Proof of Operations for Continuous Manufacturing and Real Time Release Testing of Film Coated Tablets

Robert Meyer, Christine Moore, Yanxi Cain, Cindy Starbuck, et al.

While technical proof of concept for a continuous process can be achieved in a laboratory setting, the production environment provides unique challenges that are difficult to replicate in a lab.  For existing products manufactured through a direct compression (DC) process, continuous manufacturing with real time release testing (RTRT) offers an opportunity to implement next-generation manufacturing technologies and process analytical technologies (PAT) while mitigating the operational risk associated with new technology deployment in a manufacturing setting.  This case study will describe the conversion of such a product from batch to continuous manufacturing, and the associated implementation of fully automated PAT to enable RTR.

For a high volume DC product, use of batch equipment may necessitate numerous valueless material transfer, subdivision, and accumulation operations between processing and sample testing steps. For production volumes on the order of 1 billion tablets/yr, a typical production process may involve operators dispensing ~500kg of powder into a intermediate bulk container (IBC).  This IBC would then be transported to one room for blending and lubrication via rotation of the blender, and subsequently transported then docked to a high speed rotary tablet press.  Following the startup checks, the tablet compression step may run over several hours at ~200kg/hr, while operators sample and adjust periodically to ensure that the process remains in a state of control.  The compressed core tablets would then be transported again for the film coating operation, where the ~500kg may be split into subparts and each subpart would undergo ~2hr of additional processing.  Finally, the finished film coated tablets would be sampled, and in combination with the core tablet samples, laboratory testing would be conducted and a release decision would be made.  For a core tablet weighing 500mg and a batch size of 500kg, each released lot would have a theoretical yield of 1 million tablets.  Given a yearly demand of 1 billion tablets, this process would be repeated ~1000 times per year, and the release of each lot would be based on laboratory measurement of ~10 to 100 tablets.

When fully automated continuous manufacturing coupled with RTRT is applied to a high volume film coated DC product, numerous advantages can be readily recognized in areas such as facility size, production yield, process cycle time, range of available batch sizes, material work in process (WIP), labor requirements, and product quality.  As implemented at Merck, continuous manufacturing will utilize GEA’s CDC50 + Consigma Coater equipment, with Bruker’s Tandem IIIA used for RTRT.  Specifically, the CDC50 integrates the raw material refilling, precision loss-in-weight feeding, continuous blending, and tablet compression operations into a compact single unit operation.  Core tablets sampled post-compression will be analyzed for weight, thickness, breaking force and composition via transmission NIR spectroscopy.  Finally, the system will include automatic transport of core tablets to multiple Consigma Coater units running in parallel, where small batches of ~7kg are coated in ~10min.

Figure 1: Continuous direct compression and film coating using GEA CDC50 and Consigma Coater technology.

To illustrate the benefits of a converted manufacturing and RTRT approach, we consider a production rate of 100kg/hr = 200,000 tablets/hr, such that meeting the yearly demand of 1 billion tablets would require 5000 hr of operational uptime.  If one were to divide this evenly across the year, the operational cadence is an independent variable that can be chosen based upon business need.  As a simple example, 100hr/wk spread across ~4 x 24hr days would satisfy the production demand.  Each week’s production of ~10,000 kg could then serve as a releasable lot of material. However, in contrast to the batch manufacturing process where quality is checked and a release decision is made for a 500kg lot after batch completion, the Bruker Tandem enables in process control and quality decisions at a greater frequency, commensurate with the risk of the process. Accumulation of unchecked material is kept at minimal levels, and non-value added transfer and subdivision operations are eliminated. For example, sampling every 15min would provide the majority of the information needed to assess the quality of that period’s 25kg of tablets before they reach the bulk container where released tablets are held.  For processes that have more or less variability, more or less frequent sampling plans could be freely chosen to ensure production of quality product while also minimizing business risk.  In combination with appropriate models to relate core tablet density and breaking force with tablet disintegration and dissolution, and other models along with statistical process control (SPC) to demonstrate that the operations are conducted within the validated range and under a state of control, significantly more information about the quality of the product can be collected, while still maintaining the business benefits realized by production of large lot sizes.  And in the case where tablets are found not to meet requirements, real time rejection capabilities can be utilized to divert a subpart without implicating the quality of the entire lot.  Because product will have changed location during the execution of some quality tests, a thorough understanding of residence time distribution (RTD) throughout different stages of the continuous manufacturing process is mandatory if real time rejection is to be utilized.  As an added benefit, in addition to providing information about material traceability, an RTD model can be utilized for monitoring the composition of a blend prior to testing of the finished tablet.  Thus it is through the utilization of process models such as RTD models, SPC, and at-line PAT that an operator can stay informed about the state of the process and assured that the process is operated under a state of control.

In summary, it is expected that continuous manufacturing holds the advantages of increasing product quality through use of online PAT to sample a higher percentage of each batch, obtaining higher equipment utilization in a smaller equipment footprint, and reducing supply chain lead times and inventory levels by leveraging fast cycle times and flexible batch sizes.  However, until these items are demonstrated in a manufacturing setting, many will remain theoretical.  Continuous direct compression plus film coating and RTRT as described herein provides a risk-prudent way to achieve multiple business benefits while also demonstrating proof of operations and regulatory acceptability, enabling the future application of additional continuous manufacturing technologies.