Dissolution Modeling for Real Time Release Testing (RTRT)Hanlin Li, Justin Prichard, Kelly A. Swinney

©2016 Vertex Pharmaceuticals Incorporated

Outline

• Introduction to continuous manufacturing and RTRT at Vertex• RTRT for dissolution – model development approach• Case Study

©2016 Vertex Pharmaceuticals Incorporated2

Early finalization of formulation/process on commercial scale

“Data rich” QbD commercial design space

High quality, consistent product

Vertex Business Drivers for Continuous Manufacturing

©2016 Vertex Pharmaceuticals Incorporated3

©2012 Vertex Pharmaceuticals Incorporated4 4 ©2012 Vertex Pharmaceuticals Incorporated .

Powder In

Day 1 AM

Day 1 AM Coated Tablets Out

Vertex’s Continuous Manufacturing Rig

Multi-product Line

• Smaller scale equipment• All unit ops in one facility

PAT Automated Control Strategy => IPCs + RTRT

Tablet Press

PFLS

W Th H

PAT5b

Waste

STEP 6, COMPRESSION

Fluid Bed Dryer

drying air in

drying air out

Granulation liquid 1

PAT4 LHP

100L

1000L 1000L 1000L HC

10L

Mill

PAT3bPAT3a LHP 10L

100L100L

10L

Deduster

MC

Bucket Lift

STEP 5, FEEDER/BLENDER 2 STEP 1, FEEDER /BLENDER 1

STEP 2, TWIN SCREW GRANULATOR

PAT1 NIR, measures material attributes during screening of raw materials

PAT2, NIR , measures composition and BU

PAT3a, NIR, measures granule uniformity, LOD, solid state form and physical attributes of granulesPAT3b, Laser Diffraction, measures particle size distribution

PAT4, NIR , measures composition and BU

PAT5a, Raman, measures assay and CUPAT5b, Weight, hardness, thickness

PAT6, Raman, measures coat thickness

STEP 7, COATING

STEP 3, FLUIDIZED BED DRYER

STEP 4, MILLING

Coating Liquid Finished Product

STEP 1, FEEDER/BLENDER 1

PAT5a

• Tablet Tester• Raman

• NIR• Laser Diffraction

• NIR

PAT Locations Available for IPC and RTRT Measurements

5

• Loss In Weight Feeders

• Dryer Thermocouple

5 ©2016 Vertex Pharmaceuticals Incorporated

CM Control Strategy Building Blocks

In-Process Controls

Design Space Monitoring

Unit Operation Control to Set Point

RTRTMaterial considered for release is manufactured within the DS (CPPs) and conforms to IPC criteria

Material is segregated from the process

IPC failure

Outside DSL

66 ©2016 Vertex Pharmaceuticals Incorporated Vertex Confidential Information

Example of RTRT for Continuous Manufacturing

7

Critical Quality Attribute PAT Technology RTRT Method Material

Identification Raman Confirm presence of API Core Tablet

AssayNIR

WeightAPI Content

Tablet WeightFinal BlendCore Tablet

DissolutionLaser Diffraction

NIRWTH

Granule Particle SizeAPI Content, Water Content

Tablet Weight, Hardness, Thickness

Milled GranulesFinal BlendCore Tablet

Water Content NIR Water Content Final Blend

Content Uniformity

NIRWeight

Variance in API ContentVariance in Tablet weight

Final BlendCore Tablet

Physical Form Raman API physical form Core Tablet

RTRT for Dissolution

8

Dissolution

Tablet Weight

Hardness

Final BlendAPI Content

Granule Particle Size

Compression Force

Thickness

Granulation SolutionPump Rate

DS Particle SizeGranulation Powder

Feed Rate

Individual components & granule powder feed rate

DSbulk density

Final Blend Water Content

Paddle speed

Drying Time

Dryer Fill time

Dryer inlet air flow rate

Mill Speed

VX-770 SDD bulkdensity

CompressionForce

Granule Water ContentBlender speed

Dryer inlet air temp

Paddle speed

Paddle speed

DS bulkdensity

• The inputs are based on knowledge of the process and factors influencing dissolution performance at the time of batch release.

©2016 Vertex Pharmaceuticals Incorporated

DS Bulk Density

Dissolution Model Development Approach

1. Determine the dissolution rate from the reference dissolution profiles

2. Model Z using measured attribute data• Core Tablet (PAT 5 - Kraemer): Hardness, Thickness, Weight• Final Blend (PAT 4 - NIR): water content, API content• Granules (PAT 3b – Malvern): particle size distribution

3. For routine use, Z is predicted and used to predict the a dissolution profile

©2011 Vertex Pharmaceuticals Incorporated9

Step 1: Determine the dissolution rate from the reference dissolution profiles

• LC: dissolution % at time t• Dose: dose• Fixed parameters

• n: shape factor • Vol: volume• S: solubility

• Parameters to be fitted:• z: rate (scale) factor• p: plateau

𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑

= 𝑧𝑧 𝑝𝑝 − 𝑑𝑑𝑑𝑑 𝑛𝑛(𝑆𝑆 −𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑉𝑉𝐷𝐷𝑉𝑉

𝑑𝑑𝑑𝑑)

©2011 Vertex Pharmaceuticals Incorporated10

Step 2: Model dissolution rate using measured attribute data

©2011 Vertex Pharmaceuticals Incorporated11

Reference Dissolution Rate

Pre

dict

ed D

isso

lutio

n R

ate

Reconstruct Dissolution Curve using Predicted Dissolution Rate

12

RTRT Dissolution Model: Case Study

13

B a tc h 1

T im e

% D

iss

olv

ed

0 2 0 4 0 6 0 8 0 1 0 0

4 0

6 0

8 0

1 0 0

Q C M e th o d

R T R T M ode l

B a tc h 2

T im e%

D

iss

olv

ed

0 2 0 4 0 6 0 8 0 1 0 0

4 0

6 0

8 0

1 0 0

Q C M e th o d

R T R T M ode l

USP <1092>: Absolute difference not more than 5% for time points > 85% released

©2016 Vertex Pharmaceuticals Incorporated

In Summary

14

Process knowledge and identified factors influencing dissolution performance used to develop RTRT dissolution method

Dissolution Rate PLS Model

Modified Noyes-Whitney Equation

RTRT Result

• Vertex Team• Pharmaceutical and Preclinical Science• Technical Operations• Supply Chain Management• Quality• CMC Regulatory• Facilities• Global Information Systems

• Equipment Manufacturers

• Our CMOs, Suppliers, and Research Collaborators

• Regulatory Agencies (FDA, EMA, MHRA, etc)

Acknowledgements

15 ©2016 Vertex Pharmaceuticals Incorporated