Zhuang Yingping from East China University of Science and Technology: The Biomanufacturing Industry Has Entered a 'Three-Domain Era'—How to Bridge the Pilot-Scale 'Valley of Death'?

Click to read the series of articles:China's Top 100 in Biomanufacturing

“Biomanufacturing has become the focal point of technological and industrial competition among countries worldwide,Among these, high-performance strain breeding and bioprocess scale-up are key steps to enhancing the efficiency of bio-manufacturing., which directly impacts the development level of industries such as bulk chemicals, biopharmaceuticals, and enzyme preparations.”

Recently, Professor Zhuang Yingping, Director of the National Engineering Research Center for Biotechnology (Shanghai) at East China University of Science and Technology and Executive Deputy Director of the State Key Laboratory of Bioreactor Engineering, stated in an interview with VCBeat.

In the view of Professor Zhuang Yingping,Pilot-scale testing, a critical step in the scale-up of bioprocesses, has become one of the key bottlenecks in the industrialization of innovative achievements in China’s biomanufacturing sector.

“Because the intracellular processes of microbial fermentation are extremely complex, involving the mixed transfer of tens of thousands of genes, thousands of metabolites, and bioreactors; encompassing gene networks, cellular metabolic networks, and bioreactor networks across different spatial and temporal scales; addressing the multi-input multi-output relationships of material flows, energy flows, and information flows among systemic networks; and further involving the spatiotemporal cascade reaction relationships unique to life attributes. Moreover, these phenomena are not merely simple statistical thermodynamic relationships.”

“For the extracellular environment, multiple factors must be considered, including the distribution of concentration, temperature, and velocity fields within the bioreactor, as well as particle aggregation and bubble coalescence and rise.”

As biomanufacturing confronts the intricate and profound challenges of life systems, Professor Zhuang Yingping believes that,Engineering studies of biological processes, bioreactor design, and the application of intelligent technologies are particularly important.

It is reported that biomanufacturing is a green production method that utilizes renewable raw materials to achieve substance synthesis and energy conversion in bioreactors.

As a critical pillar for advancing ecological civilization and achieving carbon neutrality, biomanufacturing facilitates feedstock substitution (such asVarious types of biomass, including waste biomass, carbon dioxide, etc.) and mild production conditions, which can effectively address challenges such as energy shortages, climate change, and environmental pollution.Currently, bio-based products worldwide have accounted for petrochemical products'10%, and at an annual rate of over20%rate of growth.

According to Professor Zhuang Yingping’s review, industrial biomanufacturing has undergone four stages from the perspective of historical evolution:

• From traditional solid-state fermentation in the early stages (wine brewing, vinegar production) to anaerobic fermentation for primary metabolites in the first stage (such as acetone-Butanol-Ethanol);

• Subsequently, the second stage involves liquid aerobic microbial fermentation to obtain secondary metabolites (e.g., penicillin fermentation);

• Then to the reorganization in the third stageDNATechnology (genetic engineering) and large-scale cell culture (e.g., production of recombinant proteins);

• Currently, the fourth phase is driven by technologies such as synthetic biology and gene editing, focusing on constructing high-efficiency microbial strains alongside advanced biological tissues., it can be dedicated to addressing critical needs such as food security, the dual carbon goals, and disease treatment, including applications in the medical field like artificial organs and cell therapy.

Divided by industrial sectors, biomanufacturing has roughly formed a "tripartite" landscape:

• Green Biomanufacturing (Agriculture):covering hybrid crops, gene-edited crops, agricultural microorganisms, biopesticides, and livestock farming;

• White Biomanufacturing (Industrial):including bioenergy (ethanol, hydrogen), biomaterials (PLA、PHA), bio-based products (sugars, amino acids), artificial food and feed, and industrial enzyme preparations;

• Red Biomanufacturing (Pharmaceuticals):Involving recombinant protein drugs, nucleic acid drugs, vaccines, diagnostic reagents, and artificial organs.

Professor Zhuang Yingping stated that biomanufacturing technology is driving innovation and industrialization in multiple fields, including cosmetics, food, pharmaceuticals, and industrial materials, at an unprecedented pace. Its core advantage lies in its ability to replace traditional chemical synthesis or natural extraction methods with a more sustainable, efficient, and controllable approach, thereby producing products with superior performance, greater environmental friendliness, and lower costs.

