Continuous 
manufacturing of solid dosage forms

Test bed lead:      Marianthi Ierapetritou, Rutgers   

TESTBED 1

Test Bed 1 - Direct Compaction setup in Rutgers University with participants

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Glatt Continuous Fluid Bed Dryer at Rutgers

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Three-level direct compaction line at Rutgers

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Test Bed 1 - Direct Compaction setup in Rutgers University with participants

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Testbed 1 Participants
(Past and Present)
Faculty
Members
Muzzio, Reklaitis, Romañach, Davé, Litster, Cuitiño, Bilgili, Wassgren, Velázquez, Nagy, Ramachandran, Glasser, Ramachandran, Venkatasubramanian, Pinal, Liu, Singh, Callegari, Scicolone
Post-doctoral Associates
Jayjock, Dubey, Zhang, Ghoroi, Giridhar, Muliadi, Joglekar, El-Hagrasy, Kalbag, Quiñones, Koynov, Mendez, Mujumadar, Pingali
Graduate
Students
Oka, Escotet, Engisch, Austin, Gupta, Louvier, Osorio, Gurumurthy, Ropero, Boukouvala, Obregon, Jerez Rozo, Zarate, Cebeci, Román, Colón, Kumar, Ming, Sahay, Patterso`n, Sayin, Rogers, Pawar, Koynov, Gao, Vanarase, Li, Beach, Han, Vasilenko, Vanarase, Sánchez, Karry, Hernández
Undergraduate
Students
Ban, Woody, Skiles, Liang, Patel, Acevedo, Vélez, 
Industrial
Mentors
Lodaya, Sienkiewicz, Almaya, Leavesley, Kiang, Kremer, Gopinathan, Kientzler, Forness, Brown, Shi, Givand, Seyer, Anderson, Zheng, am Ende, 
Summary

Test bed 1, Continuous manufacturing of solids dosage forms, facilitates the transition from open loop batch processes to continuous processing operating in a state of robust and automated closed loop control. The test bed is focused on the simultaneous development of formulations, continuous manufacturing processes, and analytical and control methodologies for solid oral products (tablets and capsules). The current focus is on using predictive models to understand and control the effects of material properties and process parameters on product quality and process performance. 

The objective of the automated continuous operation is to demonstrate the capability to effectively mitigate the three most common problems affecting the quality of finished products made by batch processing, namely, segregation, agglomeration, and compact quality, while simultaneously improving process controllability and robustness. 

Goals

The major goals of test bed 1 are: 

  1. Development and integration of technologies for effective continuous manufacturing of solids oral dosage forms

  2. Development, integration, and optimization of models for efficient in-silico process simulation

  3. Implementation of effective in-line sensing strategies for optimal process control

  4. In partnership with C-SOPS member companies, the support of commercialization efforts to make continuous manufacturing technologies available to the pharmaceutical industry 

Recent efforts have focused on the implementation of a variety of PAT tools to design closed loop control strategies for integrated direct compaction, wet-granulation and dry-granulation lines.
 

Key Accomplishments

Some of the key accomplishments of this test bed are: 

 

  • Built and demonstrated efficient operation of one of the first continuous direct compaction lines in the world

  • Enabled integrated closed loop control of the continuous direct compaction line

  • Developed a QbD approach for the simultaneous development and optimization of formulation and process variables

  • Created the first integrated dynamic flow-sheet model of continuous manufacturing lines in all major three modes of operation (DC, WG, DG)

  • Demonstrated that size segregation can be arrested in continuous manufacturing 

  • Demonstrated the capability to predict dissolution of tablets manufactured by direct compression based entirely on measurements of tablet density and their NIR spectra

  • Implemented and validated algorithms for dynamic real time optimization of continuous line operation, and integrated it with the model-based control architecture

  • Created a methodology for sensitivity analysis and risk assessment based on flow-sheet modeling that enables companies to make science-based decisions regarding process risk factors

  • Identified and begun to populate databases of key material properties relevant to continuous manufacturing.

  • Demonstrated the ability to monitor powder density using NIR sensors

  • Demonstrated the ability to design a process control system for tablet manufacturing via wet granulation using process flow-sheet models

  • Implemented and demonstrated the Residence Time Distribution framework for supporting materials traceability and product diversion decisions 

  • Developed a combined feed-forward/feedback control system for the direct compaction tablet manufacturing process.

  • Created a model using population balances to simulate and control the twin screw wet granulation processes. 

  • Established relationships between material properties and segregation indices in blending performance and within intermediate blends

  • Design space identification methodologies have been developed using feasibility and flexibility analysis techniques. 

Impact
  • Helped enable implementation of continuous manufacturing systems across the pharmaceutical industry

  • Currently supporting adoption of continuous manufacturing methodologies by contract manufacturers, thus enabling access to continuous manufacturing methods to a wide range of industries

  • Demonstrated feasibility and developed methodologies and tools being put into use by industrial first adopters and regulators of continuously manufactured solid dosages. 

  • Partnerships with member companies to translate test bed developments directly into commercial activity through process/product development projects.

Future Plans

The scope of the test bed over the next few years is to standardize the existing platforms to broaden the spectrum of products that can be manufactured continuously, and to facilitate adoption and regulatory approval of continuous processes. For that we envision three parallel and complementary thrusts that will be implemented: 

 

  • Expansion of the current direct compaction line to include two additional pathways for the production of tableted pharmaceutical: dry and wet granulation (HS, FB, TSG). 

  • Integration of models, PAT tools, and unit operation controls in the flow-sheet modeling that allows open loop product performance predictions and closed loop control design. 

  • Identification of a set of materials able to mimic physical properties of a vast range of known APIs, to be used as placebos from the manufacture process point of view.  

  • Understand how critical process parameters and critical material attributes effect intermediate blends and final products.