• Early phase scale-up

Our early phase project team focuses on quick familiarization and optimization of the process to meet the scale-up needs and timelines of our clients. The early stage project team serves as a bridge between the medicinal chemistry team and the late phase project team. The appropriate process development will be carried out to meet the scale-up needs with the consideration of cost and timeline, so as the project moves forward quickly and efficiently.

All projects require process safety assessment using equipment that can accurately simulate larger commercial equipment prior to scale-up production.

Our quality system clearly defines the requirements for tech-transfer, documentation, process deviations and investigations for the project at early phase to ensure such projects are executed with efficiently. The similar approach is adopted by the ARD team for the analytical method development and quality related studies.

• Late phase API and intermediates manufacturing

Our late phase project team focuses on process robustness and process safety. Process robustness starts with RSM studies, the impurities prior to RSMs will be controlled by setting releasing criteria of the RSMs, and the rest of the impurities in the intermediates and APIs after RSMs will be controlled in the corresponding steps of the process, to satisfy the quality control of the final APIs.

Process safety will be supported by a set of rigorous safety evaluation data, including but not limited to DSC, ARC, RC1, and flammable, explosive and dust explosion assessments.

Bellen Chemistry provides cGMP APIs and intermediates manufacturing services for late clinical phase and commercial new chemical entities(NCEs). Our manufacturing plant in Yantai, China, has a total released volume of 300KL and has passed several audits from pharma, biotech and local government representatives. Our hydrogenators are ranging from 100L to 2000L that operate up to 80 bar and cryogenic reactors with an operating range down to -78 °C, volume ranging from 500L to 3000L. A lot of thought has gone into the design of our production plant in terms of operation flexibility and efficiency, so it serves as a multifunctional plant to meet various needs of our customers.

• Technology transfer

Our team of plant-based process chemists/engineers work closely with process development chemists to prepare procedures for scale up and manufacturing, including comprehensive process safety evaluations together with plant EHS team. The success of tech-transfer lies in the strength of teamwork and best practices for process operational procedures.

Process chemistry engineers are typically involved during the route screening stage and provide inputs and recommendations on the scalability of each unit operation. Once the route is finalized, we will start to consider optimizing the process to ensure scalability and reliability. Timeline, scalability, and safety are critical for the early projects. As the project moves into later clinical phases, our team will revisit the process to ensure it is reliable and optimized. Our technical package consists of process, analytical and EHS aspects prior to scale-up. For projects that have been scaled up in a kilo lab, the detailed procedures are incorporated into the technical package. In-depth discussions are held between the project management team and all related departments to identify risks and provide mitigation plan if needed. A review is conducted at the production site by all relevant personnel prior to start-up to ensure that information has been shared and comments and suggestions have been captured.

The plant-based process engineers, PRD team and ARD team will provide 24 hours technical support throughout the first production run. And they will continue to follow the first few batches and then the production team will take over until the process is validated and production is complete. A report is generated collectively following each campaign incorporating risks, challenges and recommended improvements.

Chemistry is scaled in our kilo-labs with results incorporated into the technical package. An in-depth discussion takes place between stakeholders, facilitated by the project management team to identify risks and provide mitigation where necessary. A Pre-start up review is performed at the execution site with all concerned to ensure learnings are shared and inputs are captured. Process engineers, process development chemists and analytical teams provide 24-hour coverage for first campaigns of a newly scaled process. Process engineers remain to demonstrate the first few successful batches, then the operation team team takes product ownership until a process is validated. A technical report will be generated following each campaign incorporating risks, challenges, and recommended improvements.