“For example, in the manufacturing of cosmetic ingredients, biomanufacturing technology has demonstrated strong capabilities for substitution and optimization., which can promote the production of more raw material products through biomanufacturing, offering dual advantages in quality and production efficiency.”

Professor Zhuang Yingping stated,With VitaminsB5as an example, recognized as the “king of skin repair,” is widely used in skincare products. Through “heterologous pathway reconstruction+“Metabolic Pathway Optimization” strategy, including key steps such as enhancing pyruvate supply, regulating carbon flux, and cofactor regeneration, combined with fed-batch fermentation process,Significantly increased fermentation yield, making it suitable for industrial-scale production. Moreover, vitamins produced via fermentationB5Closer to natural sources, with better biocompatibility and easier skin absorption.

Hyaluronic AcidAs a "natural moisturizing factor," its biosynthesis also relies on the systematic reconstruction of metabolic pathways. By attenuating byproduct pathways and enhancing the target metabolic flux through glycolysis, researchers achieved in bioreactorsUp to28.7 g/Loutput. This process utilizes simple raw materials such as carbohydrates and nitrogen sources as substrates, thereby avoiding extraction from animal tissues, while enhancing yield and simultaneously addressing environmental protection and sustainability.

CoenzymeQ10As a star antioxidant ingredient, its microbial fermentation method is characterized by high biological activity, low cost, and high yield. Through systematic optimization of the fermentation process—particularly precise nutrient supply and metabolic regulation during aerobic fermentation—Resolved metabolic bottlenecks during high-density cultivation, enabling efficient and stable industrial-scale production.

SophorolipidsAs a high-performance biosurfactant, sophorolipids can be produced efficiently through high-throughput screening and metabolic regulation. The use of mutagenesis and multi-stress screening to identify high-yielding strains, combined with metabolic mechanism analysis, has significantly increased sophorolipid production.This technological pathway features low ecotoxicity and utilizes renewable raw materials, aligning with the trend toward green manufacturing.

Furthermore, in the field of high-value biomaterials, Professor Zhuang Yingping further pointed out thatSignificant Progress Has Been Made in the Biofabrication of Spider Silk Proteins.By optimizing the culture medium using response surface methodology, developing feeding strategies, and implementing precise control of the fermentation process, in50LTo500LProcess scale-up was achieved in large-scale fermenters. Although the total yield remains low (e.g.,500LCanyue Chan450grams), but this technologyThis approach circumvents the infeasibility of spider farming, paving a new path for the sustainable production of high-strength, biodegradable protein materials.

From this perspective, biomanufacturing technology is achieving increasingly widespread application in fields such as cosmetics, functional foods, and specialty materials.

However, it should also be recognized that in most fields, the advantages of biomanufacturing technology can only be fully realized through large-scale production,However, the complexity of biological systems renders manufacturing processes fraught with challenges and uncertainties, making the translation from laboratory to industrial scale particularly arduous.

2025At the beginning of the year, Professor Zhuang Yingping and other researchers published an article in *Bulletin of the Chinese Academy of Sciences*, pointing out that the complexity of life systems is not only reflected in the intricate interactions among biomolecules but also includes the dynamic changes in the intracellular and extracellular environments, as well as the mechanisms by which organisms respond to external stimuli.

These complexities often lead to a series of challenges—such as process parameter optimization, stability enhancement, and cost control—when scaling up small-scale laboratory research findings to industrial production levels.Furthermore, there is a significant disconnect between basic theoretical research and industrial application, making it difficult to rapidly translate scientific achievements into actual productive forces.

“Bioprocess engineering research plays a crucial role in addressing the complexity of living systems,” stated Professor Zhuang Yingping.

Analysis indicates that the optimization and scale-up of fermentation processes are core components of biomanufacturing. This process is, in essence, a complex engineering endeavor involving two types of reactor systems:First, the external physical fermenter or bioreactor; second, the internal “cell factory,” where microorganisms or cells themselves function as complex reactors.

