biosafety Technical Consultant
November 2020

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Disclaimer:
Views expressed in this
talk constitute my
professional opinion.
Quality by Design Principles Applied to Sterilizing Filtration | November 2020

Steve Jobs Image via Wikimedia Commons
“Design is a funny word.
Some people think design
means how it looks. But of
course, if you dig deeper,
it’s really how it works.”
4

Agenda
1 Concepts, Terminology & Target Focus
2 Regulatory Guidance
3
Example of Critical Aspects & Requirements
for Sterilizing Filtration
4 Product Lifecycle Comments

Quality by Design in the biopharmaceutical industry. RA = risk assessment; PC = process characterisation
Presentation Objectives & Scope
✓ Provide generic information
✓ Review Quality by Design (QbD)
✓ Focus on sterilizing filtration for aseptic filling
✓ Discuss current regulatory documents on sterilizing filtration
✓ Show how to gather information for a sterilizing filtration design space
❖Will not focus on Quality Risk Management
❖Will not focus on vendor / supplier product QbD
6

Poll
Question #1

✓ Must demonstrate that patient is not at risk from
drug product
✓ Must demonstrate drug product quality, safety,
identity, purity, & efficacy
Requirements for Final Filling Operations
Downstream of Purification and Final Filling considered greatest patient risk
8

Sterile Medicinal Products by Aseptic Processing
Drug
Product
Sterilization
Process
Closure Sterilization
Process
Sterile
Closure
Excipient Sterilization
Process
Sterile
Excipient
Aseptic
Processing
Sterile
Drug
Product
Container Sterilization
Process
Sterile
Container
Sterile
Final
Product
Multiple sterilization process conditions each optimized for individual component type
Aseptic processing is then the focus of optimizing and troubleshooting9

Production Formulation / Filling Suite & its Filters
Stopper
Washer
Dryer
Autoclave
WFI
CIP
Freeze dryer
Formulation
Bioburden & Sterile
Filtration
Sterile
Filtration
Aseptic Filler
Prefilter Bioburden
Filter
WFI
API
Excipient
Sterile Hold Tank
Vial
Washing
Sterilizing
Filter
Depyrogenation
Clean Room
Utility Gas
Filters
Gassing
Filter
Blanket /
Transfer
Gas Filter
IT gas inlet
filter IT gas
inlet filter
Vent filter
Vent filter Vent filter
Vent filter
Drying
filter
Washing
filters
Vent filter
Protection
filter
Protection
filter
Circled filters have a critical duty – require full
qualification under defined range of conditions

Concepts,
Terminology &
Target Focus

Quality cannot be tested into the product - should be built-in by good quality
systems & good manufacturing practices
Starting Points
We should have a systematic approach to
• Product specifications and design
• Process design & control
• Process performance & continuous improvement
• Knowledge retention and use
• We should have (or have access to)
• Drug product/substance and drug manufacturing process knowledge
• Scientific understanding of in the establishment of design, specifications and
manufacturing
• Company mission that patient safety & quality are paramount
• Understanding of quality risk management (QRM) & QbD
12

What do we know about Quality by Design (QbD)?
x QbD isn’t “new” (first draft 2004)
x QbD does not have to be focused on Design of Experiment (DoE)
✓ Quality system manages a product’s lifecycle
✓ Intended to increase process & product understanding, decrease patient risk
✓ Multidisciplinary & Multidepartmental exercise
✓ Applicable to whole manufacturing process OR a unit operation (one process
inside another process)
✓ Defines “opportunities for continuous improvement and real-time release”
✓ Expected by regulatory agencies
✓ Defines “'design space' and ‘what is and is not a change’”
13

