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K1 Competence Center - Initiated by the Federal Ministry of Transport, Innovation and Technology (BMVIT)

and the Federal Ministry of Science, Research and Economy (BMWFW).

Funded by the Austrian Research Promotion Agency (FFG), Land Steiermark and the Styrian Business

Promotion Agency (SFG).

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Recent Advances in Secondary Manufacturing of Solid Dosage Forms

evon up2date, 22.6.2016

RCPE – Key Facts

Research Center Pharmaceutical Engineering GmbH – RCPE

Independent Research Center for pharmaceutical process and product development

Located in Graz, Austria

100% owned by research institutions

Our objectives:

Develop Innovative science driven platform knowledge for process and product design & development

Increase the sustainability profile reducing costs and time in pharmaceutical development (e.g. enlarge the knowledge space)

Create business advantages for our partners

22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 2

Joanneum Research:

15%

Graz University of Technology:

65%

University of Graz:

20%

RCPE – Mission

Combine multi-disciplinary competence

to develop a coherent scientific basis for a predictive understanding of

process and product development fundamentals

Close interaction with national and international partners

to develop methods for designing, optimizing, scaling and controlling

the manufacturing of next-generation products

Targeted educational, gender and HR development activities

to implement science-based approaches for design and optimization

products, while protecting the IP generated in the Center


A Success Story…

RCPE was founded on 1st of July 2008

> 100 employees and researchers

Turnover 2014/2015: € 8.5 M

> 30 Scientific Partners, > 100 Industrial Partners

Scientific Output:

7 Licences granted

5 Patents granted, 27 Patent applications

276 Conference talks refereed

195 Papers refereed

10 Bachelor, 100 Diploma/Master, 30 PhD Theses

Recent Advances in Secondary Manufacturing of Solid Dosage Forms 22.6.2016 Slide 4

Office building with state-of-the-art laboratory facilities (as per 01st of March 2016)

Area I

Modeling and Prediction

Pharmaceutical process modeling & simulation

Granular flows

Fluid mixing and multiphase flows

Molecular simulations and structure optimization

Material Science & Characterization

QbD/PAT

RCPE – Scientific Area

Innovation for our partners

Area II

Advanced Products and Delivery

Pharmaceutical proteins

Protein drugs

Oral & Inhaled Dosage form

Nano technology

Novel drug delivery systems

Simplification on ODFs

Area III

Process and Manufacturing Science

Continuous processing development and implementation

Process Understanding & Control (including PAT)

Process development & Scale up

Design Space and CPPs qualification


Supporting partners:

Scientific partners: Industrial partners:

Partner Structure


Advanced Pharmaceutical Manufacturing in a Broader Context

Continuous manufacturing is one flavor of advanced pharmaceutical manufacturing

End-to-end CM will be rarely found

Partial solutions will dominate: mix and match

Lessons learned from CM will also impact other process architectures, i.e., advanced batch manufacturing and individualized (stratified) manufacturing

Advanced pharmaceutical manufacturing (AMP) definition:

PAT-enabled

Closed-loop controlled

Model-based design

Science-based optimization and scale-up available

Robust for a broad range of material properties

Defined material properties


RCPE’s Vision Continuous Manufacturing

Designing and developing manufacturing strategies capable of delivering the product that meets patient needs

by an interdisciplinary team of process-, pharmaceutical- and chemical engineers

by multidisciplinary, unique approaches

Developing agile, flexible and economically efficient processes

by a close collaboration with industrial and scientific partners

by learning from existing industries (e.g., food)

by exchange and interaction with existing networks (CMAC, C-SOPS)

Translating continuous manufacturing from research to production

through RCPE’s Continuous Manufacturing Consortium

by working on real-world use cases

Focused research on the gaps defined


Key Success Factors and Gaps for Advanced Manufacturing


Fields of Research

PAT / Release


Parametric release (PR) Release based on information collected during the

manufacturing process and on the compliance with specific

GMP requirements

Real Time Release Testing (RTRT) Is the ability to evaluate and ensure the quality of in - process

and /or final product based on process data (ICH Q8 (R2))

Based on PAT

Research Focus Development of innovative PAT systems (e.g., OCT, CI)

Online and inline monitoring of critical quality, material and

manufacturing attributes

Development of surrogate models for not direct measurable

QA’s (soft sensors)

Image size: 5 x 0.6 mm²

Surface defect

Image size: 5 x 5 x 1.6 mm³

Online OCT system

02.02.2016 CM at RCPE

Online Coating Thickness & Variability by Optical Coherence Tomography

Slide 11 22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms

In-line Monitoring of Tablet Coating Processes

22.6.2016 Slide 12 Recent Advances in Secondary Manufacturing of Solid Dosage Forms

In-line OCT

Two-dimensional (2-D) cross-section images

In-line characterization of coated particle in real-

time:

Mean coating thickness of a single particle

Inter-particle coating variability

Intra-particle coating variability

Coating thickness of film-coated tablets

Fields of Research

Process Integration


Process Integration Many unit operations (e.g., roller compaction, tablet

compression) are continuous

Some are not (e.g., fluid-bed drying, coating)

Integration of these unit operations into a single line by

incorporating existing powder handling technologies, monitoring

systems and comprehensive data management is required

Research Focus Definition of interfaces and buffers

Integration of material transport systems between the unit

Integration of PAT tools

Data collection and management

Approach for Process Integration Data Collection and Management

Data acquisition and process control

system are essential for a continuous

manufacturing line.

Each process (e.g., feeder, extrusion)

is equipped with univariate (e.g.,

temperature) and multivariate (e.g.,

spectrometers) sensors and actuators

from different manufacturers.

Significant activities and events must

be traceable.


