In recent years, the green transformation of the pharmaceutical industry has become a widely discussed topic, with continuous manufacturing emerging as one of the key technologies driving this shift.  From the national Opinions on Accelerating the Comprehensive Green Transformation of Economic and Social Development to the implementation of the ICH Q13 guideline, continuous manufacturing has become a key lever in the industry's green transition, thanks to its ability to streamline processes and reduce energy consumption. However, challenges such as domestic equipment localization, process validation, and regulatory alignment remain significant obstacles in its adoption. It closely resembles the rise of biologics years ago: everyone recognized it as the future, yet no one could pinpoint exactly when the turning point would come. 

Efficiency Leap Driven by Technological Gap between Generations

If traditional batch production is akin to an old-fashioned train, continuous manufacturing resembles a high-speed rail system - while the former requires frequent stops to load and unload materials, the latter enables uninterrupted, high-speed operation. This generation gap is especially evident in the synthesis of active pharmaceutical ingredients (APIs). In traditional processes, ingredients are repeatedly transferred between separate reactors, with each stage followed by lengthy periods of cooling, sampling, and testing. In contrast, continuous manufacturing enables dynamic flow of ingredients through microreactors, allowing real-time control of reaction temperature, pressure, and flow rate. As a result, production cycles that once took weeks can now be completed within hours. Take the synthesis technology of cardiovascular drugs as an example: after transitioning to continuous manufacturing, the reaction efficiency increased by 30%, and energy costs per kilogram of product dropped by 25%. In today's environment of routine price-cutting through centralized procurement, such gains in efficiency are especially valuable. 

Policy momentum has further fueled industry enthusiasm. In 2023, the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) issued the Technical Guidelines for Continuous Manufacturing of Chemical Oral Solid Preparation, providing a clear regulatory pathway for the implementation of this technology. Innovative local government initiatives have also set examples for continuous manufacturing. In Shenzhen, the "industrial upscaling" model places production equipment vertically within multi-story factory buildings, optimizing the physical space for continuous manufacturing through a three-dimensional layout. This approach - pursuing efficiency by building upward - is now rapidly being replicated in land-constrained regions such as the Yangtze River Delta and the Pearl River Delta. 

Low localization rates of equipment, complex process validation, and lengthy regulatory approval cycles - how can the industry tackle these tough challenges? 

While the industry envisions a promising future for continuous manufacturing, engineers on the ground are grappling with real-world obstacles. Step into any pharmaceutical company undergoing transformation, and you'll likely hear similar complaints: "An imported reactor costs as much as an apartment, but we don't dare to use equipment made in China on our main production lines." Currently, the localization rate of core equipment such as microreactors and continuous chromatography systems remains below 30%, with multinational companies like Corning and Sartorius continuing to dominate the high-end market. This dilemma is not solely about technological gaps. For example, a Chinese equipment manufacturer may have developed microreactors with precision that meets international standards. Yet pharmaceutical companies are still willing to pay three times the price for imported equipment - just to avoid potential risks during process validation. This trust deficit is proving more difficult to overcome than the technical shortcomings themselves. 

The restructuring of quality control systems represents another quiet revolution. Traditional batch production relies on end-product testing - akin to a final exam where everything hinges on one test. In contrast, continuous manufacturing demands real-time monitoring of every stage in the process, like installing hundreds of surveillance cameras along an assembly line for live, continuous oversight. To this end, Tofflon has introduced intelligent continuous production lines that integrate process analytical technologies such as near-infrared spectroscopy, laser particle size analyzers, and others, theoretically enabling millisecond-level monitoring of parameters like blending uniformity and moisture content. However, in real-world operation, fluctuations in humidity during the rainy season in southern China have triggered frequent false alarms from sensors, revealing limitations in current algorithms' ability to adapt to complex environmental conditions. This tension - where machines flag a product as non-compliant while experienced technicians deem it acceptable - is accelerating the shift from empirical quality control to a data-driven approach. 

The mismatch between supportive policies and the practical hurdles of regulatory approval has created hesitation among many pharmaceutical companies on the path to transformation. Although the FDA approved the first drug produced via continuous manufacturing as early as 2015, it still took Johnson & Johnson five years to transition its HIV medication, Prezista, to continuous production. Over 2,000 process validation runs were conducted during this period - a scale of effort that can be daunting for small and medium-sized pharmaceutical companies. China's regulatory authorities have demonstrated greater boldness, with the Center for Drug Evaluation (CDE) allowing the use of dynamic control strategies - meaning that process parameters can be adjusted in real time within an approved range. This effectively opens a green channel for the adoption of continuous manufacturing. What concerns enterprises, however, is whether stability tests after process changes will still require six months to complete. When the technological advantage of "rapid adjustment" collides with a "step-by-step" regulatory review system, such institutional friction may erode the first-mover benefits of innovation. 