Target
Target Range
Proven Acceptable Range
Observation ObservationDiscrepancy Discrepancy
Alert Limit
Action Limit
QbD Concept – Multidimensional Design Space (ICH Q8)
Knowledge space (information of the product / process / activity outside our company)
Design space (information on the product, process, activity inside our company)
• Demonstrated range of all process parameters (CPPs or KPPs) where process meets the
product’s Critical Quality Attributes (CQAs)
• Moving out of the design space is a change and may require post-approval change
Control space (how we control the product, process, activity inside our company)
14 Quality by Design Principles Applied to Sterilizing Filtration | November 2020

Example of Iterative QbD Workflow & Systemic Approach
From Quality by Design I Biopharmaceuticals
Anurag S Rathore & Helen Winkle, Nature Biotechnology 27, 26 - 34 (2009)

QbD Concepts - Quality Target Product Profile (QTPP)
”prospective summary of the quality characteristics of a drug product that ideally will be
achieved to ensure the desired quality, taking into account safety and efficacy.” (ICHQ8)
What is the drug and what must it do to be safe, effective, (convenient)?
 Intended use, dosage form, strengths, closure system (stability), route of administration, delivery
systems, mechanism of action
 Concept brief (clinical, drug metabolism, pharmacokinetics, safety & marketing) to set product
specifications
Should have a target value or an acceptable range
Quality attribute is critical when it has an impact on the patient
Strength/Efficacy – Effect of wrong dose?
Purity/Safety – Effect of potentially harmful impurities?
Quality – degradants

Example of Quality Target Product Profile (QTPP) - Mab
17
Source: CMC Biotech Working Group, (October 2009), A-Mab: A Case Study in Bioprocess Development, V2.1
Provides a
metric when
reviewing the
filtration
processes in all
clinical phases

Raw material and component attributes & process
parameters linked to output product CQAs
From a Process Viewpoint
Courtesy of Engineers Journal July 2014
Source: How QbD and the FDA Process Validation Guidance Affect Product Development and Operations, Part 1, Peter H. Calcott, (November 2011), Bioprocess International
(http://www.bioprocessintl.com/analytical/downstream-validation/how-qbd-and-the-fda-process-validation-guidance-affect-product-development-and-operations-part-1-323457/
& Process parameters

Poll
Question
#2

EMA / PICS / WHO
Regulatory
Guidance

ICH Q10 and Change Management: Enabling Quality Improvement
Dr. Bernadette Doyle, GlaxoSmithKline
US FDA Use ICH Documents as Guidances
Focus on Product Lifecycle – Development to Removal from Market
Linkage of Q8 -> Q12
Joseph C. Famulare, “Workshop on Implementation of ICH Q8/Q9/Q10 and
Other Quality Guidelines” Beijing, China, 3-5 December 2008
Add ICH Q11 (Development and Manufacture of Drug Substances), ICH Q12 Lifecycle Management

Traditional style sterile filtration system with bioburden
reduction filter and EMA/PICS/WHO compliant
22
Aseptic Filler
Sterile Hold
Tank
Vent FilterVent Filter
Sterilizing
Filter
Bioburden
Reduction
Filter
Sterilizing
Filter
Compounding
Formulation
“Due to the potential additional risks of
a sterile filtration process, as compared
with other sterilization processes, a
second filtration through a sterile
sterilizing grade filter, immediately
prior to filling, should be considered as
part of an overall CCS.”
(CCS = Contamination Control Strategy)
Annex 1 July 2020 Draft

EMA Guideline on manufacture of the finished dosage form
– Effective January 2018 EMA/CHMP/QWP/245074/2015
Table of contents
1. Introduction (background)
2. Scope
3. Legal basis
4. Manufacture
− 4.1. Manufacturer(s)
− 4.2. Batch Formula
− 4.3. Description of Manufacturing
Process and Process Controls
− 4.4. Controls of Critical Steps and
Intermediates
− 4.5. Process Validation and/or Evaluation
Definitions
Control Strategy:
Critical Process Parameter (CPP):
Critical Quality Attribute (CQA):
Design Space
Hold Time:
− Real Time Release Testing:
References
Annex
23