Fields of Research

Control Strategies / RTD


CM Control Strategies Development of closed loop systems based on models of the

respective unit operations and interfaces

Understanding of the cumulative RTD of unit operations

Research Focus Control architectures (MPC, etc.)

Development of process models

shifting from empirical control to model-based approaches

RTDs from models of unit operations

Development of hierarchical plant wide control strategies

supported by flow sheet simulation (gSolids) and sensitivity

analysis tools

Example for RDT Modeling: Extruder


start max. tracer

hot melt extrusion Tracer

Camera

Strands

RGB (or LAB) color values

RTmax MRT(=50% of area)

0.1*peak

RTstart

peak

0.5*peak

RTraise

RTFWHM

Fields of Research

Formulation Development


Formulation design Utilization of physicochemical, material science and

biopharmceutics principles towards the development of

immediate/modified release solid oral formulations intended

for APIs with challenging pharmaceutical portfolios

Research Focus Enabling APM platforms for bio-enhancement of poorly

soluble APIs (amorphous, nanocrystals, co-crystals) Spray drying

HME

Taste-masking

Oral inhalation drug products (DPIs)

Modified release products

Formulation approaches to meet the challenges to continuous

process lines

Fields of Research

Materials Behavior


Materials Behavior Extensive Characterization via

advanced analytical tools:

Powder rheology (ffc, etc.)

Surface energetics

Micro-meritics

Thermo-chemical properties

Materials Characterization


Solid-state

DSC, TGA

PXRD, SAXS

GVS

PLM

FTIR, Raman

Force, energy

Tensile strength

Cohesion-adhesion

Contact angle, IGC

Charge

Friction behaviour

Micromeritics

(density, pores, size, shape) Laser diffraction

Specific surface area (BET)

MIPS, He-pycnometry

Tapped /bulk density

Microscopy

Surface (rugosity,

topography, composition) SEM, TEM

AFM

TOF-SIMS

XPS, EDX

Dispersion, aerodynamics

Next Generation Impactor (NGI)

LD-pressure titration

Quantitative analysis

HPLC/UPLC-MS

UV-Vis

Residual moisture (KF), etc

Powder rheology

Shear stress

Angle of repose

Compressibility

Flow and Cohesion (BFE,

Aeration, FFC)

Segregation

Material attributes

Fields of Research

Particle Design / Engineering


Particle Design Applying integrated engineering approaches to build the

desired characteristics in API and excipients, for enhanced

BA properties and manufacturability

Research Focus Engineering of API, carrier and tertiary agents for improved

lung deposition

Multiple particle engineering platforms including spray drying,

coating, fluidization, micronization, etc.

Co-processed API/excipient particles to induce improved

feeding (flow), processability (e.g., direct compressibility) for

continuous processing

Particle Engineering at RCPE


Fields of Research

Process Economics


Process Economics Especially, when replacing a batch by a CM process,

the economic benefit of the high investment has to be

proven.

The main economic benefits of CM are caused e.g. by

shorter processing times, more flexible manufacturing

processes and less end product testing.

Research Focus Evaluation of process chains in early stage

development

Comparing of process options by techno economic

profiling

Evaluation of the replacement of a batch vs. a

continuous line

Approach for Techno Economic Profiling


Step 6: Interpretation of results1

Step 5: Computation of weighted and total process scores1

Step 3: Definition of weighting factors1

Step 4: Evaluation of investigated manufacturing process options2

Step 2: Definition of quantitative and/or qualitative ranking criteria1

Step 1: Definition of ranking criteria and risk profile elements1

1Done once per comparative process evaluation 2Done once per investigated process option

Detailed evaluation with selected options required?

Result: Process options evaluated and ranked. Most favorable option identified.

Start: Need to evaluate and rank different manufacturing process options

Yes

No

Labo

rato

ry-s

cale

ana

lysi

s, fe

asib

ility

stu

dies

, te

st ru

ns w

ith p

ilot-

scal

e eq

uipm

ent

etc.

Economic Evaluation of Process Chains

Figure: Methodology for evaluating process chains in early stage development.

Figure : Techno economic profiling of process alternatives

1

Wetgranulation FBG Reference

Figure : Final ranked process alternatives

1.

2.

3.

Fields of Research

Process Automation


Process Automation The centerpiece of the control system is the controller

structure that initiates the corrective actions based on the

provided measurement information.

(PI(D)) control systems are currently state of the art, showing

often insufficient performance.

Use of advanced process control structures, such as MPC,

is often recommended.

Research Focus Development of MPC control structures

Enabling real time optimization

Development of dynamic process models for process control

Design and implementation of controllers

Approach for Process Automation


NIR

Model Equation for Impulse Response

Controller

Adjust rpm

Controller Design Based on Dynamic Process Models

In gSolids implemented

dynamic process model

Monitored quality attribute

Controller design in Matlab

Control action - changed set point of process parameter

Process Control Model Predictive Control (MPC) for a Feeding Blending Unit

Recent Advances in Secondary Manufacturing of Solid Dosage Forms 22.6.2016 Slide 26

Actuating signals are computed by solving an optimization problem

Constraints (e.g. minimum/maximum mass hold-up) are considered

Multi-input, multi-output systems can be handled straightforward

Setup:

Block diagram:

Idea of MPC:

Mathematical plant

model, e.g.:

- first principles model

- data driven model

RCPE Contacts


Thank you for

your attention!

Prof. Dr. Johannes G. Khinast Director – Science e-mail: [email protected]

phone: +43/316/873/30400

Dr. Thomas K. Klein Director – Business e-mail: [email protected] phone: +43/316/873/30900

Massimo Bresciani Director Scientific Operations e-mail: [email protected]

phone: +43/316/873/30915

mailto:[email protected]



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