“Cell factories, as active systems with complex metabolic networks, are central to achieving the synthesis of target products. Therefore, the fundamental goal of manufacturing process optimization lies in precisely regulating cellular metabolism to enable efficient, directed production of target products while minimizing byproduct formation. This necessitates in-depth engineering studies of the integrated system comprising cells and the bioreactor environment to elucidate its underlying operational mechanisms,” pointed out Professor Zhuang Yingping.

According to Professor Zhuang Yingping’s review,Her supervisor, Professor Zhang Siliang, and others proposed that complex systems in bioprocesses can be understood through “multi-scale” models, encompassing multiple levels from molecules to bioreactors:

• Gene Scale:The genetic background of a strain or cell line determines its inherent production capacity and serves as the fundamental basis for product synthesis.

• Cellular Scale:By regulating cellular metabolic flux through process optimization strategies, the expression efficiency of the same strain can be significantly enhanced, achieving a leap in yield from the gram level to the tens-of-grams level.

• Reactor Scale:In macro-scale bioreactors, the transfer and supply of environmental parameters such as nutrients (e.g., carbon and nitrogen sources) and dissolved oxygen are critical. For instance, in aerobic fermentation, oxygen supply must be precisely controlled; both excess and deficiency can lead to shifts in metabolic pathways, thereby affecting yield.

For instance, in the case of reactor scale, the internal environment is critical, and this issue can be understood from both spatial and temporal dimensions.

Professor Zhuang Yingping stated,At the spatial scale, achieving absolute uniform distribution of materials within large-scale industrial reactors (e.g., those with capacities of hundreds of tons) is difficult.Gradient fields of nutrient concentration, temperature, velocity, and oxygen distribution exist within the bioreactor. Factors such as bubble size and distribution generated by aeration, as well as agitation-induced shear stress, directly influence mass transfer and mixing efficiency. Therefore, it is crucial to optimize bioreactor configuration (e.g., impeller type, baffle arrangement, and coil layout) using methods such as computational fluid dynamics (CFD) simulations.

“Practice has shown that even with identical tank bodies, slight differences in internal components can lead to production efficiency variations exceeding10%or greater significant fluctuations.”

On the time scale, the physiological states and metabolic activities of microorganisms or cells continuously change across different fermentation stages (early, middle, and late)., thus requiring dynamic regulation of environmental parameters to keep the microbial cells in a metabolic state most favorable for target cell growth or product synthesis.

“Therefore, successful process scale-up relies not only on precise bioreactor design and flow field simulation but also on on-site verification of actual plant equipment configurations and online monitoring of cellular physiological and metabolic parameters. Integrating the regulation of spatial and temporal scales is key to achieving stable and efficient industrial fermentation.”

“Moreover, the fermentation process is a typical complex system with multiple inputs and outputs, where any change in operational parameters may trigger a chain reaction that affects the final outcome.“Therefore, coordinated research and precise regulation across the three scales of genes, cells, and bioreactors are key to achieving efficient optimization and successful scale-up of fermentation processes,” emphasized Professor Zhuang Yingping.

However, even with these measures in place, it remains difficult to guarantee a perfect response to the complex challenges posed by living systems. To achieve comprehensive control over the complexity of living systems,It is also necessary to leverage digital, model-based, and intelligent approaches.

Professor Zhuang Yingping further stated that in the design of bioreactors, it is essential to achieve online monitoring of cellular physiological and metabolic characteristics; this can be accomplished through the application of sensors such as online Raman and online infrared spectroscopy. Furthermore, after acquiring massive amounts of data, data science research must be conducted to ultimately realize intelligent biomanufacturing.

“Intelligent biomanufacturing, as a new form of advanced productive forces, achieves comprehensive monitoring, in-depth analysis, and precise control of the biomanufacturing process by integrating information technology, control technology, and biotechnology.”

“This process relies not only on advances in bioprocess engineering but also on the support of digitalization and modeling technologies. By digitally describing and model-based prediction of biomanufacturing processes, we can gain a deeper understanding of the complexity of living systems, optimize production processes, reduce production costs and energy consumption, and promote the development of the biomanufacturing industry toward a green, low-carbon, and sustainable direction.”Ultimately, by leveraging intelligent technologies, autonomous decision-making and adaptive control of biomanufacturing processes can be achieved, thereby realizing truly intelligent biomanufacturing.”Professor Zhuang Yingping stated.