The major activity over next two years will involve establishing bench scale film forming capabilities as well as a flexible, pilot scale facility at NJIT. At present, the TB2 Working Group is coordinating the plans for accomplishing this with help of Fritz Fiesser, in collaborations with two New Jersey based companies, Sandvik and FMC. Sandvik has developed an edible film casting line for FMC, while FMC has the materials knowledge for edible film formulations. Thus together, they bring significant technical expertise required for developing an industrially relevant, scalable facility. In addition, Sandvik and FMC can provide the help necessary in technology transfer to pharmaceutical companies, when the Center has fully developed the capability of making sub-micron and micron API loaded edible films. Initially, we will explore the physical implementation of the formulation Option A; and in parallel explore the materials and formulations that are capable of addressing the Option B. Depending on those results and the mentor input, the option C will be pursued after one of the other two options is well developed. Our group is also communicating with Catalent, Inc, also a New Jersey company for a potential collaboration for testing out Option B formulations containing API particles at their site, without having to develop a facility within ERC sites.   

 The activities planned within individual project tasks for the next two years are outlined below.

 Particle Formation and Suspension Stabilization

• Develop and test continuously operating versions of selected particle formation methods
• Finalize the list of APIs for particle formation based on the mentor input as well as the basic understanding of the influence of API molecule properties on the produced particle size, size distribution and stability 
• Prepare particles and their suspensions for a class of APIs for use in other test-bed projects
• Develop experimental approaches to solvent removal and study the effect on particle and suspension stability during and after the solvent removal process

 Gel and Film-precursor Formation

• Determine the surface charge and polarizability of API particulates to understand their influence on potential particle aggregation and instability in the gel matrix
• Perform rheological characterization of high density colloidal dispersions with micron or smaller sizes (effect of concentration, size, surface chemistry)
• Develop practical guidelines for continuously producing slurries of high polymer loaded API suspensions utilizing suspensions from project A-1
• Using experimental and theoretical data determine the optimal window for reversibly aggregated API in the model systems
• Prepare API loaded film precursors starting from the suspensions produced in project A-1
• Explore the materials and processing for various options (A, B, and C) for making film-precursors
• Develop methodology to optimize particle dispersion in polymeric matrixes for three formulation options while understanding the polymer mechanical stability and API release profiles
  

Film Formulation

• Determine critical material and product properties for meeting specifications for product attributes (drug content and content uniformity) and performance (content uniformity, API stability, and dissolution)
• Develop specifications of the properties of the films as an oral dosage form containing micron and smaller API particles
• Develop experimentally validated formulations for edible films (based on the material input from projects A-1 as well as A-2) containing APIs, and an understanding of the influence of materials and processing conditions on the final film properties
• Carry out assessment of particle stability and content uniformity during film formation
• Develop formulations for alternate paths for scalable film formation, carried out in conjunction with project(s) in thrusts A and B
  

Film Manufacture

• Review methods and commercially available equipment for the production of pharmaceutical thin films in collaboration with project A-4
• Develop a database on the effect of plastiziers and film forming excipients on the microstructure and properties of film precursors
• Carry out design, fabrication, and preliminary tests of lab-scale setups for processing film precursors of Option A in conjunction with project A-4
• Compare the films produced via continuous manufacturing with those made in our laboratories in a batch mode
• Develop techniques for measuring the microstructure evolution in materials coming out from the processing equipment
• Understand the effect of material properties of film precursors produced from A-2 project on the microstructure and properties of pharmaceutical films
  

Sensing, Integration and Control

• Carry out a survey of available sensing instruments for all critical operations of the test-bed 2.
• Acquire, install and test the operation of key sensing instruments within the integrated test-bed facility. It is noted that the aim of this effort is not quality by inspection, but analysis of critical quality attributes and real time control
• Develop strategy for developing and incorporating near-IR, optical and/or Raman based sensing methods for achieving 100 % analysis of critical attributes such as API uniformity, state, and spatial distribution, as a demonstration of real time quality assurance system where the product would be available for sale immediately after the manufacture
• Working with thrust D projects, develop hardware integration and control strategies for the process-train
  

Product Testing and Characterization

• Develop the protocol and methodology to measure and understand the dissolution properties of the films, done in conjunction with projects in thrust C
• Carry out dissolution testing for films made in projects A-4 and B-3 and examine the results as a function of particle, suspension, pre-cursor, and film properties and processing conditions
• Develop methods to characterize various physical properties of the films and employ key methods for measuring properties of the films made in projects A-4 and B-3
• Develop the methodology for characterization of content uniformity/homogeneity and stability, developed in conjunction with projects in thrust C via exploring Raman type chemical mapping and/or near infrared chemical imaging and multivariate methods to quantify the precise spatial distribution of very small amounts of APIs
• Explore possibility for developing an innovative dissolution method based on Raman and/or near infrared chemical imaging of the gel strip surface

F. Timed Deliverables

 While laboratory scale experiments for various test-bed 2 operations are on going at various ERC sites, development of an integrated test-bed facility that is flexible and capable of working with multiple formulation options is a major undertaking that would require significant capital equipment and space allocation along with associated renovation costs. At the time of this writing space allocation has been made and plans for space renovations are being worked out. In parallel, we are also discussing possibility of leveraged contributions or acquiring of significant amount of equipment from technology partners such as FMC. The time-line for test-bed 2 implementation for the next few years is discussed in this section.

