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8/9/2019 Chris Potter
1/27
Design Space and Regulatory
Flexibility A Way Forward
EFPIA Team producingEFPIA Team producingMock P2 DocumentMock P2 Document
AZ (Chairman)Boehringer-IngelheimPfizerNovartis
Sanofi-AventisAZGSKRoche
Pfizer
Chris PotterRafael BeerbohmAlastair CoupeFritz Erni
Gerd FischerStaffan FolestadGordon MuirheadStephan Roenninger
Alistair Swanson
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Use of Design Space(A simple example)
Supports Continuous improvement
Change without prior approval
Scale, site, packaging Making process validation redundant
Moving to Real Time Quality Control
(reduce/remove end product testing) Reduction of confirmatory stability studies
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Concepts Included
Use of models and algorithms
Use of in-line and at-line tools
Design Space based on prediction
Design Space not requiring edge of failure
Link of Control Strategy to Design Space (Q8) Use of Q9 principles of Quality Risk
Management
Not all information may be available at time of
initial filing.
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Pharmaceutical Development ApproachTarget Product Profile
Drug substance properties; prior knowledge
Proposed formulation and manufacturing process(Risk Identification)
Cause and effect process(Risk Analysis)
Risk-based classification(Risk Evaluation)
Proposed Parameters to investigate (e.g. by DOE)(Risk Reduction)
FORMULATIONFORMULATION
DESIGN SPACEDESIGN SPACE
PROCESS DESIGNPROCESS DESIGN
SPACE BY UNITSPACE BY UNITOPERATIONOPERATION
CONTROL STRATEGYCONTROL STRATEGY(Risk Reduction)
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Pharmaceutical Development
The example
Immediate release tablet 20mg active, highly soluble, highly permeable
drug (BCS Class I)
Drug properties Low bulk density, crystalline, single stable
polymorph
Primary amine salt
Some susceptibility to aqueous degradation
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Target Product Profile
Description Round normal convex uncoated tablet
Identification Positive
Assay 20 mg 5% active at time of manufacture
Degradation products Qualified meeting ICH Q3B and Q6A criteriaDissolution Immediate release
Uniformity of dosage units Meets pharmacopoeial acceptance criteria
Microbiological limits Meets pharmacopoeial acceptance criteria
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Proposed Formulation and
Manufacturing ProcessKey Formulation Design Decisions
High bulk densityDirect Compression
Wet Granulation
Primary amineLactose
Mannitol
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Unit Operations
Dispensing
Blending
Fluidized BedDryer
Packaging
Tableting
Granulation
Air
Scale
Proposed Manufacturing Process
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Cause and Effect Process
WaterContent
Drying
Granulation
RawMaterials
Compressing
PlantFactors
Operator
Temp/RH
Precompressing
Main Compressing
Feeder Speed
Press Speed
Punch Penetration
Depth
Temp
RH
Air Flow
Shock Cycle
Drug
Substance
P.S.Process Conditions
LOD
Diluents
P.S.LOD
Other
Lubricant
Disintegrant
Binder
Water
Binder
Temp
Spray Rate
Spray Pattern
P.S.
Scrape Down
Chopper Speed
Mixer Speed
Endpoint
PowerTime
Age
Tooling
Operator
Training
Analytical
Method
Sampling
Feed
Frame
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Initial Classification of Importance of Unit
Operation to Have an Impact on Quality Write down, what you know already
Unit operation
Qualit
yAttributes
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Example of FormulationDevelopment DOE (3.2.P.2.2.1)
Previous knowledge
Potential Formulation
DOE
Dependent VariablesIndependent Variables
Levels of excipients
DissolutionHardnessAppearanceDegradation rate
Dose uniformity
Disintegration
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Magnesium Stearate
Design Space 1-3%Compression Force (kN) vs Crushing Strength (Kp)
Effect of Lubricant Level
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
0 5 10 15 20 25 30 35
Compression Force (kN)
CrushingStrength(Kp)
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Dissolution Profiles made withDifferent Lubricant Levels
0
20
40
60
80
100
120
0 5 10 15 20 25 30 45
Time (minutes)
Mean%di
ssolution
1% Mg St
2% Mg St
3% Mg St
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Magnesium StearateDesign Space
One dimension univariate range No edge of failure
Maybe not useful in this case as a formulation
variable Does help conclude a robust formulation
Risk of failure of dissolution, disintegration,hardness at blending step significantlyreduced
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Key Process Variables for WetGranulation
Dependent variables for tablets
Wet granulation parameters Input material attributes
Mixing speed API particle sizeWater addition rate Mannitol particle sizeMixing time
Appearance
Assay
Degradation
Dissolution/Disintegration