Innovation Born from Adversity 

Faced with numerous obstacles, industry pioneers are finding breakthroughs from different angles. A notable example is Hisun, which invested RMB 170 million in building a digital factory. By deeply integrating synthetic biology with continuous manufacturing, the company has achieved fully unmanned operations from raw material input to final product packaging. Its vertical logistics design connects reactors and purification systems through vertical pipelines, reducing material transfer time to zero. This approach - trading space for efficiency - offers a new solution for enterprises operating under land constraints. Multinational giants, on the other hand, are promoting innovation by exporting technological ecosystems. Corning, for instance, has established a continuous flow innovation center in Zhangjiang, operating under a "technology supermarket" model. Pharmaceutical companies can bring in molecular formulas and receive a customized lab-scale process within 48 hours. This turnkey service model is effectively lowering the barrier for experimentation and reducing the cost of trial and error for companies. 

The "upstairs-downstairs equals upstream-downstream" model promoted by Tofflon brings equipment manufacturers, pharmaceutical companies, and academic institutions together in a same industrial park. What once required cross-provincial coordination for technical problem-solving has now become real-time collaboration between neighboring floors. As one park administrator aptly put it: "The real competition today isn't about who has the most advanced equipment, but about who can pull all the elements of innovation together." 

Looking ahead, this transformation may go further than expected. Novo Nordisk has brought a disruptive change to the biologics field by achieving cell densities five times higher than traditional batch processes using continuous perfusion technology. At this crossroads of industrial transformation, every player is searching for their breakthrough. Equipment manufacturers, while tackling critical "chokepoint" technologies, are beginning to offer process development services. Pharmaceutical companies are building cross-disciplinary continuous manufacturing teams and investing in digital infrastructure. Regulatory authorities are working to introduce more supportive and flexible policies to greenlight emerging technologies. 

From a broader perspective, the promotion of continuous manufacturing is set to drive the pharmaceutical industry's transition from high energy consumption and pollution to a low-carbon, environmentally friendly model. This shift is not only a matter of responsibility but an inevitable choice as the global economy moves toward sustainability. Much like the automotive industry's early-stage shift from internal combustion to electric vehicles, the pharmaceutical sector's move toward continuous manufacturing is destined to be a marathon - not a sprint. 

At its core, continuous manufacturing brings more than just a change in the hum of machines on the factory floor - it represents a fundamental reset of the industry's cognitive framework. It forces enterprises to rethink three essential questions: how to define pharmaceutical quality, how to measure production efficiency, and how to build sustainable competitive advantage. Those enterprises that complete this mental shift early may well secure the most fertile ground in the coming decade's reshaping of the pharmaceutical industry landscape. 

Reference: 

[1] 葛淵源, 曹輝, 胡彥臣, 王亞敏, 胡迪. 連續(xù)制造技術(shù)的監(jiān)管策略及挑戰(zhàn)J. 中國醫(yī)藥工業(yè)雜志, 2022(06): 904-911.

[1] Ge Yuanyuan, Cao Hui, Hu Yanchen, Wang Yamin, Hu Di. Regulatory Strategies and Challenges for Continuous Manufacturing Technology. Chinese Journal of Pharmaceuticals, 2022(06): 904-911. 

[2]BOSTIJN N, VAN R J, VANBILLEMONT B. Continuous manufacturing of a pharmaceutical cream: Investigating continuous powder dispersing and residence time distribution (RTD)J. Eur J Pharm Sci, 2019,132:106-117.

About the author: 

Aiden

Aiden works at a Chinese pharmaceutical equipment company and brings over eight years of hands-on experience in pharmaceutical manufacturing. He specializes in optimizing continuous manufacturing processes and driving breakthroughs in domestic equipment development. His focus includes process improvements and intelligent upgrades for core systems such as solid preparation and aseptic filling. Aiden has led numerous projects involving equipment selection and validation, covering critical fields such as powder engineering and automation control systems, and is committed to advancing the green transformation and technological innovation of the pharmaceutical industry.