In additional to three formulation options discussed before, active ingredients may be incorporated into the films in a variety of manners. Moreover, the range of possible film compositions and their flexibility in accommodating many particle types or even eutectics of APIs with other materials offer the promise of tailoring the final product to meet a variety of release profiles of a single or a combination of actives. Thus while the initial focus of the test-bed will be on single API, relatively low dosage cases; in future, other possible scenarios will be explore. These possibilities that can be envisioned are; (1) Single-API-high-dosage: API in either particulate form, loading of up to 50 %, (2) Multiple APIs: Incorporation of multiple APIs and/or multiple modes of API forms with API loading in range 1-25 %, and (3) Future Forms: based on the previous results and input from the IAB.

For the period 1/1/2009 – 6/30/2009:

Three major tasks for this period are: (i) Development of the specifications for film formulations and precursors; (ii) Identification and selection of test-bed integrator and/or technology partner to assist in test-bed design, planning, and installation; and (iii) Development of the system design for the first formulation option A.

More details on these tasks are:

·         Develop plans of test-bed development for Option A. These are readily flowing formulations meant to produce very thin (~ 100 micron) films with little or no plasticizer. It is envisioned that this type of formulation would present advantages for the case of highly potent drugs, present at low concentration in the films.

·         Evaluate the feasibility of developing Option B formulations. This type of formulation is aimed at taking advantage of existing manufacturing technologies such as those employed for making soft gel capsules. These formulations will produce films in the range of 100 - 500 microns with a wide range of API concentrations.

·         Continue communications with industry partners and mentors to finalize technology integrator and retain a consultant for help with test-bed establishment effort.

·         Select several API candidates for particle formation and suspension stabilization experiments based on the intrinsic material properties for BCS Class II drugs with input from the industry mentors.

·         Develop a beta version of continuous LAS system employing ultrasonic input, and develop optimal conditions for producing fine, narrow PSD, stable suspensions of several newly selected APIs.

·         Perform a comparative study of polymer-API interaction for micro- and nano-sized griseofulvin particles in a dense-phase slurry.

·         Measure rheological properties of HPMC-surfactant-plasticizer system as function of the water content and temperature.

·         Develop film formulations and prepare films using newly selected APIs.

·         Develop preliminary specifications for standardizable dissolution testing protocol for films.

·         Working with thrust 1 team, develop a plan for incorporating sensing and control in various test-bed operations.

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 and test-bed implementation activities planned for the next three years include:

• All individual operations necessary for at least one of the formulation options are sufficiently developed and implemented as bench-scale, continuous mode operations at one ERC site.
• Building from the results of the bench-scale operations, test-bed process-train designs finalized, space renovations done, and an instance of test-bed implementation carried out at NJIT for at least one of three formulation options, most likely formulation A.
• Feasibility of preparing option B and C formulations is carried out. Practical and theoretical aspects of preparing film pre-cursors and films are investigated in order to develop plans for test-bed plan development.
• In parallel, formulation option B is tested out at an industry partner site.
• Major operations of the test-bed are instrumented with sensors, and they are integrated for control and monitoring of the test-bed operation.
• On-line and off-line characterization capabilities are developed for the possibility of performing on-line inspection.
• A second generation unit for the test-bed is developed at another ERC site.

For the period 7/1/2009 – 6/30/2010

The major tasks for this period will be: (i) Develop beta versions of all individual operations necessary for at least one of the formulation options, and implement as bench-scale, continuous mode operations at NJIT; and (ii) Work with the industry partner and install a version of the test-bed, capable of demonstrating the capability of continuous film manufacturing. 

For the period 7/1/2010 – 6/30/2011

The major tasks for this period will be: (i) Develop on-line sensing capabilities and product characterization capabilities for the test-bed process train at NJIT; (ii) Working with thrust D team, incorporate sensing and control and bring the test-bed to robust closed loop control with EEM capabilities to accommodate the most common exceptional event; (iii) Develop advanced film manufacturing capabilities, including coating of the films and multi-layer structures; and (iv) Develop plans for extending or modifying the process-train for other formulation options.

For the period 7/1/2011 and 7/1/2012

Test-bed is expected to be operating in a continuous mode under full control by the beginning of this period. During this period, several other possibilities will be explored: (i) Fully install test-bed for another formulation option; (ii) Initiate manufacturing of multiple API loaded films; (iii) Develop full capability of quality by design for one of the formulation options.