Batch vs. continuous manufacturing
Advantages and disadvantages
Industry trends and adoption
Advancing continuous manufacturing
Conclusions
References
Historically, pharmaceutical products have been produced in a traditional ‘batch’ system, in which every operation is executed separately using a defined quantity of materials. In batch manufacturing processes, manufacturers can collect and evaluate intermediate products before continuing to the next phase1.
Comparatively, the continuous manufacturing process involves a single line of different unit operations in which the flow of materials is uninterrupted.
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Batch vs. continuous manufacturing
For many years, the pharmaceutical industry was hesitant to incorporate continuous manufacturing into their production processes due to perceived advantages associated with the batch method, some of which include flexible unit operations, simple optimization, and easy traceability.
Despite these advantages, batch manufacturing is associated with various limitations, including the numerous operations needed to handle, store, and monitor intermediate products between each phase1.
The higher proportion of manual procedures involved in batch manufacturing increases production times and costs, as well as the risk of variability.
Advantages and disadvantages
The aim of continuous manufacturing is to modernize the supply chain, enhance the robustness of the manufacturing process and thereby reduce product failures and enhance product quality3.”
Some of the key strengths associated with continuous manufacturing include optimized production time and costs, reduced environmental impacts, as well as a high degree of automatization and monitoring1.
In fact, researchers estimate that continuous manufacturing can reduce product variations, the time required for quality control, and power consumption by 50%, 50-70%, and 40%, respectively2.
The scale of continuous manufacturing processes can also be adjusted to meet higher or lower demands, such as during crisis situations, which prevents unnecessary stockpiling of medications in the event of an emergency2.
One of the key advantages associated with continuous manufacturing is the option to modify batch sizes by increasing run times; however, this modification requires the consideration of certain issues that may arise, such as equipment overheating or the accumulation of materials during longer runs.
Pharmaceutical companies also can increase the throughput of manufacturing processes through continuous manufacturing and/or change the size of equipment. Importantly, any of these changes will require significant alterations to the control strategy for the process and possibly re-validation of the entire process3.
The integration of all operations into a single production line also prevents the segregation of any material, thereby increasing the uniformity of final products.
Specific amounts of product are utilized at each step of the continuous manufacturing process; therefore, any discrepancies will only lead to the rejection of a limited product quantity. This is a key advantage as compared to batch manufacturing, in which the identification of any discrepancies in final products can lead to the rejection of the entire batch.
Batch vs Continuous Manufacturing - Pharmaceutical Industry
Industry trends and adoption
Major regulatory agencies throughout the world have largely supported the implementation of continuous manufacturing technologies due to their numerous advantages.
Nevertheless, between 2015 and 2022, only seven drugs produced through continuous manufacturing processes were approved by major regulatory agencies, including the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Product Development and Management Association (PDMA).
Despite interest from regulatory authorities and the pharmaceutical industry in approving continuous manufacturing, the adoption of these approaches has been slow due to the potential difficulties of registering these products and their cost implications3.
In 2022, the International Conference on Harmonization (ICH—Q13) published global guidelines on continuous manufacturing to support the widespread adoption of these technologies within the pharmaceutical industry. These guidelines incorporate quality-related considerations specific to continuous manufacturing processes.
For example, although a robust control strategy must monitor both batch and continuous process manufacturing products, a performance-based control strategy is the optimal approach.
In this approach, which is otherwise known as a Level 1 control strategy, real-time monitoring is achieved through Process Analytical Technology (PAT) tools and other sensors.
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Advancing continuous manufacturing
The transition from batch manufacturing to continuous processing has been particularly evident in the production of oral solid dosage (OSD) forms. The production of pharmaceutical tablets typically begins with a blending step that creates a homogenous mixture of the active pharmaceutical ingredient (API) with one or multiple excipients.
After that, this mixture is loaded into a large vessel that is tumbled for a set duration to ensure a homogenous mixture with uniform particle size and density.
For this aspect of tablet production, continuous manufacturing processes are associated with reduced mixing time, which leads to superior blend homogeneity and API uniformity in the final product. To further optimize tablet production, researchers have become increasingly interested in applying continuous powder blending into their manufacturing process.
Whereas batch blending processes often rely on excipients with specific flow profiles and low internal friction, these criteria are not necessary for continuous blending processes, as the impact of powder material properties is minimal4.
In fact, the choice and number of excipients do not appear to significantly alter the uniformity of continuous blending processes, thereby presenting a unique advantage over batch blending processes.
Conclusions
There are numerous financial and practical benefits associated with the continuous manufacturing of pharmaceutical products.
The implementation of continuous manufacturing into the pharmaceutical industry has been slow due to various technical challenges; however, increasing investments into pharmaceutical manufacturing innovation and expediting the approval for products produced through continuous manufacturing can accelerate advancements in this field and, ultimately, the routine use of these technologies.
References
- Macchietti, L., Melucci, D., Menarini, L., et al. (2024). Analytical comparison between batch and continuous direct compression processes for pharmaceutical manufacturing using an innovative UV-Vis reflectance method and chemometrics. International Journal of Pharmaceutics 656. doi:10.1016/j.ijpharm.2024.124090.
- Diego, Malevez & Copot, D. (2021). From batch to continuous tablet manufacturing: a control perspective. IFAC PapersOnLine 54-15; 562-567. doi:10.1016/j.ifacol.2021.10.316.
- Wachlich, J. (2021). Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms. Pharmaceutics 13(8); 1311. doi:10.3390/pharmaceutics13081311.
- Jaspers, M., Kulkarni, S. S., Tegel, F., et al. (2022). Batch versus continuous blending of binary and ternary pharmaceutical powder mixtures. International Journal of Pharmaceutics. doi:10.1016/j.pjpx.2021.100111.
Further Reading