Changing the status quo is always difficult. In pharmaceutical manufacturing, history is on the side of batch processing, which explains why continuous processing continues to face high barriers to acceptance.
Not every pharma process can, or should, run continuously, progress is being made in areas such as mixing and crystallization. “Not a lot of people in the pharmaceutical industry are experienced with continuous processing. They know and understand fluid bed drying and high shear granulation,” says Carl Anderson, PhD, assistant professor of pharmaceutical sciences at Duquesne University.
“They also perceive that regulatory problems and issues will be associated with the continuous process.” However, batch processing at some plants can be characterized by high labor costs and an excess inventory, leading to higher production costs.
“Continuous manufacturing promises efficiency because it is a wellcontrolled and flexible process,” says Bernhardt Trout, a Massachusetts Institute of Technology (MIT) associate professor of chemical engineering. “There is less waste and higher quality. You won’t have to throw out any batches, because they must adhere to tight specifications that are built into the process.” There are further advantages to a continuous process.
According to Lee Proctor, technical director at the pharmaceutical intermediate manufacturing company, Phoenix Chemicals (Bromborough, U.K.), utilizing continuous processing and flow reactor technology is a strategy for achieving improved efficiency. It delivers lower raw material and waste costs; it reduces environmental emissions and energy consumption, as well as overall unit operations and operational costs.
In addition, FDA has championed process analytical technology (PAT), Quality by Design (QbD) and the Critical Path Initiative, clearing the regulatory hurdles for continuous processing. These approaches identify critical processing variables and their effect on performance and quality, with the goal of improving product quality by designing it into the process.
This is exactly what continuous processing aims to achieve.
The $65 Million Investment
Last year, Novartis announced it would invest $65 million over the next 10 years to fund research activities at MIT and establish the Novartis-MIT Center for Continuous Manufacturing. The collaboration is enough to support research efforts for seven to 10 faculty members and dozens of graduate students, postdoctoral fellows and staff scientists.
Each researcher’s specific skill set will be needed. The goal is not to reinvent the batch process but to establish a new, never-tried process with all of the benefits of continuous manufacturing. “We are trying to make a quantum leap in the drug industry and transform how drugs are developed and manufactured,” says Walter Bisson, Novartis’ program leader for continuous manufacturing. “This means reducing cycle times and development times as well as looking at the efficient use of equipment, building costs, energy savings and raw material generation.” However, making this leap will not be easy.
The “blue sky” approach this collaboration is taking means throwing out existing processes and starting from scratch. It calls for inventing new methodologies and a new set of technologies. “We are investigating all aspects of the pharmaceutical process – from synthesis to the final drug form,” says Trout. “We hope to come up with a fully integrated, fully controlled system.” One area of particular concern to Trout is crystallization, a chemical solid-liquid separation technique in which mass transfer of a solute occurs, from the liquid solution to a pure solid crystalline phase. Factors such as impurity level, mixing regime, vessel design and cooling profile can have a major impact on the size, number and shape of crystals produced.
Poor control of the crystal size can result in longer process times and an inefficient process. The success of a crystallization step often depends upon how the crystals were designed and characterized in the lab. Analytical tools have already been developed to help measure the composition and particle size on-line.
The Insitec by Malvern Instruments (Southborough, Mass.) can make these measurements through a laser diffraction-based particle size analyzer, lending itself to a continuous process. “Particle size is determined from the pattern produced as light is scattered by particles in a sample,” says Malvern project engineer Alon Vaisman, project engineer. “The instrument is already used in chemical processing.”
The Novartis-MIT partnership is piloting easy to synthesize, small molecule drugs that the company already manufactures, as well as brand new chemical drugs in the R&D phase. The researchers are not yet ready to tackle the biologic drugs. Not everyone is taking as radical approach to continuous manufacturing as the MIT-Novartis project. Many companies are focusing on bringing continuous manufacturing to some of their unit operations and then fitting the pieces together.
This is often called semicontinuous manufacturing. Industries such as food, chemical, automotive and electronics have used continuous manufacturing systems for years. However, there is a certain inherent risk involved with the process. Continuous processing does not solely rely on out-of-process measurements. In a batch environment, a product recall is easy because each one has lots and batch numbers. In a continuous environment, product would have to be defined by the time when it was produced.
“How do you know which tablets are manufactured from the same batches of individual components as the bad product?” says Ron LeBlanc, engineer from the Little Island, Ireland engineering firm, PharmEng Ltd. “Risk is a major consideration as well as process knowledge and understanding.” However, FDA experts have said that using time rather than batch number, there would be little difficulty tracing recalled materials in a continuous environment.