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January 7, 2020

High shear wet granulation (HSWG) is an established pharmaceutical technology that is currently carried out in one batch at a time which creates several limitations:
(a) Very limited number of batches can be manufactured during product development because of containment requirements for relatively high powder loads and time required for processing. This leads to:
  1. High API, development time, and FTE requirements, which are opposed to current industrial trends to try to minimize API and time consumption in early drug development.
  2. Low resolution Design of Experiment (DoE) studies and inability to test process and formulation variables to identify the critical parameters/factors.
  3. Statistical significance interpretation in the DoE studies is based on variability at one point of the DoE design – typically center point. The random variation is likely different at different points in the DoE space and an ability to run replicates at different points would provide greater scientific and statistical confidence in the DoE results.
(b) Difficulty in assessing the impact of bulk powder parameters to process scale-up in the context of process analytical technologies (PAT) that can be applied to larger scale manufacturing equipment. Miniaturized granulator might allow measurement of:
  1. Torque using a calibrated shaft.
  2. Powder wettability and flow parameters.
  3. Rapid assessment of technology options for enabling new chemical entities and newer modalities of drugs through wet granulation routes in early stages of drug development.
A miniaturized, high throughput, multi-container granulator is proposed to address current limitations in the industrial practice of wet granulation (WG).

Download the Request for Information and submit your response.




Questions Received (updated 1/30/2020)

On Pages 14-15 of the RFI, Section “Manufacture at different tunable pressure/shear forces acting on the powder mixture” please clarify if all bullets points are being requested of if these are different alternatives to achieve a similar goal. If all are required, please confirm if all features are being requested to act at the same time or sequentially.  For example, could mixing be completed, and then pressure be subsequently applied?  Is there a specification for the required pressure?

The listed options in the bullet points are examples of different alternatives to achieve a similar goal. Not all are required. Any one or a combination might suffice, however the tunable pressure/shear forces would be desired throughout the liquid addition and wet massing stages of the wet granulation process. There are no specifications provided. The scientific merit and technical feasibility of identification of the selection of feature(s) should be justified. Also, importantly, this is not an exhaustive list and a feature outside this list may also be used.

On Page 15 of the RFI, Section "PAT" are the requests for “Flow force of the granules” and “Needs integration of the Drag Force Flow (DFF) sensor” referring to the same measurement?  If they are different, please clarify.

Flow force of the granules is the property that is sought to be measured. Drag Force Flow (DFF) sensor is indicated as a possible example of the kind of technology that can serve this purpose. This is not exhaustive or all-inclusive of PAT technology options that might be available, but an example. A PAT technology option or a feature outside this example may also be used. The scientific merit and technical feasibility of the selection of feature(s) should be justified.

On Page 17 of the RFI, Section “Assessment of quality of granules and conformance with expected patterns of changes to input variables for the off-line measurement of granule size, porosity, and density, are there existing, preferred instruments that will be used?  We are currently assuming that no instruments would be provided by the vendor.  Do these instruments have requirements that affect the design of the wet granulation station beyond what is stated in this RFI? Should analytical data be saved in a central database to support analysis/modeling as part of this RFI?  
These are routine off-line measurements that can be carried out using a variety of instruments that are routinely used in pharmaceutical development. The selection of the instrument for measuring these responses would be made by the collaboration partner doing these measurements based on scientific merit and technical feasibility. The assumption that these instruments would not be provided by the vendor is correct. These instruments are expected to be already present in the facilities of the collaboration partner and sponsors of this research. The selection of these instruments is not expected to affect the design of the wet granulation station. These instruments would only be used to assess the quality of granules manufactured by the wet granulation station. Storage of the analytical data in a central (shared) database to support analysis/modeling can be considered. Data sharing is anyway implicit in the work package.

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