Guideline on process validation for finished products -
information and data to be provided in regulatory submissions
– Effective November 2016 - EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1
Table of contents
2. Scope
3. Legal basis
4. General considerations
5. Process validation
5.1. Traditional process validation
5.2. Continuous process verification
5.3. Hybrid approach
5.4. Design space verification
6. Scale-up
7. Post approval change control
8. Standard vs. non-standard methods of manufacture
Definitions
References
Annex I: Process validation scheme
Annex II: Standard/non-standard processes
24
Target
Target Range
Proven Acceptable Range
Observation ObservationDiscrepancy Discrepancy
Alert Limit
Action Limit

EMA Guideline on the sterilisation of the medicinal product,
active substance, excipient and primary container
- Effective 1 October 2019 - EMA/CHMP/CVMP/QWP/850374/2015
Table of contents
2. Scope
3. Legal basis
4. General requirements
− 4.1. Requirements for the manufacture of sterile medicinal
products and sterile components
− 4.1.1. Steam sterilisation
− 4.1.2. Dry heat sterilisation
− 4.1.3. Ionization radiation sterilisation
− 4.1.4. Gas sterilisation
− 4.1.5. Sterile filtration
− 4.1.6. Aseptic processing
− 4.2. Good manufacturing practice for sterile active substances,
sterile excipients and sterile containers
− 4.2.1. Active substances
− 4.2.2. Excipients
− 4.2.3. Containers
4.3. Selection of sterilisation method
5. Decision trees
6. Definitions
7. References
25
Key Document
Especially when used
with PICS/WHO
Annex 1 (Manufacture
of Sterile Medicinal
Product (currently
under 3rd review)

EMA Guideline on the sterilisation of the medicinal product, active
substance, excipient and primary container
4.1.5. Sterile filtration
This table mirrors many aspects of the
US FDA Compliance Guide for
Inspection of Sterile Drug Product
Facilities and ISO 13408-2
A CLOSE alignment across major
regulatory agencies and organisations.
Regulator highlights both critical (i.e
sterilizing) and moderately critical
(i.e. bioburden reduction) filter
AND shows some of what should be
qualified and what fluid should be
used

DRAFT Annex 1 Manufacture of Sterile Medicinal
Products (Document Revised July 2020 – 3rd revision in 3 years)
Filtration of medicinal products which cannot be sterilized in their final container
“8.81 The selection of components for the filtration system and their interconnection and
arrangement within the filtration system, including pre-filters, should be based on the
critical quality attributes of the products, documented and justified.”
“8.87 iii. Filtration process conditions including:
• Fluid pre-filtration holding time and effect on bioburden.
• Filter conditioning, with fluid if necessary.
• Maximum filtration time/total time filter is in contact with fluid.
• Maximum operating pressure.
• Flow rate.
• Maximum filtration volume.
• Temperature.
• The time taken to filter a known volume of bulk solution and
the pressure difference to be used across the filter”
27
Alignment with
QbD Approach
Note the process
parameters
referenced

Some Key Design Space Points in EMEA Documents
Design Space Defined
➢ The multidimensional combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to provide assurance of
quality.
➢ Working within the design space is not considered as a change.
➢ A design space will normally be developed at laboratory or pilot scale.
➢ During scale-up the commercial process is generally conducted and validated in a specific
area of the design space, defined as the target interval or Normal Operating Range (NOR).
➢ Movement out of the design space is considered to be a change and would normally initiate
a regulatory post approval change process.
➢ Design space is proposed by the applicant, supported by data and is subject to regulatory
assessment and approval
28

Poll
Question
#3

Example of
Critical Aspects
& Requirements
for Sterilizing
Filtration

Objectives of Sterilizing Filter Discussion
• Identification of characteristics that could affect filter performance and
hence patient safety
• Review characteristics that should be determined in drug product
development
• Be a reminder of some characteristics that can be compromised during
drug product lifecycle
• Not to expand the design space but to define the design space
(early stage clinicals have a much smaller design space)

