The business case

Nasr also stressed the business case for continuous manufacturing given current challenges in batch manufacturing. He emphasized two key advantages: elimination of scale-up and related challenges, and increased manufacturing flexibility. He noted the value of applying platform technologies in a modular approach to meet evolving market product demand as a way to reduce manufacturing footprints, in terms of facilities and equipment, which would allow for more flexible operations, lower capital costs, and less work-in-progress materials.

Alex Chueh, director/team leader of the technology, science, and operations group of Pfizer's Global Supply Division, who also spoke at the Interphex panel, agreed. "From a new-product point of view, you really need to minimize the scale and take advantage of continuous manufacturing," he said. He pointed to improved manufacturing efficiency, reduced operating costs, reduced cycle time, lower inventories, a smaller manufacturing footprint, reduced capital expenditures as well as improved product quality and consistency by applying steady-state processes, QbD approaches, and real-time release. But he pointed to challenges as well, including the financial justification for investment in continuous processing projects in light of excess existing batch capacity, declining production volumes as result of maturing products, potentially more costly continuous processes, and the existence of already optimized and lean batch-manufacturing processes.

Project work

Using these proof-of-concept principles, Chueh offered several examples of specific projects in continuous solid-dosage processing at Pfizer. The first was a continuous dry-granulation process that was implemented as a multiproduct platform at a cost of $16 million, which included $7 million for a new building housing the operations, and which produced $4 million in annual cost savings. The dry-granulation process consisted of several steps: meter feeding of excipients and lubricants, in-line blending, roller compaction, milling, and further in-line blending. The equipment train used in continuous dry granulation is not dissimilar to the direct compression process with the addition of roller compaction and milling steps, which is the most straight forward type of continuous manufacturing process for solid oral dosage forms, according to John Groskoph, senior director, global chemistry manufacturing and controls, also at Pfizer.

"From a PAT perspective, at a preselected processing point, we identified all of the critical process parameters (CPPs) as well as critical quality attributes (CQAs) that needed to be measured and controlled," said Chueh. In continuous dry granulation, raw material variability, blend uniformity, compaction, and particle size are the key CQAs. PAT applications, such as near infrared (NIR) and focused beam reflectance measurement (FBRM, for particle characterization) were developed to ensure good measurement, monitoring, and control with data fed into a supervisory control and data acquisition (SCADA) system. For blend uniformity, Pfizer developed an on-line PAT measurement system to sample, measure, and monitor the blend potency and uniformity in a continuous mode. Further, a three-way diverting system that interfaced with the on-line NIR was developed to validate rejection of detected nonconforming materials. A more robust on-line blend potency sampling and measurement system is currently being evaluated.

Pfizer applied a similar proof of concept approach for developing a continuous high-shear, wet-granulation–fluid-bed drying process. The $13-million project was for a high-volume product with an estimated annual savings of $7 million. Pfizer integrated metered feeding, blending, continuous granulation, continuous drying, and final blending operations into a single-pass, first-in–first-out system. The company worked with an equipment vendor to develop the continuous granulator and continuous dryer aspects. In this process, the continuous wet granulator and dryer units operate more like a tunnel rather than a sealed chamber. Dry powder can be fed into the entrance, fluidized, and sprayed with granulation solution in the initial portion of the unit. As the moist powder travels through the granulation unit, it forms granules that move onto the drying unit and begin the drying phase. The now dry granulate passes through the exit and onto further continuous blending before being collected into an intermediate bulk container.

Chueh also pointed to the company's interest in developing continuous direct-compression processes. "We are hoping that in the future we have more direct compressible formulations and processes because it is the most effective, simplest and, easiest process. But it's not easy to develop based on API characteristics," he said. In using the same proof-of-concept criteria for its continuous processing operations, Pfizer integrated multiple loss-in-weight feeders, used a proprietary, in-house developed continuous mixer, followed by lubrication, and on-line NIR monitoring of the blend potency and uniformity during the blending process. The project's investment was $3.5 million with a projected annual savings of $1 million.

In developing these continuous manufacturing processes, Chueh outlined some specific technical considerations. "Since blend uniformity is always a critical quality attribute, the feeding accuracy and precision as well as the in-line blending and mixing efficiency became one of the [key] technical focus areas." He also emphasized the importance of managing start-up and shutdown losses. "One of the disadvantages of a continuous process is the start-up and shutdown losses, so we have minimized [those] as much as we can," offering as an example the company's work with a vendor to develop a second-generation continuous coater that has minimal start-up and shutdown losses. Achieving more consistent and uniform spraying and drying conditions in the continuous coating zone were other key focus areas during the development of the continuous coater, he added.