The process of scaling up from the kilo lab to full production in API manufacturing can be filled with anticipation. As you scale up, the efficiency of your API synthesis becomes increasingly important. While the ultimate goal is to create a production-level process that yields the best results in each batch, this doesn’t always happen for reasons often out of a Contract Development & Manufacturing Organization’s (CDMO’s) control.
With scale-up can come a number of challenges – from making sure the chemistry works in larger equipment, to eliminating new impurities. Problems that arise in production can be quite costly when compared to the smaller quantities produced in earlier stages. For this reason Process Optimization is key.
Process optimization lays the groundwork for effective scale-up, so it’s important to select the right CDMO for the job – one with related experience and expertise to help you avoid any set-backs as you move into GMP. The process optimization stage fully establishes and tests the process that will form the basis for the whole program.
After familiarization and tech transfer between the sponsor and the CDMO, the process optimization stage helps to determine what will be required to scale up the molecule and turn the chemical into a drug substance that is free of impurities. During this stage that sets the stage for the kilo lab, the team will determine the quantity and quality of the raw materials needed, and the chemistry and analytical requirements that will ensure that yields are reasonable and that the end-synthesis can eliminate impurities to meet FDA requirements and ICH guidelines.
During this stage, CDMOs need to understand as much as possible about the process. This includes the Critical Process Parameters (CPPs), or the key variables affecting the production process. CPPs are monitored to detect changes in production operations and product output quality or changes in Critical Quality Attributes, such as temperature, the time it takes for a reaction, crystallization and agitation speed and other factors.
Other activities that ensure thorough research, is the Design of Experiments (DOE), a way to determine the relationship between factors affecting a process and the result of that process. A DOE is used to find cause-and-effect relationships, and is needed to manage process inputs in order to optimize the output, and to determine where there might be roadblocks to the manufacturing process.
Ultimately, process optimization is only as good as the scientists handling it. This phase can often last several months and continuity is crucial to meeting timelines and budgets.
After the familiarization and process optimization stages comes scale up of materials in the kilo lab. This is a critical phase that can often minimize unpleasant surprises when the process is tested in the pilot plant for the first time and provides the ability to produce relatively small amounts (1 – 20Kg) of non-GMP compounds to address customers’ needs in a timely manner.
While some sponsors don’t want to pay for a trial run in the kilo lab, it’s a cost-effective step to make sure everything performs as expected and can scale. The kilo lab lets you simulate plant conditions to ensure, for example, that the desired characteristics of the API are obtained before you rack up higher costs in the production plant.
Handling familiarization, process optimization and scale-up in the kilo lab can go a long way to minimizing issues in large-scale manufacturing. Below are five ways you can minimize challenges on the road to the plant.
Scaling up your API in full production mode is the final stop on the road to commercialization. Being overly diligent in earlier stages can go a long way to making it an easier and less costly one for CDMOs and sponsors alike.