Understanding the Science of Scale-Up in API Manufacturing

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 – The Key to Effective Scale-Up in the Kilo Lab and the Plant

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.

Scale-Up Begins in the Kilo Lab

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.

1. Create multiple batches in the kilo lab. You can’t create one batch in the kilo lab and expect it to be ready for large-scale production.  It’s important to run the substance in the kilo lab through three batches to make sure the chemistry works for GMP manufacturing.  If it doesn’t work after three times in the kilo lab, we look for the issues, which may entail going back to the DOE in the Optimization Phase.
2. Don’t minimize tech transfer. One of the most important jobs in the kilo lab is tech transfer at the end of the process. Once you demonstrate that there are no issues during the scaling up phase you should assign a chemical engineer to talk with the kilo lab team to prepare a master batch record of the processes necessary to move to GMP manufacturing.
3. Focus on quality, not cost. You can expect to pay approximately $16,000 to $20,000 per week in the kilo lab, which should include doctorate-level scientists conducting research and scale-up studies, documenting results, testing assumptions, and steadily improving the process. When developing a new chemical entity for clinical supply and eventual commercialization, hourly rate should be irrelevant.  What should be more important is expertise and experience, since that will help you avoid greater costs in the long run.
4. Stick with a single CDMO through all stages. It’s wise to work with the same CDMO through all stages to ensure seamless transfer of critical information, challenges and resolutions. A CDMO that is vested in your project and intimately understands the chemistry and how it has behaved throughout each process can go a long way to bringing the project in on schedule and budget.
5. Don’t rush it. Make sure that timelines allow for issues and problems to come up. There always will be new impurities that are found, issues with processing or yield problems during scale-up, but with realistic timelines that factor in these potential set-backs one problem won’t have rippling effect across the entire project.

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.

About the Author

Ed is President & CEO of SEQENS North America (formerly PCI Synthesis). He serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA)...

Do you have questions? Talk to Ed.