Design & Scale-up of Material Structuing Ops

Thrust lead:        James D. Litster, Purdue University
# of faculty:         17
Disciplines:        Chemistry, Chemical Engineering,
                                Food Science, Mechanical
                                Engineering, Pharmacy

THRUST B

Simulation and validation using lactose and glass beads at 70 RPM.

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Averaged solid fraction and velocity vectors in a drum granulator

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The optimal formulation of stabilizers that provides improved suspension stability also results in faster and higher extent of dissolution than a poorly stabilized suspension, or the unprocessed/pure drug.

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Simulation and validation using lactose and glass beads at 70 RPM.

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Current Thrust B projects
B4
Optimization & Design Modeling for Continuous Roll Compaction Granulation
B7
Continuous Wet Granulation
Summary

The unit operations by which we manufacture solids dosage forms (material structuring operations) are difficult to model and scale because the structure of the products is complex, and the geometry and powder flows in the equipment is complex. As a result, our quantitative understanding of how the micro-structure of complex multi-phase delivery forms develop during processing is still lacking.  There remains an absence of quantitative scaling rules between single particle and macroscopic properties and process design models that track multidimensional distributions of properties are still rare.  For this reason, current equipment designs are based on heuristics rather than in depth process understanding.  To address these issues, we are taking a multi-scale approach to process modeling, incorporating key fundamental physics and using multidimensional population balance framework for tracking particle property distributions.  The design models so produced are a key deliverable from the thrust. 


Thrust B takes as its input starting materials particles designed, produced and characterized through Thrust A. Much of the research in Thrust B is to develop design models that predict the properties distributions and structure of the solid dosage forms and intermediates given the primary particle characterization (from Thrust A) and process stress and velocity fields (Thrust B).  The structure of the solids dosage form provides the link to Thrust C.  We use the characterization methods developed in Thrust C to validate our process models.  Conversely, the structures developed in the Thrust B processes are the starting point for the structure-function product models that are the core of Thrust C research.  Thrust B links to Thrust D through (a) implementing and testing the on-line measurement approaches, and (b) providing rigorous models that are the starting point for developing reduced order model for flow-sheeting, control and optimization.  The Thrust B project portfolio provides strong support for the development of all test beds:  Projects B1, B2, B4 and B7 directly support Test Bed 1 including wet processing; Test Ted 2 is supported directly by Project B3; Projects B3 and B6 support Test Bed 3.

Goals

The vision for this thrust is to bring the manufacturing processes that produce controlled structure delivery forms to the point of clear, quantitative engineering design by:
  

  1. Developing new design models that predict delivery form properties as a function of process variables and formulation properties;

  2. Developing sensible scaling rules to expand the use of QbD in pharmaceutical manufacturing;

  3. Applying new techniques for on-line measurement of micro-structure and other property distributions to improve system dynamics and real time operation; and

  4. Developing new or improved process designs for continuous manufacturing.

 

The thrust scope covers both dry powder systems (feeding, blending, roll compaction, tablet compression), wet powder systems (continuous wet granulation) and melt, solution and slurry systems.  Thus the thrust is supporting all three test beds. 
 

Key Accomplishments

Some of the key accomplishments of this thrust in the last 12 months are: 

 

  • To determine the properties and behavior of powder in the tablet press feed frame and dies, (1) the feed frame was experimentally decoupled from the tablet press with a custom made die disc (no compression); and (2) DEM modeling of flow behavior and segregation within the feed frame and dies was undertaken.

  • Comprehensive characterization of the Gerick GCM-250 and Glatt GCG70 continuous convective tubular blenders has been completed including studies of the effect of material properties, impeller speed and blade configuration on performance.

  • Implementation of online PAT tools to provide real time information of process performance during continuous blending.

  • Demonstrated the feasibility of fabricating polymer films, loaded with poorly water soluble drugs, using API nano/micro-suspensions or dry powders: (1) 30-200 micron thick films using nano/micro API suspensions (WSMM or LASP) or dry API microparticles (FEM); (2) Superdisintegrants incorporated to enhance precursor viscosity, content uniformity, and dissolution rate; (3) Surfactant-free films containing stable API nanoparticles; (4) Redispersibility and immediate release for multiple APIs; (5) Fast/Immediate or controlled/sustained release (formulation, film thickness) of several BCS Class II drugs irrespective of the manner of drug particle manufacture; (5) Robust performance irrespective of which particle/suspension form employed, mixing methodology, and drying mode.

  • Solid plug model predictions of the powder stress at the outlet of the roll compactor feed screw have been compared to experimental measurements.  It has been demonstrated both experimentally and using the solid plug models that there is a linear relationship between feed screw torque and feed screw outlet stress (which is equal to the roll compactor inlet stress).  This relationship may be used to improve roll compaction control schemes.

  • Development of a proposed multi-scale modeling framework for roll compactor ribbon milling was completed, which couples population balance modeling techniques with discrete element methods to create a more mechanistic and predictive model. 

  • Optimization of flow profile for drop on demand in project B3 using a priming phase to maximize drop size and minimize probability of satellite drops.  The flow profile was first predicted numerically and then validated experimentally on test bed 3.

  • Built a framework for bi-directional coupling of DEM and PBM for twin screw granulation modeling to capture mechanistic and spatial behavior and performed proof of-concept simulations of coupled model.  Mechanistic rate behavior and multidimensional powder properties has been incorporated in the coupled PBM-DEM framework.

  • Completed experimental studies using the extended screw elements for the TSG and completed characterization of Glatt GCG 70 continuous granulator.

Impact
  • In the time span of the C-SOPS, continuous drug product manufacturing has developed from an exciting new challenge into the route of choice for a number of the world’s largest pharmaceutical companies who are members of our Industry Advisory Board.  Through Thrust B, C-SOPS has played a key role in developing science based design and scaling procedures that give the confidence for companies and regulators to make this transition happen.

  • The C-SOPS model driven approach to designing these operations has become accepted as best practice for a QbD approach to continuous manufacturing, reflected in both industrial practice and advice from regulators. 

  • A number of companies have initiated significant associated projects that spin out from thrust B research, particularly as related to test bed 1.   The partnership with Janssens for development of their integrated continuous manufacturing capability is the outstanding example.  Other company partnerships include Vertex, GSK and Eli Lilly.

  • Thrust B has a strong publication record, combined with many invited presentations on thrust B research at national and international conferences.  Models developed on almost every thrust B project are highly regarded internationally and publications are highly cited.

Future Plans
  • Continued development of hybrid, multi-scale modeling approaches for design which links macroscopic models such as population balances and FEM simulations with particle level simulations such as DEM.

  • A greater focus on wet processing (wet granulation, fluid bed drying, etc) to complement the existing work on direct compression and dry granulation, funded in part by the new NSF AIR program.

  • Development of a raw material data base for use in both mechanistic and empirical data driven models to support flow-sheet modeling developments.

  • Development of major new international collaborations for research on dosage form manufacturing, including the new partnership with major Irish centers in Limerick (SSPC) and Queens University, Belfast.