Uniformity of Dosage Units
+ Suitability parameters for next processing step
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Relative Importance of Process Parameters on
Disintegration from Coefficient Plot from Partial
Least Squares (PLS) Model
-3
-2
-1
0
1
2
3
4
Drug Substance Mannitol PS Mixing Speed Water Amount Wet Mixing Time Compression Force
Series1
DoE Coefficients for Disintegration
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Effect of Water Addition Rate and Mixer Speed onDisintegration (red does not meet quality requirements)
Disintegration
Mixer speed
W
ateradditionrate
Disintegration
Faster
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Wet granule Dry granule
Water contentParticle size
Water contentAPI Size distribution
Outlet RH
Outlet Temp
Bed TempAir flowInlet Temp
NIR FBRMgranule sizedistribution
water content
Fluid Bed Drier
colour code: Red - input variables; Green - derived parameters; Blue - on-line measurements
controlled bygranulation operation
Examplain: Drying Operation
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Process Variables and Quality Attributes for the
Fluid Bed Drying Operation
Process variables
Drying parameters Input material attributesInlet air temperature Water content
Inlet air humidity Granule particle size distribution
Air flow rateFill level
Filter sock cycleHeating rate
Cooling rate
Quality attributes
Dried granule Tablet
Particle size distribution (fines) Disintegration
Water content Dissolution
Degradation (des-ethylexamplain)
Weight uniformity
Content uniformity
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Effect of inlet temperature and air flow on degradation andgeneration of fines, as shown by the DOE (red = does notmeet quality requirements) (1 kg scale)
Air flow
Inlettem
perature
Fines
Air flow
Inlettem
perature
Degradation
Air flow
Inlettem
perature
Fines
Air flow
Inlettem
perature
Fines
Air flow
Inlettem
perature
Degradation
Air flow
Inlettem
perature
Degradation
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Interaction of Inlet Temperature and AirFlow for Combination of Failure Modes
(Red = Does Not Meet QualityRequirements)
Air flow
Inlettem
perature
Degradation and fines
Air flow
Inlettem
perature
Degradation and fines
Air flow
Inlettem
perature
Degradation and fines
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Examplain Design Space
Graphical Description(1 kg Scale)
Known edge of failure due to fines
%
H2O
2.0%1.5%
18.5%
Drying time
Known edge of failure due to degradation
Regions of uncertainty17.5%
Trajectories describing the
boundaries of the design space
where product quality is assured
Known edge of failure due to fines
%
H2O
2.0%1.5%
18.5%
Drying time
Known edge of failure due to degradation
Regions of uncertainty17.5%
Trajectories describing the
boundaries of the design space
where product quality is assured
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Process Trajectories for 5 Batches
Manufactured at 25 Kg Scale
%H2O
2.0%1.5%
18.5%
Drying time
17.5%
Trajectories describing the
boundaries of the design space
where product quality is assured
Test batches (see text)
ICH registration stability batches
%H2O
2.0%1.5%
18.5%
Drying time
17.5%
Trajectories describing the
boundaries of the design space
where product quality is assured
Test batches (see text)
ICH registration stability batches
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Summary: Design Space for FluidBed Drying
Multivariate for degradation, disintegration,uniformity of content Inlet temperature
Air flow
Drying time
Trajectory for water content, a criticalparameter
Change of scale understood
Areas of failure found in this case
Clear control strategy
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Use of Design Space for Fluid Bed Drying
Manufacturing changes
Change of fluidised bed dryer
Allows change of packaging within pre-defined criteria
Introduce real time release, linked to riskmanagement tools and based onProcess Understanding
Quality parameter output assured
Process controlled and monitored (advanced processcontrol strategy)
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Use of Design Space for Fluid Bed Drying
Process validation is redundant
Process reproducibly produces materialfor blending and compression
Change of site and scale
Scale factored into design space Site independent
D i i f D i S
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Determination of Design Space
Conclusions Requires experimentation or prior knowledge
But not necessarily formalised designs such as
factorials Can be a very simple or more complex concept
May require multi-factorial approaches using PAT
tools Could (will) be multidimensional
Per definition, quality attributes of the finished
product are achieved when operating within theDesign Space
As a consequence, any process modification withindesign space should be acceptable without anyfurther regulatory approval