QBD for Downstream Virus Filtration

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Quality by Design (QBD)
for Downstream
Virus Filtration
Tathagata Ray
Nov 6, 2020

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

Agenda
1
2
3
Quality by Design
Virus Filtration
QbD in Virus Filtration

Introduction
LOW
HIGH
Concept Design Testing Production
Quality by Design (QBD) for Downstream Virus Filtration | 6 November 2020

Quality Has Key Economic Attributes
Introduction
Costscausedbypoorquality
Characteristics critical to the customers' experience
Lower Limit Upper LimitTarget
Traditional
perspective
Realistic
perspective

Quality in Biopharmaceuticals
Introduction
1
100
10000
1000000
2σ 4σ 6σ
DPMO
Restaurant bills
Airline baggage arrival
Aviation industry
Nuclear industry
Quality to
patient
How do we follow “absolute” quality? By Testing!
Or, it has to be built in by design...
DPMO – Defects per million opportunities
Healthcare industry

Quality Can Be A Key Regulatory Concern
Introduction
Does the production process result in
product/residues that interfere with final
product strength or efficacy?
product/residues that interfere with final
product purity?
product/residues that are toxic to the
patient?
Suitability of either a drug substance or product for its intended use (ICH Q6A)

QbD: Overall Approach
Introduction
CQ
A 4
CQA
2CQA
1
CQ
A 3
PRODUCT DESIGN SPACECLINICAL DESIGN SPACE PROCESS DESIGN SPACE
TARGET PRODUCT PROFILE
CONCEPT > DESIGN > PRE-CLINICAL > CLINICAL > MASS PRODUCTION
Animal studies
PROCESS
PARAMETER
S

QbD: From Process to Step
Introduction
Quality target product
profile (Safety !)
Identify CQAs
(virus retention)
Design Process
Design formulation
Material attributes and Process parameters
CQAint
1
CQAint
2
Identify and control sources of variability
Monitor and update
Process Step
Characterization
based on risk
assessment /
control

Risk Management
 Minimizes risk by identifying high risk/impact
parameters and implementing a
control/monitoring strategy
 Results in a more robust/controlled/consistent
process
 Reduces chance of out of spec. batches,
deviations, etc.
Simplifies Process Development
 Holistic development of a design space to
accommodate multiple diverse molecules within
a pipeline
 Less repetitive “reinventing the wheel” studies
with each new molecule using a bracketing
approach
Simplifies Validation
 Differentiating critical vs. non-critical processing
parameters enables more compact validation
study designs
 Facilitates a modular validation approach for a
multi-molecule pipeline
 Faster validation time and lower associated costs
Stronger Regulatory Submission
 Demonstrates a proactive understanding of your
process to regulatory bodies
 Rationale for design space makes regulatory
submission package more defendable
Why Apply QbD?
Introduction
1
2
3
4

A Key Component of Viral Safety Assurance
Virus Filtration

Virus Removal via Size Exclusion
Virus Filtration
Membrane Pore Size Distribution
 All membrane pore paths < virus size: expect complete retention
 Reality: membrane morphology is complex and has an inherit size distribution
 Other parameters may impact retention in extreme cases
− E.g. very high flux decay => preferential plugging of smaller pores leaving larger
pores more accessible to virus passage
Vendor Controls: Viresolve® Pro Device
 Recurring (every lot)
− Membrane pore size distribution measurement and control via liquid – liquid
porometry
− Membrane and finished goods device binary gas and air/water diffusion testing
− Selective layering process to increase performance consistency
 Control factors can be incorporated into the FMEA

How Could Plugging/ Flux Decay be a CPP?
Virus Filtration
Breakthrough at High Flux Decay / Plugging
 Membrane has an inherent pore size distribution
 Pores on the upper end of the distribution could be non-retentive
 Preferential plugging of smaller pores first
− Redirects more flow through the larger pores
− At higher plugged states, virus breakthrough is possible
 Different filters exhibit different behaviors!
− Membrane pore size distribution ultimately dictates retention performance
− Process endpoints of V90 or more are possible without significant loss of retention
(Viresolve® Pro Device)
Breakthrough in
Large
(Non-Retentive)
Pores
Functional
(Retentive)
Pores
1 nm 100 nm10 nm
MVM
(20–25 nm)
fX-174
(25–30 nm)

Risk Assessment: Process Parameter Inputs
Introduction
Feed Stream Characteristics
 pH, conductivity, titer, aggregate loading, buffer matrix, hold time, temperature, etc.
 Consider for both inter and intra lot
 Consider molecule to molecule across entire pipeline for a template approach
Virus Filter Operating Parameters
 Pressure, volumetric/mass loading, process interruptions, flux decay endpoint, etc.
Virus Filter Characteristics
 Filter brand/model, scale, integrity test result, lot to lot variability, etc.
Goal
 Understand which are the critical processing parameters which might affect virus retention
 Document the sensitivity/insensitivity of retention to each parameter within your expected
operational window

