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Mini-Manufacturing Using Drop-On-Demand Technology
Faculty: Aldo Acevedo (UPRM), Osman Basaran (Purdue), Michael Harris (Purdue), Boris Khusid (NJIT), Gintaras Reklaitis (Purdue), Rodolfo Romanach (UPRM), Lynne Taylor (Purdue) and Paul Takhistov (Rutgers).
Postdoctoral Fellows: Pradeep Bhat, Yueyang Shen, van Eerdenbrugh
Graduate Students: Yijie Gao, Jared Baird, Qing Zhu, Sahay, Marlena Brown, Motamedvaziri, Santosh Appathurai
TEST BED PLAN
Note: Goals, Scope, and Challenges of the test bed plan have been already described in Section 2.2.6 of this report, but are reproduced here for completeness of presentation.
A. Goals
This test bed seeks to demonstrate the integrated application of drop-on-demand technology for predicable and highly controllable deposition of active substances onto an edible substrate to form two- and three-dimensional dosage structures with precisely engineered release profiles.
B. Scope
Test Bed 3 will exploit drop on demand technology for the production of composite products with precise control of composition, phase, morphology, particle size, as well as release profile. Drop-on-demand formation from complex fluids offers the potential of creating very uniform drops of a wide range of size, depositing them on an edible substrate and assembling the resulting dried or solidified deposits in either a two dimensional layer or into engineered 3-D multilayered structures constructed from the bottom up. While the short to medium term focus is on film substrates, a variety of other substrates can be utilized. The range of architectures and flexibility in accommodating many functionalizing coating alternatives offer the promise of tailoring the composite to meet a variety of release profiles of a single or a combination of actives. The technology offers the potential for rapid reconfiguration to accommodate different products or dosing levels largely through the software controlling the drop formation, environmental conditions of the solidification process, and substrate advancement subsystems. Furthermore, this test bed lends itself naturally to semi-continuous or small product run operation and by virtue of the minimal in-process material inventory will allow quick product change-overs.
C. Challenges
DOD technology has been applied in a variety of applications, including deposition of a protein formulation on a coated fiberglass substrate. However, these applications have been developed purely on a trial and error basis, with extensive experimentation on the formulation of the complex fluids, the design of the micro-nozzles and their operating conditions and adjustment of conditions to insure uniform spread and adhesion of drops on the substrate on impact. The extensive trial and error process required for each new product is impractical for the pharmaceutical domain because the continuous introduction of innovative new drug products does not allow extended development periods, especially not for clinical trials purposes. To advance beyond such empirical design and operating modes, a number of fundamental scientific challenges must be addressed:
· Prediction of nozzle operating conditions required to form drops from complex fluids of specific size required by
dosage performance targets
· Prediction of the operating conditions of the DOD line required to control the deposition of drops of complex fluids on
solid substrates.
· Understanding and control of the formulation as well as transport rates so as to assure that the final microstructure of
the solid phase that is formed meets product performance requirements.
· Understanding and control of the deposit stability during and after processing
· Prediction of the effects of multilayer deposition process conditions on drug release
Additionally, to allow active automation of the integrated manufacturing system, sensing technology is required to monitor the formation and deposition of the fluid formulation and the morphology of the resulting deposits. Models of the transport processes occurring during these steps are required in order to allow model predictive process control as well as determination of the optimal set points required for different active molecules and their drop formulations. Furthermore, feasibility maps need to be constructed so as to facilitate determination for what types of actives and performance requirements this mode of manufacture is competitive.
D. Integration with Thrusts and Project Interdependencies
The fishbone diagram for this test bed is shown in Figure 2R-55 in section 2.2.6 of this report and it is not repeated here. Although by its very nature this test bed is designed to obviate the use of traditional particle technology, it nonetheless draws from all four planned Thrusts of the center, taking significant inputs from 5 projects from Thrusts A-C and all five projects of Thrust D. Table 2P-2 succinctly presents the main role played by each project on the test bed.
