4 Ways To Building A Better CMC Tech Transfer

By Katie Anderson, Chief Editor, Pharmaceutical Online

A technology transfer can falter long before a process reaches the plant. Gaps in process knowledge, mismatched equipment, and insufficient scale-up data can all undermine reproducibility, timelines, and cost. For Tuneer Ghosh, president of CMC at Sai Life Sciences, reducing those risks starts with a shared technical understanding between the sponsor and its CDMO. In our conversation, Ghosh outlined four areas CMC teams should prioritize to build a more robust and successful transfer.

1. Check R&D Acumen

According to Ghosh, the sponsor and CDMO must both know the manufacturing process in detail.  “What’s happening inside those pots and pans, so mechanism of reaction and kinetics of reaction. Have we spent enough time on understanding the thermodynamics or the modeling part? These are extremely important if you've got to go for a robust scale up,” explained Ghosh. He continued that project deadline pressures may make CMC want to rush through parts of process understanding, but it cannot be rushed. “There are certain things which are pretty much non-negotiable, and that's something you really got to step your foot down on if you go to succeed in scale up.”

If it is a sponsor’s first time doing a technology transfer, they may neglect to verify the CDMO’s R&D capabilities. This can result in a huge gap, according to Ghosh. “It's very important to have an R&D backbone along with quality manufacturing facility, because if you run into problems, then you have the right team to jump in and troubleshoot the problems for you. You need a very good group of scientists, engineers, analysts and process safety guys to back up your scale up because without that, you will never succeed in your manufacturing. I've seen a lot of this being underestimated by a lot of customers,” continued Ghosh.

2. Compare Equipment

Using the same equipment in R&D as in the plant leads to better scale up success, according to Ghosh. “Often in R&D, we end up using round bottom flasks and test tubes, which are never going to be comparable with the equipment that you would use in the plant for scale up.”

His team has chosen to use the same reactors that they use in the plant. “This means that if you've got positive results out of that batch in the lab, you can be sure that you're going to be able to reproduce the same results in the plant,” he explained.

3. But First: Plant Entry Study

Ghosh does not believe a sponsor should ever take production from a plant directly to another one, even if they have similar equipment. Whether they are looking for a second site, site diversification or one outside their own network, he recommends a plant entry study in the lab to know exactly what equipment is needed and where adjustments need to be made.

“A 4,000-liter reactor that a customer uses, let's say in a site in Ireland, is not going to be the same as the 4,000-liter reactors that we are going to use in our manufacturing facility. A 4,000 liter reactors would hold 4,000 liters of liquid for sure in Ireland and in India, but then a lot of things would be different. The mixing pattern of those reactors could be different. The type of agitators in those reactors could be different. The way heat transfer takes place in those reactors could be different in terms of jackets. Even if you use similar equipment, the facilities are different. So it's very important that when a process gets transferred from one facility, we don't transfer it from plant to plant. We get the process from the plant to our lab. We do all the plant entry studies that are relevant to [our facility], and then transfer the process back to the plant,” explained Ghosh.

Ghosh continued that there are 20 different kinds of dryers available for unit operations, so whether it is dryers, mixers, filtration, or reactors, a plant entry study with the capabilities of the prior plant and the capabilities of the current plant will indicate adjustments that need to be made early on for maximum success.

“We put a lot of focus and effort on plant entry studies before we take the process to the plant. And all of this has been learning. Look, it's not that I'm telling you that we are perfect or we've done this right from day one because we've gone through a lot of tech transfers. We have seen a lot of failures.

4. Use Process Data

When it comes to process parameters must be accurately characterized. CMC must conduct enough experiments so that there is enough data to support its process parameters; however, it is extra insurance when your CDMO also verifies these parameters before moving it to the plant.

Ghose noted that while process parameters are oftentimes accurately characterized, at times they are suboptimal. He gave the example of temperature, as it is a very important parameter for the reaction. Some labs may give a range, while others may identify more exact reaction temperatures for best yield. As previously mentioned, his lab conducts the study with their high throughput experimentation kits, so they can run 96 experiments in parallel. They generate a lot of data, but more importantly, it is what they do with that data that matters.

Ghosh continued, “Generating data is one side of the story. The most important thing is how you use that data. We use modeling, so all of this data is then fed into these modeling software platforms, and these platforms tell us that, ‘Hey, look, your reactor is not a perfect fit for this particular reaction, but then this is the best that you can offer.’”

Ghosh’s team integrates process analytical technologies (PATs) into facilities, allowing them to see a similar crystal growth that they see in the lab.  He emphasized, again, that a backbone of R&D at any facility is able to proactively see similar trends and different behaviors before the batch is completed and sent over for analysis.

Shared Technical Understanding

The path to a successful tech transfer begins with the end in mind. That means selecting a CDMO with the scientific depth to understand and troubleshoot the process, accounting for differences in equipment and facilities through plant entry studies, and turning process data into informed scale-up decisions. When sponsors and CDMOs establish that shared technical foundation early and refuse to compromise on the work required to build it, they are better positioned to reduce risk, improve reproducibility, and move a robust process into the plant.