8 Elements of Sterilizing Filter Qualification
Should represent “worst case” process conditions, process fluid, & filter characteristics
all of which come from the qualified design space
Integrity
Testing
Compatibility
Sterilization
Extractables
& Leachables
Duty
Binding
Retention QS, VMP &
Documentation
Prove the filter meets all
performance & duty
requirements within
product & process
conditions.
Prove the sterilization
method is effective and does
not compromise the filter.
Prove the filter does not
unacceptably remove
stream components.
Prove the stream does not
adversely impact the filter
duty or process stream
Identify, quantify, and assess impact
of compounds that are added to
process product stream.
Prove the filter removes
bacteria from the stream
compliant with ASTM and
relevant regulations
Prove the filter’s
bacterial retention
capabilities with a non-
destructive test.

Assumption is that drug product production is under GMP with robust QS
Quality System
ICH Quality Working Group Training. How ICH Q8, Q9, Q10 guidelines are working together throughout the product lifecycle. Nov 2010.
Product
Discontinuation
Commercial
Manufacturing
Technology
Transfer
Pharmaceutical
Development
Pharmaceutical Quality System
Investigational products
GMP
Management Responsibilities
Knowledge Management
Quality Risk Management
Process Performance & Product Quality Monitoring System
Corrective Action / Preventive Action (CA/PA) System
Change Management System
Management Review
Enablers
PQS
elements

Some Considerations in Sterilizing Filtration for
Early Phase Clinical Trials
• Collect data as per xGMP
• Design space and control space are similar or same
• QbD objective is to collect data and expand
design space without affecting QTPP
• Critical equipment should be qualified
• Process conditions are sometimes based on convenience e.g. available equipment
but this may not represent conditions used in later process runs or clinical phases
• Sterilization processes are as per compendial requirements
• Filtration process parameters should be collected
• Time, pressure, flowrate, temperature, etc. (as per Annex 1)
• Keep the end in mind – phase 3 & manufacturing
• Gain knowledge of larger scale filling operating conditions during phase 2
Image https://blogs.biomedcentral.com/on-medicine/2018/05/18/clinical-trials-and-trial-registration/
34

Division of the Elements of Sterilizing Filter Qualification
Part 1
Phase 1-2a – Development or Prior to Small Scale Tech Transfer
Integrity
Testing
Compatibility
Sterilization
Extractables
& Leachables
Duty
Binding
Retention QS, VMP &
Documentation

Duplicate or Triplicate trials using small equipment provides;
 Filter integrity testing (FIT) information
− Pre-use water bubble point
− Post-use product bubble point
− Water volume to flush to get pre-use value
 Filter loading / capacity (L/m2) determines area
− Graph Volume/time vs Time
− Filtrate flowrate
 Adsorption studies (active/excipient/preservative etc.)
− Take samples throughout filtration
− Graph concentration vs loading
− Determine volume for saturation
− Mimic filling process – e.g. hold / header tanks / bags
 Compatibility
− Visual inspection / Weight change
Using small (~33-50mm) disk filter flow decay equipment.
Small Scale Membrane Trials in Process Development
36
Confirmed Outputs
✓ Filter MOC
✓ Filter Area
✓ Likely FIT result
✓ Flush volume
✓ Flowrate/Area (flux)
✓ Time for volume

Collected during early phase using calculated area, flushing conditions
Filter Duty & Compatibility Data Confirmation
Scale-up Parameters to Hold Constant
➢ Loading (i.e. V/A), Flux (Q/A)
Process Parameters
➢ Feed fluid pretreatment
➢ Temperature, differential pressure, flowrate, volume
➢ Surface area
➢ Exposure time
Attributes
➢ Sacrifice volume before first container in batch
➢ Process yield
➢ Visual filter inspection before and after filtration
37
Confirmed Outputs
✓ Product preparation
✓ Filter preparation
✓ Filter area
✓ Flush / Discard volume
✓ Likely FIT result