Risk Assessment: FMEA
Introduction
Too Many Variables!
 Limit parameters to those rationally significant (i.e. operator, feed turbidity not likely critical)
FMEA Approach Example (not prescriptive)
 Rank each parameter based on:
− Severity (impact on LRV): 1 – 10 (low – high)
− Probability of occurrence: 1 – 10 (low – high)
− Detectability via controls: 1 – 10 (detectable – undetectable)
− Risk priority number (RPN): Severity x Probability x Detectability => prioritize and work top down
Estimating Severity
 How would you know if flux decay, process interruptions, etc. would impact retention?
 Leverage internal data sets for previously tested molecules
 Leverage vendor supplied / industry publication data sets
 The goal is to minimize the exploratory testing required

QbD Approach for Virus Filtration
Introduction
1
2
3
4
Risk Assessment
 What are the theoretical processing parameters
that could impact viral retention performance?
 Not all parameters are critical or equal…
 Use an FMEA approach
 How can we determine the relative risk
(severity/probability/detectability)?
Characterization Studies
 Which processing parameters actually affect retention
and to what extent?
 Every commercially available filter behaves differently!
 How can we determine the effect?
 Univariate or multivariate analysis?
 In house and/or vendor supplied data
 Update FMEA based on findings
Design Space Establishment
 Understanding of what to expect for retention at
the boundaries of your multidimensional design
space
 Establishment of allowable ranges of processing
parameters to ensure CQA is met
 Can be established for single or multiple molecules
Control Strategy
 Develop control/monitoring strategy for CPPs to
ensure operation within the established design
space validated during spiking studies
 Focus top down on high risk items from FMEA
Virus Filtration: CQA is achievement of a predetermined LRV of virus from drug product

QbD Applied to CQAs and Process Performance
Case Study
CPP identification
(parameter ranges
omitted here)
Risk estimation
based on knowledge
gaps
Parameter
understood => no
study needed
Knowledge gap =>
medium risk
Product quality Process performance
Process Parameter
Aggregate
content
(% by HPSEC)
Viral
clearance
Yield
Average
flow flux
Volume
throughput
Protein concentration
(mg/ml)
Medium Medium No study Medium Medium
Conductivity (mS/cm) No study Medium No study No study No study
Temperature (oC) No study Medium No study No study No study
pH Medium Medium No study Medium Medium
Feed hold time No study No study No study No study No study
Pressure during filtration No study Medium No study No study No study
Process time No study No study No study No study No study
% flow decay No study Medium No study No study No study
Volumetric & mass
throughput
Medium Medium Medium Medium Medium
Recovery flush Medium Medium Medium Medium Medium

QbD Applied to CQAs and Process Performance
Case Study
Vendor supplied
data sets
addressed most
knowledge gaps
Constituted a
significant
reduction
of study effort
needed
to implement QbD
Product quality Process performance
Process Parameter
Aggregate
content
(% by HPSEC)
Viral
clearance
Yield
Average
flow
flux
Volume
throughput
Protein concentration
(mg/ml)
Medium Medium No study Medium Medium
Conductivity (mS/cm) No study No study No study No study No study
Temperature (oC) No study Medium No study No study No study
pH Medium Medium No study Medium Medium
Feed hold time No study No study No study No study No study
Pressure during filtration No study Medium No study No study No study
Process time No study No study No study No study No study
% flow decay No study Medium No study No study No study
Volumetric & mass
throughput
Medium Medium Medium Medium Medium
Recovery flush Medium Medium Medium Medium Medium
Vendor
supplied
data

Hypothetical Example
Effect of Feed/ Process/ Filter Parameter on Retention
Category Process Parameter
Example Molecule Mfg.
Range
Example Template Mfg.
Range
Variation Causes
FeedCharacteristics
Protein concentration 5-10 g/L 0.5-25 g/L Titer, flushes, CEX cuts
Conductivity 8-10 mS/cm 0.5-25 mS/cm
Buffer variability, dilution, batch to batch, in-line pH
adjustments
Temperature 22-24°C 10-30°C Environmental controls, cleaning water temperature
pH 4.9-5.1 5.4-8.0 Feed variability, in-line pH adjustments
Hold
time/temperature
1-4 hr @ 23°C 0.5-24 hr @ 23°C Scheduling, buffer temp.
Aggregates < 1% <2% Hold time
Prefilter Shield None/Shield/Shield H/VPF Batch variability
Protein pI 8.5 6-9 Amino acid content
Protein molecular
weight
150 kD 50-150 kD Amino acid content
Buffer species Acetate
Acetate, phosphate, MES,
citrate, histidine
Protein specific

