After the Familiarization and Process Optimization phases of drug substance development, we understand the Critical Process Parameters (CPPs) and the key variables that will affect the production process.
As we wrote in the prior article about Optimization, a Design for Experiment (DOE) was undertaken to determine the relationship between factors affecting a process and the output of that process. At this point, we need to conduct the process development necessary to scale up materials for our clients’ pre-clinical studies.
Kilo labs, which don’t need to be GMP compliant are capable of carrying out any procedure that has been done in a conventional lab, and can be used to prepare materials for a large number of activities, including:
The lab can also carry out runs of modified processes to demonstrate new procedures on a larger scale prior to being used in the more expensive cGMP suites, which PCI Synthesis operates, or scaled up further in our cGMP manufacturing plant.
The kilo lab phase is important because it 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.
In some cases, clients don’t want to pay for 1 or more runs in the kilo lab, but we feel it is an important step that can actually save time and money.
In the kilo lab, which can cost between $10,000 and $20,000 per week, you can produce a first kilo to make sure that everything works as expected. Kilo labs offer the ability to mimic plant conditions to ensure, for example, that the desired polymorph of the API is obtained – but the benefit is that because it’s non-GMP, it limits the expense. Also, keep in mind: you want to get this phase right because it takes more time and money if you go directly to GMP manufacturing and have to start over again at the Optimization Phase. Beyond the cost, there is also the time delays since equipment, personnel and raw materials have to be scheduled again.
Because FDA requirements include the necessary paperwork and compliance efforts as well as the preparation for possible inspections, GMP manufacturing is much more expensive and can cost between $70,000 and $80,000 per week. You can chew up tremendous resources if you find out during cGMP that the process does not scale up.
In fact, at PCI Synthesis, we run the process in the kilo lab three times to make sure the chemistry works and to collect the appropriate information.
The goal is to work through the three times as quickly as possible to get the substance into 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 Optimization Phase.
Once we demonstrate that there are no issues during the scaling up phase in the kilo lab, we assign a chemical engineer to work with the kilo lab team in order to prepare a master batch record.
The step-by-step details of the process that will go into GMP manufacturing. Even if everything does work, if you’re going to make changes to the process, this is the time to do it.
This part is very important because this is the start of the documentation that will be included in any potential filings, including the Drug Master Files (DMFs) and any Investigational New Drug Applications (INDs).
The kilo lab phase is an important foundational phase that can save tremendous costs in the long-run. It helps the sponsor and our team to be sure we understand the steps involved, the parameters, and also even the impurities that get produced as we scale up to get ready for GMP manufacturing. Conducted the right way, the kilo lab phase ensures that manufacturing is a smoother, more efficient process.
At PCI Synthesis, the kilo lab phase is so important that we are reluctant to work with sponsors that won’t make the short-term investment. We have found that the kilo lab can pay off big time in minimizing the possibilities of set-backs that can delay the project and increase the costs.
4 Steps to Follow for Successful Good Manufacturing Processes (GMP) Pharmaceutical Manufacturing