Table 2P-3: Major Inputs to TB 3 from projects within each Thrust
Several of the projects serve multiple purposes. Thus, project C1 both provides methodology for the determination and classification of necessary material properties as well as providing essential information for the design and operation of the drop solidification step. Likewise, project A3 provides methodology and constitutive relations for the rheology of the complex fluids constituting the drop as well as models and operating knowledge for the drop formation and drop deposition steps.
E. Planned Research Activities
The research activities associated with this test bed can be grouped following the basic groupings shown in the figure above, namely: input material properties, process component design and operation, product performance and integrated operations.
(1)Input material properties.
The key properties and their prediction involve those influencing choice of formulation elements. Specifically, these include the tendency or lack thereof of the active to crystallize, the rate at which this occurs, potential interactions between the drop formulation and the substrate and the rheological properties of the formulation fluid. While the technology underlying the test bed is applicable a wide range of actives and carriers, for test bed purposes, the model materials selected for study are the following:
· Carriers: Polyethylene glycol (PEG) of varying molecular weights (e.g., molecular weights 3000 and 8000) and
several different conventional solvents, depending on active.
· Substrates: Hydroxypropylcellulose (HPC) + plasticizer
· Active molecules: aceclofenac, loratadine, chlorpropamide, and haloperidol.
The test bed implementation is initially focusing on the polymer melt formulation and then will proceed with the solvent based formulation.
A3. Drop Formation and Layering
The scope of this project relevant to this portion of the test bed work is to develop a data base of relevant rheological properties and predictive relationships that can be used in the modeling of the drop formation and deposition process. This includes consideration of effects of drug loading as well as temperature.
C1. Solidification and Crystallization of drug polymer dispersions
The key components of this project that address the materials properties information and formulation requirements are the following:
· Produce a classification system of drug crystallization tendency and recommendations for formulation routes based
on this classification system
· Evaluate and predict impact of polymers used to form the substrate on the phase behavior of model substances.
(2) Process component design and operation
The activities in this area are associated with the drop formation, deposition, drop solidification and drop coating steps. The drop coating step will employ the same DOD methodology only using a suitable polymer coating. Therefore with some limited experimentation to confirm operating conditions, the knowledge and models developed in project A3 will be sufficient. Additionally, depending on the scenario examined, a substrate manufacture step will be appropriate.
A3. Drop Formation and Layering
Key objectives related to the test bed are the following:
· Experimental program to establish drop formation operating regime for two drop formation methods: electrodeless
DOD for drop sizes in tens to 100’s of microns and piezo-driven DOD for drop sizes below 10 microns using the
model PEG and solvent systems with range of drug loadings.
· Development of predictive models for both DOD alternatives and their use to construct operating regime maps for
these model systems.
· Develop CFD simulations of impact of drops of complex fluids on a substrate.
B3: Film Manufacture
The key objective of this project related to the test bed program are focused on producing films for Test Bed 2 which contain dispersed active particles within the film. The basic film manufacture methods for polymer without drug loading will address the needs of Test Bed 3. However, the developed knowledge and models will need to be verified for the specific substrate materials required by Test Bed 3 ( e.g., HPC).