Hypothetical Example
Effect of Feed/ Process/ Filter Parameter on Retention
Category Process Parameter Example Molecule Mfg. Range Example Template Mfg. Range Variation CausesVirusFilterOperatingParameters
Constant flow or pressure operation Constant pressure Constant pressure Plant preference
Pressure 25-35 psig 20-50 psig Gauge error
Recovery flush 8-12 L/m2 0-100L/m2 Batch variability
% flow decay (plugging) 0-30% 0-50% Hold time
L/m2 Volumetric Throughput 700-900L/m2 400-2000L/m2 Batch variability
Kg/m2 Mass throughput 3.5-6.5 kg/m2 1-10 kg/m2 Batch variability
Interruption hold durations <10 min 0-30 min Scheduling
Process time 0.5-2 hrs 0.5-6 hrs Scheduling
Pre-use caustic flush 0 L/m2 0-50 L/m2 Plant decision
VirusFilter
Char.
Shelf time 0-1 yr 0-1 yr Scheduling & demand
Device lots Magnus 2.2 lot Magnus 2.2 lot Batch variability
Integrity test value 0.5-0.784 sccm/m2-psi 0.5-0.784 sccm/m2-psi
Batch variability,
temperature, wetting

Feed: Protein Concentration
Effect of Parameter on Retention with Viresolve® Pro Device
Conclusion
No significant impact of protein
concentration on LRV
(2 – 25 g/L)
ϕX-174 LRV (grab samples) vs. mAb1 concentration
Impact of feed concentration and flow decay on MVM pool LRV
MVM retention in triplicate devices for two mAb
concentrations at processing endpoints of V75 and
V90

Feed: Conductivity and pH
Conclusion
No significant impact of pH (5-7)and
Conductivity (8-25 mS/cm) on LRV
MVM LRV including pH, Conductivity and % Flow Decay.

Feed: Temperature
conclusion
No significant impact of Temperature
(5-21 degree C) on LRV
ϕX-174 LRV vs. filtration temperature at different operating pressures

Operation: Operating Pressure
conclusion
No significant impact of Pressure
(10 – 50 psi) on LRV
MVM @ V75
ϕX-174 @ V50

Operation: Processing Endpoint: % Flow Decay, Throughput
(L/m2) or Mass Loading (kg/m2)
conclusion
No significant impact
of mass loading (2-25
kg/m2), Throughput
(10 – 2200 L/m2) and
% Flow decay (25% -
90%) on LRV
MVM @ V75

Operation: Process Interruption – Recovery Flush and Operating
Process Hold
conclusion
No significant impact of process
interruption (0-300 min) / Flush
volume (0-50 L/m2) on LRV
No impact from membrane lot No impact from molecule type or concentration
• No impact from pause intervals
• No impact from pause duration
• No impact from flush volume
• No impact from pressure (up-down)
• No impact on single membrane lot

Operation: Pre-use Caustic Flush
conclusion
of pre-post use
caustic flush (0-17
hrs; 0-0.5N NaOH;
room temperature) on
LRV
Viresolve® Pro devices (Micro, Modus and Magnus) were caustic sanitized with 0.5N NaOH (for 1h dynamic
and 16 hours static) then challenged with ϕX-174 in 24 g/L BSA in FA buffer pH 7.2 at 30 psig. Filtrate grab
samples were collected at V75 and LRVs were compared to LRVs from non-caustic treated devices.

Device: Consistency of Membrane and Device Performance
conclusion
No significant impact of
Device (0.00031-1.53 m2)
and Membrane Lot on LRV
At least 4.0 logs of virus retention was
consistently achieved across device scales
and membrane lots.

Parameter Test Range Summary
conclusion
with Viresolve® Pro
Device
• An internal database containing results of 498 small viral clearance evaluations using Viresolve® Pro
devices was analyzed using a similar approach to published reports.
• These clearance evaluations were not systematic controlled studies of the filtration design space, but rather
represent a composite of many filtration conditions executed by multiple biomanufacturers at different
testing laboratories using virus preparations prepared using a range of purification methodologies.

Feed Titer and Operational Pressure
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
0
5
10
15
20
25
30
35
40
45
VirusLogReductionValue
Drug Product Concentration (g/L)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
0
10
20
30
40
50
VirusLogReductionValue
Feed Pressure(psi)
O = non-detects (assay limit) + = detects

Download Here
Reference

Welcome
Sterile Filtration of Complex Injectables | 20 October 2020
Tathagata Ray
Head of Technology
Management
Indian Subcontinent and
South-East Asia

The vibrant M, Viresolve® Pro are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective
owners. Detailed information on trademarks is available via publicly accessible resources.
© 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

QBD for Downstream Virus Filtration

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