In pharmaceutical formulations, the most commonly used are oral solid dosage forms, such as tablets and capsules. The mainstream manufacturing process for these remains semi-continuous batch production, typically involving steps such as mixing, granulation, tableting/capsule filling, coating, and packaging. Since 2015, continuous manufacturing (CM) technology has continued to develop.
1. What is Continuous Manufacturing?
The FDA defines continuous manufacturing (CM) as a system of continuous production processes consisting of two or more unit operations. Materials are continuously fed into the system for processing and constantly output from the system after processing. In short, continuous manufacturing means the entire process runs continuously, without interruptions.
The traditional manufacturing process for solid oral dosage forms is semi-continuous, generally involving processes such as mixing, granulation, tableting/capsule filling, coating, and packaging. These processes are separate and independent in traditional semi-continuous manufacturing, not continuous.
Compared with traditional batch production, what are the core advantages of continuous manufacturing in solid dosage form production? There are four main advantages:
(1) Improved Product Quality
Production is continuous, without the interruptions of traditional batch production. Quality is controlled through process monitoring and feedback, resulting in significantly improved product quality. In conventional batch production, there are pauses and delays, which require quality testing for each batch, making quality control more cumbersome and leading to inconsistencies between batches.
(2) Accelerated R&D Speed
Reduces the development time and cost of new drugs. Because R&D and actual production are carried out on the same production line, there is no need for process scale-up studies, reducing R&D time and costs. Shorter time means pharmaceutical companies can gain market revenue earlier, and patients can access new drugs sooner. Therefore, the economic and social benefits of continuous manufacturing technology for solid dosage forms are significant.
(3) Flexible Capacity Control
The capacity of a continuous production line for solid dosage forms is determined by its operating time, making it highly flexible. It can respond promptly to market demand. When demand for a product surges due to an emergency, the production line’s operating time can be immediately extended to quickly increase output, avoiding the limitations of traditional batch production in responding to market demand. For example, the Blister Line used for solid dosage form packaging integrates multiple units, such as the blister unit, pillow-packaging unit, cartoning unit, stretch-banding unit, and case packing unit, into a continuous production line. This allows for the input of tablets, capsules, and parenteral products at the beginning of the production line, and the output of finished products in sealed cartons at the end, ready for direct shipment to the market via logistics.
In addition, through an optimized, flexible equipment design, multiple products can be produced on the same blister line, significantly reducing equipment and production facility investment. For example, the blister line launched by Jornen in 2023 uses modular connections for each packaging unit within the line; blistering can be followed directly by cartoning, or by pillow packing before cartoning. Cartoning can be directly connected to case packing, or cartoning can be followed by stretch-banding before case packing. The various packaging units within the production line can be flexibly combined, allowing a single line to accommodate multiple packaging modes; pharmaceutical companies only need to switch the blister line’s operating mode.
Due to the extensive use of servo technology in the blister line, its operation is very flexible, and one production line can meet the production needs of multiple products; for example, producing various tablets and capsules on one blister line; for parenteral products, it can meet multiple combination needs, such as: ampoules and vials combined in one blister packaging unit; or ampoules, vials, and syringes combined in one blister packaging unit. The extensive use of servo automatic adjustment and tool-free design in mold changeover makes switching between product types very convenient.
(4) Lowering Drug Prices
Compared with traditional batch production, continuous manufacturing reduces the required production space and labor force. The application of process analytical technology and online detection technology reduces the need for conventional intermediate testing steps, resulting in more stable product quality and reduced material loss. The cost reduction helps ease the financial burden on patients.
Owing to its many advantages, continuous tablet manufacturing is rapidly gaining traction in the pharmaceutical industry. Since the first drug produced using continuous manufacturing technology was approved in 2015, the number of companies worldwide adopting this technology has continued to increase. Pharmaceutical giants such as Pfizer and Merck have incorporated continuous manufacturing into their core strategies. After Pfizer adopted continuous direct compression technology for one of its products, the process development cycle was shortened by 40%, and the amount of active pharmaceutical ingredient (API) used was reduced by 35%.
After GlaxoSmithKline adopted an integrated continuous drying and tableting production line for one of its products, the equipment footprint was reduced by 60%; the use of online monitoring and real-time control reduced the defective rate from 5% to 0.5%, improving quality consistency; the same production line can quickly switch to producing four different tablets, with the switching time reduced to 2 hours (compared to 48 hours traditionally).
What are the biggest obstacles to implementing continuous manufacturing? The main challenges currently faced in continuous manufacturing include:
Most existing conventional equipment is suitable for semi-continuous production, so purchasing equipment in the initial stage will increase costs; continuous manufacturing technology requires a high level of expertise, requiring experts in statistics, process control, etc.; there is currently a lack of equipment specifically designed for continuous manufacturing; there is currently no unified global approval process.
While continuous manufacturing of tablets has made rapid progress in the packaging stage (as described above, blister lines have integrated multiple packaging steps into a continuous production line), the stages before packaging, such as mixing, granulation, and tableting, have seen limited technological breakthroughs in constant production; in recent years, direct powder compression technology has developed rapidly; the direct powder compression process eliminates the granulation step, completing tablet production directly through “mixing → tableting”; this simplification of the process can further promote continuous manufacturing of tablets. However, due to numerous limiting factors, most tablet production still requires a granulation step and cannot use direct powder compression; although some equipment manufacturers in the industry have made several breakthroughs, such as connecting mixing and tableting into a continuous production line; connecting mixing-granulation-drying into a continuous production line, etc., the technology is still in its early stages and its application scope is relatively limited; continuous manufacturing technology for tablets, from raw materials to tableting, needs further improvement.
Continuous manufacturing technology offers high production efficiency, a smaller footprint, superior drug quality, and a shorter cycle from drug research and development to finished product. Interest in continuous manufacturing technology is rapidly increasing in the pharmaceutical industry, and research into this technology is becoming more in-depth. However, due to various constraints, pharmaceutical manufacturing remains primarily batch-based, and very few drugs are produced using continuous manufacturing processes. Further breakthroughs and improvements in related technologies and methods are needed. It is believed that, with joint efforts from personnel in the pharmaceutical and pharmaceutical equipment industries, continuous manufacturing processes will continue to improve, promoting the development of continuous manufacturing technology.