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NIPTE-FDA Collaborative Case Study On Model-based Design Space Development Across Scales & with Stability Considerations. Preliminary Design Space. Define Target Product Profile (TPP). Derive Quality Attributes from TPP. Propose Manufacturing Process. Risk Analysis ( FMEA ).

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preliminary design space

NIPTE-FDA Collaborative Case Study

On Model-based Design Space Development Across Scales & with Stability Considerations

Preliminary Design Space

qbd process

Define Target Product Profile (TPP)

Derive Quality Attributes from TPP

Propose Manufacturing Process

RiskAnalysis (FMEA)

Risk Evaluation (Risk-based Classification)

Propose Parameters to Investigate (e.g., by DOE)

PROCESS DESIGN SPACE

QbD process
design space definition
Design Space Definition
  • For each unit op establish functional relationships of CPP and CQA of input materials with CQA of output materials
    • e.g. disintegration time ~ compression force and hydrophobicity
  • Establish interactions between unit ops
    • e.g. hardness ~ PSD and compression force
  • Establish design space boundaries by propagating backwards limits imposed on final product CQAs
design space definition1
Design Space Definition

courtesy: Dr. Steef. Boerrighter, Purdue University

preliminary design space1
Preliminary Design Space
  • Considered
    • Degradation
      • NMT 0.4 mole % lactam
    • Hardness
      • NLT 3 kP
    • Weight variation
      • 90 % - 110%
      • % RSD NMT 6%
  • DS definition for 15 CPPs
  • Interactions were established for some CPPs
    • one or more slides included to describe those interactions
  • There were no significant interactions for few CPPs
    • ranges for those are shown in slide 18
tablet hardness intermediate cqa
Tablet Hardness ~ Intermediate CQA

Compression Force

Median PS

Median PS

Bulk density 0.46 kg/m3

  • Bulk density 0.52 kg/m3
tablet hardness intermediate cqa1
Tablet Hardness ~ Intermediate CQA
  • PAT application:
  • Real time measurement of bulk density and particle size
tablet hardness tabletting cpp
Tablet Hardness ~ Tabletting CPP

Min Punch Gap

Comp. Height

Comp. Height

Press speed 21120 tab/hr

  • Press speed 63360 tab/hr
blending
Blending

Significant increase in STS at extreme conditions

12

tablet hardness drying cpp
Tablet Hardness ~ Drying CPP

EEF

Comp. Force

End Moisture Target = 0.5%

End Moisture Target = 1%

Comp. Force

l 0 d 0 drying cpp
L0, D0 ~ Drying CPP

L0, in-process lactam

D0, crystal damage

X – Wet Massing Time

Y – Water Content

tablet hardness granulation cpp
Tablet Hardness ~ Granulation CPP

Water Content

Comp. Force

Comp. Force

WMT=0s

WMT=60s

preliminary design space2
Preliminary Design Space
  • Granulation
    • Impeller speed
      • 500 RPM
      • Fr 1.20
        • Critical Fr determined for 4 L Gral at 250 RPM = 0.30
  • Drying
    • End Product Target Temperature
      • 25°C – 30°C
  • Blending
    • 15 – 25 RPM
    • 60% – 80% fill ratio
    • # of rotations: 42-125
summary
Summary
  • Risk Assessment helps to identify CPP
  • Preliminary Design Space is defined by backward propagation
  • Some PPs identified by RA are not critical in the explored experimental domain
  • Preliminary Design Space is constructed for:
    • Wet granulation
    • Fluidized bed drying
    • Blending
    • Tabletting
  • Some interactions between unit ops were considered
    • Tabletting and intermediate CQA
    • Fluidized bed drying and tabletting
    • Wet granulation and tabletting