Applies to devices / elements used once OR complete single-use assemblies
What Single-use System is Specified
38
Ensure design is right – iterative process
Confirm effect of SUS on product
Experience with SUS process and
handling
Key Scaling Parameters - Keep the same
✓ MOC
✓ Sterilization method
✓ Product contact time
✓ Temperature – holding, storage, processing
✓ Volume / Contact Area
Complete Systems – example has 31 different components –
need vendor discussion on extractables data, compatibility, etc.
Single-use devices

-Use physical measurements and biological indicators where appropriate
Filter / System Sterilization
Parameters
- Use validated system sterilization (autoclave / SIP / gamma)
- Use sterilizing filter documentation (e.g. CoQ, Validation Guide)
- Establish filter / system preparation (dry or wet)
- Conduct environmental monitoring
Attributes
 Passed filter integrity test result
 Visual filter inspection post SIP /Autoclave
 SIP or Autoclave chart
 Required F0
 Quarterly gamma dose audit report
from vendor
39
C
C
B
C
R
B
R
R
C
RT
L
FLT
FC
TC
FB
R
User History
Time
Temperature / Pressure
Normal
Operating
Space
Moist heat sterilization
Gamma sterilization

Division of the Elements of Sterilizing Filter Qualification
Part 2
– Phase 2b / Phase 3 or Part of Production Tech Transfer Discussion / Confirmation
Integrity
Testing
Compatibility
Sterilization
Extractables
& Leachables
Duty
Binding
Retention QS, VMP &
Documentation
All circled items
need to be done
using confirmed
process conditions
and process fluids

Trending pre- and post-use results and deviations
Process Filter Integrity Confirmation
Parameters
- wetting fluid (water, buffer, product, excipient, etc.)
- wetting conditions (temperature, flowrate, volume, time, inlet/differential pressure)
- test gas (type, temperature)
- Post-use flushing volume
Attributes
 Values before and/or after filtration
 Test result incl. trending
 Number of attempts to pass

-Use physical measurements and biological indicators where appropriate
-Checking batch records and SOPs
Process Filter Sterilization
Parameters
- sterilization conditions (autoclave / SIP / gamma)
- Filter preparation (dry or wet)
- Sterilization conditions; temperature, time, inlet/differential pressure
- Whole cycle data is vital
Attributes
 Passed pre & post-use integrity test result
 Visual filter inspection after SIP
 SIP or Autoclave chart
 Required F0
 Quarterly gamma dose audit report from vendor
User History
Time
Temperature / Pressure
Normal
Operating
Space
42

Definitions from PDA Technical Report #26
Extractables & Leachables (E&L)
Fluid
Contact
Surface
“Any chemical component that is removed from a material by the application
of an artificial or exaggerated force (e.g., solvent, temperature or time).”
Determined under “worst-case” conditions following a Model Stream
approach (e.g. BPOG)
Extractables
“A chemical component that migrates from a contact surface into a drug
product or process fluid during storage or normal use conditions.”
Determined with product under normal processing/storage
conditions.
• Solvent stream approach to identify the plastic compounds.
• Product testing (Interference between product and analytical
method has to be evaluated).
Leachables
Extractables will have a higher mass than leachables and are used in first part of
risk assessment for potential patient impact e.g. during early clinical stages

e.g. Tubing, connectors, fittings, containers, bags, filters, etc.
Examples of Polymeric Extractables & Leachables
Oligomers
PVDF, PP, PE
Etc.
Additives and Degradants
Antioxidants, UV stabilizers,
Slip agents, etc.
Residual
Manufacturing
Solvents
Material of Construction
Contact Fluid Process
Conditions
Quantity
and
Type
44
Key Leachables Parameters
 Contact fluid (media, buffer, process
intermediates, DS/ bulk, DP, etc.)
 Contact material
 Sterilization / Pre-treatment
 Temperature
 Contact time
 Dilution ratio (V/A)
 All process fluid interactions
 DON’T forget the prefilter . . . . . And
formulation container if single-use

