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.
In addressing these challenges, Chueh outlined the criteria that Pfizer uses in evaluating a continuous processing project.
He said the process must:
- Provide a wide range of throughputs/capacity to meet different product-volume requirements that meet the company's financial
- Be easy to clean and allow for facile changeover for multiple product productions
- Minimize scale-up and technology-transfer complexity for new products
- Be modular, portable, and transferrable (i.e., plug-and-play approach and skid designs)
- Provide interchangeability for plug-and-play in different continuous processing unit operations for better processing and
- Be adaptive and amenable to continuous quality verification and real-time release
- Improve specific product quality and functionality (e.g., coating uniformity)
- Require a smaller manufacturing footprint with lower capital costs
- Be hybrid in design (i.e., the process can be used either in a batch or continuous mode).
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
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
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.