Traditionally, pharmaceutical manufacturing has been done in batch mode. Although batch processes generally have some in-process monitoring, they typically involve sequentially loading quantities of materials, processing the mass, and then discharging the transformed material. At the end of a batch process, the output is evaluated and a determination is made about whether the “batch” satisfies specifications and can either be moved on to a next stage of production or processed for shipping to the marketplace. Continuous pharmaceutical manufacturing, in contrast, involves material being constantly loaded, processed, and unloaded without interruption. Semi-continuous operations have elements of both batch and continuous, in which materials are either constantly loaded or constantly removed from the process, but not without interruption. In contrast to batch manufacturing, continuous manufacturing is thought of as a process that flows from beginning to end without major interruptions or breaks in the process.
Continuous production or continuous manufacturing (CM) is a flow production method used to manufacture, produce, or process materials without interruption.
The continuous manufacturing concept originated from pig iron production using a blast furnace, where the process operates for multiple years without shutdown. The approach is followed in production processes for oil refining, chemicals, synthetic fibers, fertilizers, power generation, natural gas, and waste-water treatment. The application of continuous manufacturing in pharmaceutical and biopharmaceutical manufacturing has progressed in the past decade with adoption of the same approach as leading industries.
For a successful integration of continuous manufacturing, an orchestrated coordination amongst several industry partners is essential. The three major components for successful implementation are equipment and process analytical tool manufacturers, API and excipient manufacturers with a focus on process controls in providing consistent supply, and the finished product manufacturing facility in developing strategies for integration of techniques for implementation.
Advantages of Continuous Manufacturing (CM)
Disadvantages of Continuous Manufacturing (CM)
Barriers to the Adoption of Continuous Manufacturing
Although there is general agreement that continuous manufacturing offers substantial benefits over batch manufacturing, the pharmaceutical industry has been much slower to adopt it than other industries. This is due to a number of technical, operational, and economic challenges that have slowed progress, which are described briefly in the section below. (For a fuller exploration of these challenges, see the recently released white papers from the International Symposium on Continuous Manufacturing of Pharmaceuticals.)
There are currently a number of technical challenges associated with continuous manufacturing, which vary depending on the specifics of the product under development. For example, major issues include (though are by no means limited to) drug substance characterization and handling, the development of accurate process operations models, and optimal approaches to start-up and shutdown. Integrated pharmaceutical processes often involve the handling and transportation of materials. As such,
monitoring the flow of materials and being able to trace these materials individually throughout the integrated processes can be challenging. It is also challenging to develop small-scale continuous manufacturing lines that can be used during clinical development (i.e. before approval), due to lack of commercially available equipment. Currently, processes conducted in the lab at the clinical development
phase is largely batch in nature, and are not easily switched over to a continuous process for commercial manufacturing. Additionally, although continuous manufacturing has a number of safety advantages compared to batch manufacturing, it presents its own set of safety concerns that designers and operators will need to anticipate, including, for example, how to prevent overfilling, over pressurization, material spills, backflow of material into other parts of the equipment, and other potential hazards not normally present in batch manufacturing. In continuous processes, material is constantly flowing through the system so product quality needs to be measured in real-time. To achieve widespread adoption of continuous manufacturing technologies, new generations of equipment, sensors and automation will need to be developed that monitor and control the process in real-time. Developing or adapting continuous manufacturing processes for the generics market will present additional challenges, as manufacturing strategies differ substantially between the two sectors.
The pharmaceutical sector is highly regulated, and many companies fear that any significant changes to existing manufacturing processes could create regulatory delays. This perceived uncertainty has further contributed to a “business as usual” mindset that leads to slow adoption of continuous
Furthermore, while continuous manufacturing aligns strongly with both FDA and ICH guidelines, pharmaceutical manufacturing is a global enterprise, and companies must gain approval for their products in multiple countries with their own regulatory bodies. Although FDA has been promoting continuous manufacturing for several years, not all global regulatory agencies may be similarly willing or able to review and approve a continuous process for use. More work is likely required to resolve issues related to regulatory harmonization.
Designing, implementing, and adequately regulating these new approaches to manufacturing will
require a highly skilled and well-trained workforce, both within industry and regulatory bodies. For example, continuous manufacturing is more engineering intensive than traditional batch methods, and will require industry personnel to gain expertise in new technologies related to process control, measurement techniques, and other aspects of continuous systems. Regulators will also be required to learn about these new processes, their potential failure points, and how to assess if they are being implemented and run properly. There is concern within the pharmaceutical industry that the understanding of and enthusiasm for continuous manufacturing shown by agency leadership will not be disseminated evenly down to the ranks of the inspectors and other regulators working with companies to implement continuous processes. Continuous systems also produce a substantial amount of data compared to batch systems, which will likely require greater statistical training for engineers, scientists, and regulators alike. At present, there is a mismatch between these necessary skills and those currently being developed and recruited. Addressing this gap will likely require sustained institutional commitment and direct financial investments from a broad range of stakeholders, including academic institutions, government agencies, and industry.
Business and Operational Challenges
These various technical challenges are compounded by business and operational factors at play in the pharmaceutical industry. In order to be as effective and efficient as possible, continuous manufacturing processes should be adopted in the early stages of product development. However, aligning the design and development of manufacturing processes with clinical development timelines is challenging, and will likely require changes to current organizational structures within companies. The uptake of continuous manufacturing processes will also depend on the development of innovative enabling technologies, which take time to evaluate, validate, and implement widely. The pharmaceutical industry has historically been slow to adopt new technologies—owing in part to its significant existing capital investments in batch processing facilities—which may slow the pace of innovation among equipment vendors. The pharmaceutical industry’s conservative business culture is also perceived as being a barrier. New manufacturing approaches must often be proven superior from both a technological and financial standpoint, as well as tied to the development of a specific product, before they are implemented more widely.
Although CM is still in its infancy within the pharmaceutical industry, it stands to improve the overall quality of both small molecule drugs and biotherapies, reduce costs and lower time to market. Manufacturers of APIs, bulk formulations, and dry powders used in solid dosage pharmaceuticals are likely to be early CM adopters because conversion is relatively easy in these areas. With the FDA’s continued encouragement, CM is expected to grow rapidly within the pharmaceutical industry in the coming years.
As the practical implementation of CM is still an emerging field, it is important to gain knowledge from those in industry, regulatory agencies and academics who have prior first-hand experience and strategies, and are seeking to share and influence the progress of CM, as well as achieve regulatory acceptance. This can best be done by attending focused conferences, participating in equipment supplier webinars and trainings, and networking with similarly interested players in scientific society workgroups.
By Afandiyev R.
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