Mechanistic Model-based Digital Design framework for individual and integrated manufacturing stepsDavid Slade (Process Systems Enterprise)

Alastair Florence (CMAC, University of Strathclyde)

ADDoPT scope – a reminder

Design and control of optimised development & manufacturing processes through data analysis and first principle models

Processes Products Patients

Quality systems

Release profiles

Materials properties

Particle attributes

Surface chemistry

FormulationProcessing rules

Manufacturing classification

Improve / optimise for impact

DownstreamUpstream

Product and Process Design

Product Performance

CrystallisationFiltrationWashingDrying

ActiveIngredient

(API)

MillingBlending

CompactionCoating

Primary Manufacturing - Secondary Manufacturing

A systems-based approach to pharmaceutics

Horizontal integration: Manufacture Product Performance (breaking down silos)

Vertical integration: Length Scales & Design Operation

gPROMS FormulatedProducts – a new PSE product enabled by ADDoPT

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Enabling platform - gPROMS

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Platform functionality

Process modelling

Equation-oriented solution power

Custom model construction

Steady-state and dynamic simulation

Powerful optimisation, including mixed-integer

Advanced parameter estimation

Global system analysis

High-performance computing

Materials modelling

Molecular & ionic species

Complex species & mixtures

Gas, liquid, solid phases

Phase & reaction equilibriumA single powerful software platform- R&D engineering design operations- Formulation manufacture product performance

Pla

tfo

rm Advanced Process Modelling platformAdvanced Materials Modelling platform

Enabling platform - gPROMS

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Platform functionality

Process modelling

Equation-oriented solution power

Custom model construction

Steady-state and dynamic simulation

Powerful optimisation, including mixed-integer

Advanced parameter estimation

Global system analysis

High-performance computing

Materials modelling

Molecular & ionic species

Complex species & mixtures

Gas, liquid, solid phases

Phase & reaction equilibriumA single powerful software platform- R&D engineering design operations- Formulation manufacture product performance

gPROMS FormulatedProductsgPROMS ProcessBuilder

Olefins

Pla

tfo

rmEn

viro

nm

ents

Lib

rari

es Power & CCS

Oilfield Refining

Wastewater Process Utilities

LiquidFormulations

Food - Dairy Food - Other

API Formulation Product performance

Advanced Process Modelling platformAdvanced Materials Modelling platform

Model libraries in gPROMS FormulatedProducts

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Properties DB

Fluid-beddrying

Centr. filter

Dry millWell-mixed crystallizer

Roller compactor

Tablet press

Conveying

Bin flow /segregation

Extension of gSAFT databank

Tablet coater

Pharmacokinetics

Multizonal (gFP:CFD) Multizonal (gFP:DEM)

Active Ingredient Manufacture

Plug flow crystallizer

Wetmill

Twinscrew

granulator

Global Sensitivity Analysis

Continuous blenders

High shearwet granulator

Spraydrying

In-vitro dissolutionand precipitation

Oral absorptionin GI tract

CSTR PFR

Agglomerator

Solid form stability

Formulation Manufacture Product Performance

On roadmapAvailable in gPROMS FormulatedProducts 1.2

Parallelisation of GSA and PE

Film coater

Data import and processing

Pressure filter

Parenteral stability

External model validation

Fluid-bed granulation

2D pop balancegranulation framework

Hot melt extruder

Lyophilization

VL & VLL Flash

Extraction

nD pop balancecrystallization framework

Jet millAFD

Distillation

Introduced with gPROMS FormulatedProducts 1.3

Membraneseparation

Heat treatment

Evaporation

Solar pondoperations

Feeder

Tracking material structure evolution across the system

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Crystallization

Reaction

Blending

Dry Granulation

Tabletting

Oral Absorption

Unit operations effect transformations of complex materials

Material description reflectsearlier processing

Properties and equipment databases

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Flexible database structure compatible with

PSE provided databases

3rd party databases

corporate databases, etc.

Materials Dosage forms Equipment Physiology

Example of models developed in ADDoPT using the latest science & workflows

Ability to model the particle size and shape evolution during crystallization processes supported by new Morphological Crystallizer and Morphological PSD sensor models

Twin screw granulation - case study with AZ establishes model validation workflows and requirements, value proposition• Perform fewer, more targeted experiments.• Determine optimal screw configuration for desired granule PSD.

Models from academia and industry implemented and applied using new framework, establishing workflows complimentary to existing or challenging current practice

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Hybrid modelling

• Combining mechanistic and data driven models

• Rationale for this approach outlined earlier today

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An interface for hybrid data-driven & mechanistic models

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PharmaMV integration

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Integration of gPROMS FormulatedProducts and PharmaMV

The Virtual Process

The Controller

Measu

red Sign

als

Man

ipu

lated Sign

als

gPROMSFORMULATED

PRODUCTS

Will be presented in more detail later today at 3.25pm by • Andy Mitchell (Perceptive) & Niall Mitchell (PSE)

Applying the gPROMS FormulatedProducts systems frameworkCMAC Digital Design example

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Applying the gPROMS FormulatedProducts systems frameworkCMAC Digital Design and Digital Operation example

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Further case studies

Talks today from

- Next: Marta Moreno-Benito, Pfizer, Solid Drug Product and Process Design using Multi-Scale Interconnected Flowsheet Modelling and Global System Analysis

- 4.05pm: Gavin Reynolds, AZ, Application of hybrid models for Advanced Process Control of a Twin Screw Wet Granulation Process

Demo booths in lobby:

- Morphological crystallizer, jet mill, integrated system

Anyone from PSE…

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Summary

A mechanistic model-based digital design framework, gPROMS FormulatedProducts, has been created for • Horizontal integration: Manufacture Product Performance (breaking down silos)• Vertical integration: Length Scales & Design Operation

Enabling the creation of a Digital Twin of both complex formulated products and their manufacturing processes

These Digital Twins can be used for virtual DoEs (design space exploration), tech transfer and as a basis for Digital Operation

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Mechanistic Model-based Digital Design framework for individual and integrated manufacturing stepsDavid Slade (Process Systems Enterprise)

Alastair Florence (CMAC, University of Strathclyde)