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Biologics Drug Product Development using a Quality by Design approach –
Results from the CMC Biotech Working Group
Case Study
Satish K. SinghPfizer Inc.
01 March 2010
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Perform confirmatory formulation development study for A-mAb as we leverage the use of the prior knowledge gained from previous mAbsApply predictive mathematical models to compounding vessels to deliver a scale and equipment-independent process Establish a class-based sterile filtration process platform for X, Y, Z-mAb to build a knowledge set and apply it to a risk-based verification of the operating parameters for A-mAb as a “next in class” molecule
Apply a risk-based approach and the use of DoE to create a design space for the filling operation Use Fault Tree Analysis for a comprehensive risk assessment of the potential points of failure for the overall A-mAb drug product process and propose a mitigation strategy for highest assurance of process performance
Drug Product Case Study Intent
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Linking CQAs to Control StrategySpecifications are one element of
the Control StrategyBased on scientific understanding of
the Product and the Process
Specifications are linked to Clinical Relevance
1. What tests are included2. Acceptance limits3. Anal. Method requirements Product Stability
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Multiple Risk Assessments are used throughout Development Lifecycle
Repeat RA throughout development
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Control Strategy is Based on a Final Risk Assessment for each CQA
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Control Strategy Links all Unit Operations and Defines Testing Strategy
Product Quality Attribute C
QA
Prod
uctio
n B
iore
acto
r
Prot
ein
A
Low
pH
/VI
CEX
AEX
Nan
ofilt
ratio
n
UF/
DF
Com
poun
ding
Filtr
atio
n
Filli
ng, s
topp
er, c
ap
Test
ing
elem
ents
Aggregate Yes Form Remove Form Remove Remove Form Form LR
Deamidated isoforms No Form PM
Oligosaccharide Yes Form PM
CHO HCP Yes Form Remove Remove Remove Remove PM
DNA No Form Remove None
Protein A No Form Remove Remove None
Viral safety Yes Inact Clear Clear Biorx. IPC
CPPWC-CPP
KPP
Operation includes a parameter(s) that must be tightly controlled to achieve CQAsOperation includes a WC-CPP affecting a quality attributeOperation includes a KPP impacting a process attribute
IPCLRPM
In-process control testingLot releaseProcess monitoring
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Overview of DP Case• Based on well-established platform
(formulation, process)• Only verification of suitability of design
space is considered
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QTPP
2-13%HCP
0-5%Galactosylation (%G1 + %G2)
2-13%Fucose content
0-5%Aggregate
Meets pharmacopoeial requirements for parenteral dosage forms, colorless to slightly yellow, practically free of visible particles and
meets USP criteria for sub-visible particlesPharmacopoeial compliance
Below safety threshold, or qualifiedDegradants and impurities
Acceptable toleration on infusionBiocompatibility
Minimum 14 days at 25°C and subsequent 2 years at 2-8°C, soluble at higher concentrations during UF/DF
Compatibility with manufacturing processes
≥ 2 years at 2-8°CShelf life
20R type 1 borosilicate glass vials, fluro-resin laminated stopperContainer
Acceptable for manufacturing, storage and delivery without the use of special devices (for example, less than 10 cP at room temperature).Viscosity
IV, diluted with isotonic saline or dextroseMode of administration
25 mg/mLConcentration
10 mg/kgDose
500 mgProtein content per vial
Liquid, single useDosage Form
TargetProduct attribute
Table 5.2 Quality Target Product Profile (QTPP) for A-Mab
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A-mAb Formulation Design Space Strategy
Building on prior knowledge followed by verification of design space
Case study references: Fig. 5.2 - Formulation Verification, Figs. 5.3 and 5.4 – Formulation Characterization
Note: CQAs listed are only a sample of the relevant drug product CQAs considered in the study design
QTPPPrior Knowledge
Product UnderstandingProcess Understanding
Formulation Verification &
Characterization
Initial Risk Assessment
Comparison to previous mAbs
Design Space Verified
X, Y, Z-mAb commercial product development experience
COMPOSITIONConcentration of active, excipients
CONDITIONSTemp, light, shock, agitation, flow
STABILITYProcessing, packaging, transportation, storage, administration
CQAAggregation by SEC, sub-visible & visible particles
Final Risk Assessment
Product life-cycle, Control Strategy
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Formulation• Identified based on prior knowledge• Verification of suitability of design space
considered
CompendialSolventq.s. to final volume of 20 mLWFI
CompendialpH adjustmentq.s. to pH 5.3Sodium Acetate
CompendialSurfactant2 mg Polysorbate 20
CompendialBuffering agent20 mMAcetic Acid
CompendialIsotonicity agent1.8 gSucrose
In-house specificationActive ingredient500 mgA-mAb
Quality StandardFunctionAmountComponent
Table 5.3 Formulation Description
