chris potter

8/9/2019 Chris Potter

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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


Air flow

Inlettem

perature



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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%





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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%




Test batches (see text)

ICH registration stability batches

%H2O

2.0%1.5%

18.5%

Drying time

17.5%




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

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