Jinan Zhuocheng Bio-Tech Co., Ltd.

A Joint Breakthrough by North China Pharmaceutical Group and Tsinghua University

Recently, the "High-Precision, High-Throughput, High-Synergy Modular Micro-reactor Creation and Industrial Innovation Application Project," jointly completed by North China Pharmaceutical Group (NCPC) and Tsinghua University, won the First Prize of the 2025 Hebei Province Science and Technology Progress Award. This project has built the world's first micro-reactor antibiotic production line, achieving a comprehensive transformation of antibiotic production from traditional batch kettle processes to continuous-flow, intelligent, and green manufacturing.

Moving Away from the "Big Pot Boiling" Approach — A Transformed Production Model

Walking into the production workshop of NCPC Xiantai Pharmaceutical Co., Ltd., a 3-cubic-meter reactor stands out among the network of pipes. This workshop mainly produces penicillin-based APIs. Qin Hongliang, the workshop manager, explained that the traditional kettle process is like "big pot boiling" — a full tank of materials reacts in batch, with large liquid holdup and difficult temperature control. In addition, some solid materials need to be manually fed into the reactor, resulting in high labor intensity and safety risks.

"Liquid holdup refers to the total volume of the reaction solution participating in the chemical reaction at the same time within the equipment," Qin Hongliang explained. The larger the liquid holdup, the more heat accumulates instantly, and the higher the safety risk. At the same time, the pH value of the kettle process fluctuates significantly over time and space, which can easily lead to excessive impurity content.

Micro-chemical technology performs reactions and separations within micro- or sub-millimeter microchannels, effectively reducing equipment volume and improving process safety and controllability. Since 2019, NCPC and Tsinghua University have joined forces to pioneer the miniaturization upgrade of antibiotic synthesis processes, focusing on the high-end, green, and intelligent transformation of API and fine chemical manufacturing processes through collaborative research.

In 2020, a micro-reactor production line suitable for penicillin-based antibiotic synthesis was completed at NCPC. Today, the entire process — from enclosed material conveying and precise reaction control to online quality testing — operates automatically. A single click starts the complete production sequence. The real-time liquid holdup in the equipment has been reduced from 3 cubic meters (equivalent to 3,000 liters) to 3.5 liters, significantly improving intrinsic safety. To date, NCPC has produced over 1,000 tons of high-quality penicillin-based products.

Achieving "Precision Crafting" — Solving the Long-Standing Challenge of Mass and Heat Transfer Efficiency

In the laboratory of NCPC Hebei Huamin Pharmaceutical Co., Ltd., R&D personnel carefully took samples prepared using micro-reaction technology for testing. Seeing the significantly reduced polymer impurity peaks, Yang Mengde, Manager of the R&D Management Department at Huamin's R&D Center, could hardly contain his excitement.

He explained that traditional kettle processes suffer from low mass and heat transfer efficiency, which easily leads to increased side reactions and difficult impurity control — a long-standing pain point in the industry.

"Micro-reaction technology transforms 'average processing' into 'precision crafting,'" said Yang Mengde. The high-precision annular tube membrane-dispersion micro-reactor enables micro-level mixing of multiple materials, and with the support of digital-intelligent control, achieves precise control of chemical reactions. Droplets smaller than 6 micrometers and mixing times within 10 milliseconds allow materials to mix and react instantaneously during continuous flow, completely solving the problem of low mass and heat transfer efficiency.

Translating cutting-edge laboratory technology into industrial-scale production capacity of hundreds of tons is no easy task. In 2023, the Huamin R&D team worked side by side with Tsinghua University's expert team, conducting hundreds of experiments daily and recording thousands of data points. Instead of simply increasing the number of microchannels, both teams adopted a new approach — expanding the membrane dispersion area to achieve capacity scaling and using a symmetrical annular structure to overcome the engineering challenge of uneven distribution in planar flow fields. Together, they successfully broke through the core bottleneck of scaling micro-reactors from pilot to industrial production. After the new technology went online, the heat exchange area increased by nearly 70 times under the same production capacity conditions, significantly enhancing heat transfer efficiency.

Reconstructing the Production Process — Advancing from a "Large Antibiotic Producer" to a "Strong Antibiotic Power"

At the Xiantai Pharmaceutical production workshop, operators simply click "Start" on the micro-reactor system, and the equipment begins automatic operation — the micro-reactor automatically controls valve switches and material flow rates, peristaltic pumps automatically control the reaction pH, and pneumatic valves automatically regulate reaction temperature. Operators only need to record the reaction parameters.

"The micro-reactor precisely controls the micro-zone pH within the reaction system, allowing materials to be added in an orderly manner and achieving precise pH control, which improves product quality," said the operator on site.

Through relentless efforts, both parties have achieved a transformation of antibiotic production from "unit innovation" to "full-process reconstruction," promoting the transition of China's high-end chemicals and API industry from batch kettle reactions to continuous-flow manufacturing, from extensive production to green fine synthesis, and from manual operation-dependent processes to fully automated intelligent control.

The new process has delivered remarkable results:

• Xiantai Pharmaceutical: High-risk impurities in penicillin-based products reduced by half; total impurities reduced by 20%

• Huamin Pharmaceutical: Impurity content in cephalosporin-based products reduced by 60% compared to traditional processes, with product quality exceeding European and American pharmacopoeia standards

• Cephalosporin product yield increased by 5%, meaning a net increase of approximately 50 kilograms of product per ton of raw materials, with significantly reduced costs

"Cephalosporin products prepared using micro-reaction technology are of far higher quality than domestic and international pharmacopoeia standards, ensuring drug quality and efficacy while promoting the substitution of imported original drugs," said Yang Mengde. The application of the new production process has directly facilitated the inclusion of piperacillin sodium in centralized procurement, contributing to ensuring public antibiotic safety and making high-quality antibiotics more accessible and affordable.

The collaborative innovation model of "R&D in Beijing-Tianjin, Transformation in Hebei" has effectively driven the iterative upgrading of new technologies and products in real-world testing grounds. Professor Wang Yujun from Tsinghua University stated that both parties will continue to deepen their cooperation, allowing more seeds of collaborative innovation to take root and flourish in Hebei.