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DP Process and Unit Ops
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LowLowLowLowHCP
LowLowLowLowGalactosylation(%G1 + %G2)
LowLowLowLowFucose content
HighHighHighHighVisible particles
HighHighHighHighSub-visible particles
HighHighHighHighAggregate
Filling and stoppering
Sterile FiltrationCompoundingFormulation Composition
CQAsVariables and Unit Operations
Initial Risk Assessment connecting Formulation and Unit Ops
Assess Risk for Unit Op to have an impact on selected CQAs
Table 5.4 Initial Risk Assessment for Formulation and Unit Operations
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Risk Assessment: Formulation Composition and CQAs
Risk Assessment tool: Cause and Effect (C&E) Matrix
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Formulation Identification Strategy
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Formulation Verification
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Formulation Design SpaceFT Cycling and storage stab studies for DSDoE on composition including stability studies
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Compounding Unit Op
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Initial Risk Assessment Compounding Unit Op: C&E Matrix
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Mixing-Model guided Scale-Up for Dilution Tank
Model based on “similar mechanical stress” experienced by protein at all scales
Verification at scale
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Scaling Model based on Dimensional Analysis
Mixing power per unit volume (P/V) is calculated using vessel dimensions and fluid properties. The P/V constant is used for scaling across tank sizes to deliver equivalent mixing time, product stress and mixing characteristics
Scale-up for vessels of same configuration and scale-down for vessels of different configuration; does not address facility-dependent differences
Scale-down coefficient of less than 10 is applied to design a model used to generate data for power input, rotational speeds and examine stress on the product
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Confirmation of Hold-Times BDS, DP
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Compounding: Design Space and Control Strategy
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Final Risk Assessment; Compounding Unit Op
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Filtration Unit Op
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Initial Risk Assessment: Filtration Unit Op: C&E Matrix
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Establishment of Process Platform
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Filtration Process Platform
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Verification of Platform Process
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Filtration: Design Space and Control Strategy
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Initial Risk Assessment: Filling Unit Op (on Aggregation)
2: No (detectable) impact; 4 Minor (acceptable) impact; 8 Major (unacceptable) impact
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Recommended Process Characterization Studies
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Knowledge Space from Filling DOE Study
Size of green bubble is proportional to Aggregation
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Site-Specific FMEA
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Overall Drug Product Process Control Strategy
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Summary of DP Section• DP Section describes the formulation design,
compounding, filtering and filling steps, focusing on a limited set of critical quality attributes.
• The extensive prior knowledge of formulation and manufacturing processes for Mabs is such that it is possible to consider the product and its process to be essentially a platform process.
• Through risk assessments and targeted experimentation, it is shown that design space and proven acceptable ranges developed for other products can be re-used..
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Other Comments
• Variety of tools for Risk Assessment have been described– A Fault-tree analysis is also included for a
comprehensive risk assessment of potential failure points (not covered here)
• Rational approach to control strategy– Focus on control of CPPs
• Key is the Multivariate experimentation approach
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Expected Value of QbD Exercise
General• Increased product and process knowledge• Improved product quality and consistency• Faster and smoother development and
licensureSpecific (DP)• Easier site transfers and scale changes
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AcknowledgementsJoseph Phillips (Amgen)Michael Siedler, Hans-Jeurgen Krause (Abbott)Sherry Martin-Moe, Chung Hsu (Genentech)Joseph Rinella, Doug Nesta (GSK)Carol Kirchhoff (Pfizer)John Berridge, Ken Seamon, Sam Venugopal
and rest of CMC BWG. Also the team behind the representatives in the respective
companies
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Thank you
Satish K. [email protected]+1-636-247-9979