Core Technical System of Automated Closed Solid-Phase Peptide Synthesis
The realization of automated closed solid-phase peptide synthesis relies on the collaborative support of three core technical systems: equipment, process, and control. These three parts cooperate with each other to form a complete closed production loop. Combined with industrial practices, the core technical system is described below, which balances operability and standardization to meet industrial-scale production requirements.
Closed Reaction Equipment System
As the core of production, it must meet the requirements of closed isolation, corrosion resistance, easy cleaning, and scalability. Key equipment includes closed solid-phase synthesis reactors, reagent storage and delivery systems, waste liquid treatment systems, and inert gas protection systems.The closed solid-phase synthesis reactor is made of high-borosilicate glass or corrosion-resistant alloy, equipped with a high-precision stirring device. Asymchem has optimized the structure of the stirring impeller through LBM-based numerical simulation software, which ensures good suspension and mixing of resin and reactants while avoiding excessive shear force from damaging the resin, and adapts to elution, pressure filtration, discharge and other multi-step operations. Reagent storage tanks adopt a closed design with liquid level monitoring and pressure control modules to realize automatic quantitative delivery of reagents and prevent leakage. The inert gas protection system feeds nitrogen into the reaction system to isolate air, prevent amino acid oxidation, and ensure synthesis efficiency and product purity. The waste liquid treatment system is hermetically connected to the synthesis reactor to realize automatic collection and harmless treatment of waste liquid, meeting environmental protection requirements. In addition, some high-end equipment is also integrated with a UV online monitoring system, which can monitor the status of amino acid coupling reaction in real time, facilitate timely adjustment of process parameters, and improve synthesis success rate.
Automated Process System
Based on the classic solid-phase synthesis process (Fmoc or Boc method), the automation-adapted process is optimized, mainly including resin activation, amino acid coupling, deprotection, washing, cleavage and purification processes.The Fmoc method has become the mainstream process for automated closed production due to its mild reaction conditions and high deprotection efficiency. Its core is to protect the N-terminus of amino acids with an Fmoc protecting group, activate the carboxyl group with a coupling reagent, and perform a condensation reaction with the amino group on the resin to gradually extend the peptide chain. After each coupling step, the Fmoc protecting group is removed with piperidine, and the next coupling cycle is carried out until the peptide chain synthesis is completed. The Boc method is suitable for the synthesis of some short peptides and is still adopted by some enterprises due to its high yield.In view of the characteristics of automated production, the core of process optimization is standardization and programmability. For example, optimizing the dosage of coupling reagents, reaction temperature and time to reduce side reactions; adopting a gradient washing process to thoroughly remove unreacted amino acids and reagent impurities; optimizing cleavage conditions to achieve efficient cleavage of peptide chains from the resin while reducing peptide chain degradation and improving product yield and purity. In addition, the whole process from resin swelling to peptide precipitation can be standardized through chemical description language (χdl), realizing the automated synthesis of complex modified peptides and unlocking the technical bottleneck of automated SPPS.
Intelligent Control System
It is the core to realize automated and precise production, integrating PLC control system, host computer software system, DCS linkage system and online monitoring system to achieve unmanned intervention and full-process controllability of the entire production flow.The PLC control system is responsible for controlling the operation of each equipment, accurately regulating key parameters such as reagent delivery volume, reaction temperature, stirring speed and reaction time, with an error controllable within ±1%. The host computer software system is independently developed by the technical team, seamlessly connected with the control system, and based on formula-based automatic control, which can judge the interactive state between the synthesizer and auxiliary equipment, and automatically determine the feeding time and volume, thus realizing unmanned production of the entire solid-phase synthesis.
The DCS linkage system connects the communication of the whole plant’s DCS, PLC and solid-phase host software, eliminating information islands in the control process and realizing whole-plant control linkage. Asymchem uses this system to realize constant-pressure delivery in the solvent tank area and automatic receiving in the waste liquid tank area; the solid-phase synthesis reactor can automatically call solvents from the tank area, and when the liquid level in the tank area exceeds the limit, the reactor automatically enters a hold state to ensure production safety.The online monitoring system can monitor parameters such as temperature, pressure, pH value and peptide chain concentration of the reaction system in real time. Once an abnormality occurs, the system automatically alarms and adjusts parameters to avoid production accidents and unqualified products. At the same time, it records production data to realize traceability of the production process and meet GMP compliance requirements.