C1. Solidification and Crystallization of drug polymer dispersion
The key components of this project that address the drop solidification and deposit-substrate interactions are the following:
· Develop method for determining the effect of polymer on crystal growth rate
· Develop models to predict crystallization outcome based on experimental input parameters
(3) Product Performance
Since the purpose of this mode of manufacture is to produce drug products with well defined, predictable properties and sufficient and consistent dissolution behavior, it is critically important to be able measure and predict drug release given the structure of the deposit produced. This test bed will thus draw on the deliverables of two key Thrust C projects:
C3. Structural Characterization of Composite Solids
Technological objectives relevant to this test bed include:
· Establishing methodologies for measuring relevant microstructural attributes of the deposited solids both at
intermediate and final processing states
· Verification and validation of predictive models based on multiscale materials structure and performance
· (long term) Establishing the experimental knowledge base that will enable the development of online, at line, and
inline methods for extracting microstructural information and their use for automation purposes
C5. Drug Release from Complex Solids
The scope of this project relevant to the test bed is concerned with understanding the effect of process parameters and compacted solid microstructure on drug release profiles. While it is well known that material and processing variances can strongly affect drug release profiles, at present we lack a predictive framework for anticipating and avoiding drug dissolution problems. Moreover, since drugs are often designed to release drug over many minutes and sometimes many hours, dissolution profiles cannot be measured on-line for control purposes. Thus, the scientific and technological objectives of this project relevant to the test bed include
· Perform dissolution testing of dosage forms manufactured under variable composition and processing conditions
· Correlate matrix characteristics with drug release parameters
· Examine the distribution of actives and excipients using chemical imaging and relate to processing conditions and
dissolution characteristics (in conjunction with Project C-3)
· Develop mechanistic models to explain dissolution properties of dosage forms
· Develop and implement level-set models to simulate coupled drug dissolution and surface erosion
· Determine and calibrate constitutive parameters for level-set dissolution model
· Develop new approaches to measurement of dissolution /drug release that relate more closely to drug release and bioavailability in the body. Initially this will involve the use of new equipment from TNO (The Netherlands) that is a gastrointestinal in vitro model for drug release.
(4)Integrated-level monitoring, modeling and control.
To achieve continuous and robust operation of Test Bed 3, the test bed development effort will draw on the sensing, regulatory control, informatics and exceptional events management deliverables of projects D1 through D4. The reduced order model-based design optimization capabilities developed under project D5 will come into play once sufficiently reliable models of the individual processing steps and phase change phenomena underlying Test Bed 3 have been realized. Under the three year planning horizon used in this document, we do not expect to be able to fully implement this capability. We expect project D5 to come into play after year 3.
D1: Sensing
The key sensing technologies under investigation under project D1 will be explored to determine suitability in this application. Candidates include NIR, Raman and FTIR. Initial experiments indicate potential for latter to generate phase information.
D2: Integration
It is our expectation that the DeltaV automation software and system will be able to address the needs of this test bed. However, given the sensors available and applicable to the test bed, as demonstrated under project D1, a suitable closed loop process control strategy will be required. It is expected that the controller design will require both elements of coupling of mechanical drives and conventional environmental variable controls as well as manipulation of the drop formation profiles for drop size control.
D3: Informatics
The key TB3 deliverables required of the POPE informatics system will be to expand and revise the materials, operations and model ontologies appropriate to capture the data and knowledge characteristic of this type of manufacturing line as well as the types of models that have been developed by the associated projects.
D4: Real Time Process Management
The principal activities under this project relevant to TB3 will be confined to identifying the exceptional events characteristic of the operational steps of the line, their signatures and appropriate mitigation strategies. Additional monitoring and diagnosis strategies will be developed if those implemented for Test Beds 2 and 3 prove inadequate.
F. Timed Deliverables
For the period 1/1/2009 – 6/30/2009, two parallel tracks of tasks will be undertaken: study of interactions between key processing steps and design and implementation of prototype components of the test bed apparatus. The work will be confined to the melt formulation.
A. Study of processing step interactions: Team members will collaborate in experimental studies that actually use the conditions and mechanisms investigated by one research group to study the impact on downstream steps. Three sets of experiments are planned
1. Deposit Microstructure: Investigation of microstructure of drops as deposited by piezo DOD or electrodeless DOD . To date the investigators examining deposit phenomena and deposit –substrate interactions have used simple deposition means, e.g., pipette or similar device. Information needs to be collected with a range of drops sizes generated by the DOD methodology. Accordingly, a set of experiments will be executed first on a glass surface and then on the edible substrate of choice. The experiments will be conducted over a range of drug loadings, cooling rates and drop sizes and the microstructure of the resulting deposit characterized. The objective is to better define the feasible operating range of the test bed rig and implications on component design. The set of experiments will be repeated for the other three drug candidates. Both drop formation methods will be used to create the samples.