- User and vendor partnership
Typical E & L Test Study Information & Interpretation
BPOG GUIDE FOR EVALUATING
LEACHABLES RISK FROM POLYMERIC
SINGLE-USE SYSTEMS USED IN
BIOPHARMACEUTICAL
MANUFACTURING
Example of
information required
for E or L testing
https://bioprocessintl.com/upstream-processing/upstream-single-use-
technologies/recommendations-for-extractables-and-leachables-testing-182173/

Process Considerations of Filter Preparation & Filter
Location on Leachables – Key Process Understanding
Filtration system flushed before use
• Testing conditions (fluid, flowrate, volume, preparation, etc.)
• Acceptable levels of process residue (measurement, sampling, etc.)
• Risk to product (stability, toxicity, patient safety)
Filtration system not flushed before use
• Dilution calculation (use downstream volume)
• Risk to product (stability, toxicity, patient safety)
If Filter used for tank-to-tank transfer
• Dilution calculation (use total downstream volume)
If Filter used at true point-of-use
(no header tank or bag)
• All leachables are in final container – need product sacrifice

4 Interrelated factors can influence filter retention –> product sterility -> patient safety
Filter Retention Validation is a Combination of Parameters
Process
Size
Shape
pH
Osmolarity
Ionic strength
Surfactants
Differential Pressure
Flow rate
Microporous structure (pore morphology)
Temperature
Pore size distribution & membrane thickness
Membrane
Surface chemistry
Contact Time
Number
Organism
Product
Viscosity
Aggregation
Type
Concentration
47
1. Need to collect these
for all products
2. Prioritize high risk
products
3. Collaborate with
contract laboratory to;
• Determine grouping
• Establish design
space parameters
Often called
Bacterial Challenge Test
Bacterial Retention Test
Filter Integrity test value

Bacterial Retention Test Risk Factors
Conducted by qualified laboratories – user and vendor partnership
From PDA TR26
What to look for
in 3rd party
(mostly vendor)
laboratory test
report
This information
is used to confirm
the filter
retention
design space
Filter area
information
sterilization method
Required before
retention test can be
done

Examples of Filter Process Parameters Checked
During Changes or when Grouping
Need to qualify all sterilising filters – example has 2 operations – sterile hold tank
fill, then product filling
Example - Looking for worst case process conditions from previous runs
✓ 1st Sterilising filter – high flowrate, shortest time, highest pressure, higher area
✓ 2nd Sterilising filter – low flowrate, longest time, lowest pressure, lower area
✓ Assumes sterilising filters MOC are the same
Should be explained in bacterial retention test protocol and report
Formulation Aseptic FillerSterile Hold
Tank
Vent
Filter
Vent
Filter
Sterilizing
Filter
Bioburden
Reduction
Filter
Sterilizing
Filter
49

Summarizing the Sterilizing Filter Design Space
Process Parameters
Times, pressure, temperature, flowrate (flux), volume (loading), sterilization method
and conditions, pretreatment, integrity test results, product yield
Product Attributes
Product pH / ionic strength / osmolarity, product concentrations
(active, excipient, preservative etc.), acceptable impurity levels,
Microbiological Attributes
Species / Identity, concentration
This data should already be available from quality, production,
validation, regulatory affairs documentation

Poll
Question
#4

Product
Lifecycle
Approach
Quality by design (QbD) concept as presented by U.S. Food and Drug Administration (FDA)

