Emerson’s Jonathan Lustri explores the trend towards continuous manufacturing for solid dose pharmaceuticals and the technologies and practices that make this possible.
This past year I have become aware of a very big change that is coming to the pharmaceutical industry in the area of manufacturing solid dose form pharmaceuticals. The manufacturing of pharmaceutical tablets is moving from its traditional batch process to continuous processing. While chemical and other industries have tended toward continuous manufacturing for many years, the drug industry has been slow to change due to the impact of FDA regulation.
With the reduction of blockbuster drugs, the industry has to increase its manufacturing excellence to increase profits. The financial driver for the move to continuous manufacturing is a significant reduction in capital and operating costs. A batch process typically will have capacity utilization of 35%. This is caused by a significant amount equipment usage lost to preparation, cleaning, and scheduling.
On the other hand, a continuous process can have a capacity utilization of over 80%. This means a continuous process can make the same amount of production in much smaller equipment. Additionally, continuous processes require less human activity to transport materials between units so there is a savings in manpower as well.
One of the challenges related to moving to continuous processing is to assure production is made within its quality specifications. In batch processing, lab testing is typically performed in between each unit operation. Material is set aside until lab results confirm quality. But in a continuous process where material automatically id fed from the upstream unit to the downstream unit, quality needs to be measured in real time through on line measurement of critical quality attributes (CQA) using process analytical technologies (PAT).
Traditional instruments that easily characterize temperature, flow, pressure, and pH need to be augmented with advanced analytical instruments such as Near Infrared (NIR), and Raman spectroscopy or focused-beam reflectance measurement. Using on-line advanced analytical instruments enables the ability to perform real time measurements of critical quality attributes such as blend uniformity, percent active ingredient, particle size distribution, and moisture. Applying these types of instruments within a real-time control environment enables real-time quality control.
Process Analytical Technology (PAT) is enabling for continuous manufacturing of sold dose pharmaceuticals. Applying PAT for real time measurement and control requires significant expertise in the areas of instrumentation, chemometrics modeling, data management and system integration. Many PAT instruments output light spectra. Chemometrics models need to be developed to convert spectrum data to the critical quality attribute.
Modeling software such as MatLab or Camo unscrambler are the tools of the trade for this type of modeling. After a model is developed, in order to measure the critical quality attribute in real time, the spectrum has to be received from the analyzer, and long with the model processed by a prediction engine (e.g. Camo OLUP or Simca Q) in order to predict the quality attributes. The following figure illustrates the data flow and transformation needed to use a PAT instrument to measure a critical quality attribute.
One of the values Emerson Life Science consultants can provide to manufacturers moving to continuous manufacturing of sold dose pharmaceuticals is the complete integration and control environment to accomplish PAT measurement and control.
The following is an illustration of a simplified sold dose manufacturing line that is operating at the Engineering Research Center at Rutgers University. The process below includes hoppers to feed active API, Excipients, and lubricants.
These are blended together, milled and processed to a continuous blender. The discharge of the blender includes a site glass where a near infrared analyzer takes a reading of the blended powder before it goes to the table press.
The PAT Server is used to predict the critical quality attribute and write this to the DeltaV OPC Server. These critical quality attributes are then used as measured variables within a model predictive control strategy within the DeltaV control system.
Using this strategy, it’s possible to implement real-time quality control. The move to continuous processing completely changes the process control aspects for drug manufacturing. In batch processing, the production of each unit is a batch and its output is stored as inventory. This allows each unit to runs completely isolated from the other process units.
Variability in one unit does not impact the operation of the other units. When these unit operations are connected as part of a continuous train with the discharge of one unit feeding the next unit, the process becomes highly interactive and processing parameters become dependent upon one another. This is why capabilities in DeltaV such as model predictive control provide value.
We are now in the beginning of this industry trend toward continuous manufacturing for sold dose pharmaceuticals. Emerson is continuing to further develop the expertise required to integrate PAT instruments into a real-time control strategy to deliver real time quality control.