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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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 3
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 5
Supporting partners:
Scientific partners: Industrial partners:
Partner Structure
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 6
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 7
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 8
Key Success Factors and Gaps for Advanced Manufacturing
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 9
Fields of Research
PAT / Release
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 10
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 13
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.
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 14
Fields of Research
Control Strategies / RTD
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 15
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 16
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 17
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 18
Materials Behavior Extensive Characterization via
advanced analytical tools:
Powder rheology (ffc, etc.)
Surface energetics
Micro-meritics
Thermo-chemical properties
Materials Characterization
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 19
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 20
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 21
Fields of Research
Process Economics
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 22
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 23
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
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ana
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stu
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uipm
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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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 24
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 25
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
22.6.2016 Recent Advances in Secondary Manufacturing of Solid Dosage Forms Slide 27
Thank you for
your attention!
Prof. Dr. Johannes G. Khinast Director – Science e-mail: khinast@tugraz.at
phone: +43/316/873/30400
Dr. Thomas K. Klein Director – Business e-mail: thomas.klein@rcpe.at phone: +43/316/873/30900
Massimo Bresciani Director Scientific Operations e-mail: massimo.bresciani@rcpe.at
phone: +43/316/873/30915
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