2. Deposit Adhesion: Investigation of deposit adhesion under the conditions as deposited by DOD devices. As in (1) a set of experiments will be conducted to examine effects of drug loading, cooling rate, drops size and substrate type (glass, pure HPC, and modified HPC). Again, the objective is to better define the necessary operating range of the test bed rig. The set of experiments will be repeated for the other three drug candidates. Both drop formation methods will be used to create the samples.
3. Detection of material phase/drug distribution. The objective is to use samples of deposits obtained in the experimental work outlined in (1) and (2) to assess the capabilities and determine detection limits of the characterization methods under investigation in project D1on the types of deposits to be created by DOD methods.
B. Prototype Test Bed 3 Implementation. The conceptual design of 2R-56 will be realized by scoping, selecting, designing and implementing the necessary components.
1. Component design: The design will include the mechanisms for zoned and controlled cooling, the substrate advance mechanisms and the sensing elements to detect key intermediate and final deposit properties. The coating step will not be designed and implemented at this time. However, preliminary investigation of alternative methods will be undertaken.
2. Prototype implementation: The implementation will be made in two sections: the drop formation and deposition section with capabilities of depositing a grid of drops and the advancement and solidification of drops as deposited on the substrate.
The deliverables will be met according to the following time line:
Tasks A.1-2: completed for the initial drug by May 1
Task A.3 completed for the initial drug by June 1
Tasks A.1-2: completed for the other three drugs by July 1
Task B.1: completed by May 1
Task B.2 : first section completed by July 1
It is expected that A.3 for the other three drugs will only be completed in August and that TaskB.2 will only be completed for the second section in August.
If the proposed research program reorganization is approved, then the deliverables after 7/1/2009 refer to the new project definitions. Major components of research activities planned for the next three years include:
· The main focus will fall on the closed loop operation of the DOD line for both the melt and the solvent formulations. This includes the full implementation and integration of sensing and control systems (projects D1, D2 and D4). While initial focus will be on the piezo driven embodiment at Purdue, that knowledge will be transferred for implementation of the electrodeless embodiment at NJIT so that both lines are operational at the end of three years.
· Imaging and phase monitoring technologies will be demonstrated to allow detection of faults in drop formation and to monitor phase and content uniformity of the deposited product.
· The informatics framework developed in Project D3 will be customized and expanded in order to provide an integrated modeling platform for the Test Bed.
· The development and improvement of predictive models to allow determination of the most suitable formulation to be used in TB3 to produce a stable product.
· Preliminary capability to link the microstructure prediction models of project C1 to the product performance / dissolution models of project C5. Within this time frame, only semi-empirical models confined to the model materials used in this test bed are expected.
For the period 7/1/2009 – 6/30/2010, Test bed activities will primarily involve implementation of the test best and bringing it to robust closed loop control with EEM capabilities to accommodate the most common exceptional event.
• Implementation of prototype TB for open loop operation with PEG formulation ( 12/09)
• Integrated operation with sensing, basic control & rudimentary EEM capabilities: PEG formulation (7/10)
– Linkage to DeltaV & POPE systems
– Key automation issues to be addressed: sensing, drop formation rate, substrate advance rate, zone control strategy
For the period 7/1/2010 – 6/30/2011, Test bed activities will primarily involve implementation of the test best for the solvent based formulation and bringing it to robust closed loop control with EEM capabilities to accommodate the most common exceptional event. Additionally the coating capability will be implemented.
• Modified design & Implementation of TB3 to accommodate solvent formulations (12/10)
• Integrated operation with sensing, basic control & EEM capabilities: solvent formulation (7/11)
• Design & Implementation of coating capabilities ( 7/11)
Finally, for the period 7/1/2011 and 7/1/2012, During this period, two alternative directions can be pursued. The first is to resolve technical issues related to multilayered deposit formation, conduct the supporting research to understand product stability and integrity, and demonstrate closed loop operation of the associated TB3 realization. The second alternative is to adapt the test bed to alternative substrate forms. These could be tablets used as deposition substrates with a sealing coating or microarrays for production of uniformly sized granules consisting of active and/or polymer carrier.
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