AJIPHASE®

The Ajinomoto Group has more than a century’s worth of research and development in the field of amino acid technology. It all began in 1908, when Dr. Kikunae Ikeda of Tokyo Imperial University (now the University of Tokyo) isolated crystals that conveyed the taste he had detected. These crystals were made of glutamate—one of the most common amino acids in foods, and in the human body. Thus, the umami seasoning AJI-NO-MOTO® was born. Since then, the Ajinomoto Group has developed a wide variety of businesses by leveraging our ongoing research into the properties and functions of amino acids.

In the late 1980s, the Ajinomoto Group began manufacturing drug therapies developed by pharmaceutical companies. During the 1990s, we contributed to the production of drugs used in the treatment of AIDS, herpes simplex and hypertension. Since 2005, the Ajinomoto Group had sought to apply our amino acid technology to the synthesis of peptides, chains of multiple amino acids that are a common component of many pharmaceuticals. This has come to fruition in the development of a practical manufacturing process for peptides—AJIPHASE®.

Solid-phase synthesis has been the major manufacturing process for synthesizing oligonucleotides and peptides. In solid-phase synthesis the reaction proceeds in a column charged with a solid support through which the reagents and solvents are flowed. One elongation typically requires several reactions, with a solvent wash for each step, to remove the remaining reagents from the column. Although this process has been fully automated and is rapid, the consumption of reagents and solvents is generally higher than that of liquid-phase synthesis. Given several other limitations and drawbacks, solid-phase synthesis is known to have limited scalability, with only up to kilogram-scale synthesis having been achieved.

Contrary to solid-phase synthesis, AJIPHASE® technology uses an anchor support that is soluble in the organic solvent in which the reactions take place. This provides a uniform distribution of reagents in the system, and thus results in a higher homogeneity and efficiency of the reactions compared to solid-phase synthesis. Therefore, unlike solid-phase synthesis, the consumption of excess reagents can be decreased with AJIPHASE® technology. In addition, the manufacturing of peptides and oligonucleotides via AJIPHASE® can be performed in a conventional batch reactor, which also obviates the need for special equipment for automated controls required in solid-phase synthesis.

Combining the merits of both solid-phase synthesis and liquid-phase synthesis has provided a breakthrough in our manufacturing strategy. Crucially, the discovery of anchor supports that dissolve in a specific organic solvent but not in others provided a powerful alternative to the insoluble resin beads used in solid-phase synthesis. The target crude can be easily precipitated in a batch reactor by adding insoluble solvent. The precipitates can then be obtained by filtration, and a simple wash with poor solvents can eliminate all reagents used in reactions. This easy workup has largely contributed to our development of a robust and practical manufacturing method for peptides and oligonucleotides.

Moreover, AJIPHASE® makes it possible to perform process analysis directly during the synthesis of the target compound, enabling timely processing. Through stringent process control, the manufacture of active pharmaceutical ingredients, or APIs, can be performed on the order of several tens of kilograms at a time while still ensuring high quality. Being able to synthesize very small to very large quantities of API ensures drug companies a stable supply. And because the amount of solvent used is significantly reduced compared to the solid-phase synthesis method, AJIPHASE® is also environmentally friendly.