Product Life Cycle Considerations
Phase 1
 Environmental monitoring , filter sterilization method, batch size, filter area,
operating pressure, product stability, pre-flush?
Phase 2
• Process condition data collection, CAPA responses, change control activities
Phase 3
 Sterilization, Integrity testing, capacity
Product Grouping for Retention Testing if Product becomes a Family
 Use of parameter and attribute spreadsheets
 Focus on products where DS concentration is the only formulation difference
 Review all process parameters
 Ensure process parameters are the same or inside the design space
53

Suggestions for checking before transferring filling operations
Product Life Cycle Considerations
Contract Filling or Site Transfer
 Validation status of aseptic filling suite and services
 Bacterial retention test done (if not then by whom)
 Filling area environmental monitoring data review
 Volume/Area, Flowrate/Area, time confirmed to be within established conditions
 Sterilization conditions
 Formulation preparation tank / container check (type, MOC), hold times
 Process controls within established conditions
Change Control & Annual Product Review
 Excursions / deviations checked
Change or Implement Single-use Systems
 In-depth discussion required with change control team & vendor

Examples of Filter Process Parameters to Check when
Changing or Transferring a Process
Has the process been validated?
If so;
• Review older validations against
the current process conditions.
• Have there been filtration process
changes?
• Has the product formulation
changed since the validation?
These changes should be part of
change control checks for sterilising
filtration operations

✓ Regulatory agencies look for product quality built into the process not tested into
the process
✓ Quality by Design (QbD) is a scientific approach to build-in & ensure quality in
drug products by emphasising process understanding, relationship between CPPs,
CQAs, QTPPs using a methodical approach including risk assessment
✓ Process control strategies help ensure that process parameters are maintained
within the desired range to ensure product quality and reliable process operation.
✓ QbD relatively “simple” in processes like sterilising filtration
✓ Developing a design space can be done using information already available from
previous batches (e.g. clinicals), previous testing especially bacterial retention
testing questionnaires
✓ Vendor support is valuable at many times during initial studies,
tech transfer, scale-up and process confirmation
Conclusion

“Everything should be made
as simple as possible.
But not simpler.”
Thank YOu
Albert Einstein
Image via Creative Commons

Some Reference Materials
ICH Q8(R2). Pharmaceutical Development. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8r2-
pharmaceutical-development
ICH Q9 Quality Risk Management https://www.fda.gov/media/71543/download
ICH Q10 Pharmaceutical Quality System https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q10-pharmaceutical-
quality-system
ICH Q11 Development and Manufacture of Drug Substances https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/q11-development-and-manufacture-drug-substances
ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Core Guideline Guidance for Industry
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q12-technical-and-regulatory-considerations-pharmaceutical-
product-lifecycle-management-core
Guideline on manufacture of the finished dosage form – Effective January 2018 - EMA/CHMP/QWP/245074/2015
Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container - Effective 1 October 2019 -
EMA/CHMP/CVMP/QWP/850374/2015
Guideline on process validation for finished products - information and data to be provided in regulatory submissions – Effective November
2016 - EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1
DRAFT Annex 1 Manufacture of Sterile Medicinal Products
https://ec.europa.eu/health/sites/health/files/files/gmp/2017_12_pc_annex1_consultation_document.pdf
PDA Technical Report No. 26, Revised 2008, Sterilizing Filtration of Liquids
PDA Technical Report No. 66 Application of Single-Use Systems in Pharmaceutical Manufacturing
BPOG www.biophorum.com/download/extractables-testing-of-polymeric-single-use-components-used-in-biopharmaceutical-manufacturing/
BPSA Recommendations for Extractables and Leachables Testing
CMC Biotech Working Group, (October 2009), A-Mab: A Case Study in Bioprocess Development, V2.1
Quality by Design I Biopharmaceuticals, Anurag S Rathore & Helen Winkle, Nature Biotechnology 27, 26 - 34 (2009)
When do you need to consider revalidating the performance of your sterilizing-grade filter? Merck Millipore AN32450000

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Quality by Design Principles Applied to Sterilizing Filtration by Michael Payne

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