The Most Important API Scale-Up Lessons Learned


Readers of this blog know that for many years we have been banging the drum for bringing API candidates into the kilo lab for scale-up.  The kilo lab’s importance lies in the ability to minimize any stomach-churning unpleasant surprises at far less cost.  If processes need to be adjusted, the manufacturing suite is not the place to do that for the first time, resulting in pausing production and idling the plant.  It’s a costly mistake that causes severe headaches all around – we hate it as much as our clients do.

In the kilo lab, relatively small and gradually greater amounts (1 – 20 Kg) of non-GMP compounds are produced.  As this scale-up takes place, if issues are encountered, they can be resolved so that there is greater likelihood that GMP manufacturing will go more smoothly.  

As well, kilo labs do not need to be GMP compliant, so any procedure that has been tested in a conventional lab can be scaled, as when preparing API materials for non-clinical use and other applications.

That is just one lesson about scale up we have learned over the decades that we have been producing APIs, GMP functional foods and polymers.  This article will focus on additional lessons learned that also help wring costs out of the early phases of drug development.

Employ a very methodical approach to scale-up

Customers always want everything yesterday.  However, nothing can cause a project to encounter delays and cost more than moving too quickly or cutting the wrong corners.  Investing more time up front to understand the chemistry involved can save a great deal of time and money.   A scale-up phase is where the investment should be made.  Scale-up is a balancing act, and requires judgment calls.  Knowing when a process is ready to move to the next level is as much of an art as a science.  And that judgement has best results when it’s applied by highly experienced hands in the kilo lab.

Don’t begin analytics too early

Yes, regulatory requires that every process be documented. The question is when to start analytics, and this may come as a surprise to some: it is a waste of resources and money if the analytics team is brought in too early.  Although R&D and analytics always work closely together, it’s prudent to wait until R&D is at a point where the scientists are comfortable that no new chemicals or raw materials will be introduced, and no other impurities are expected to materialize. Once that’s understood, that’s the time to bring in the analytics team. 

Generally, it is not the level of impurities that’s of concern. Higher or lower levels of an impurity are OK. The impurity is known and there are ways of adjusting processes to remedy and meet specifications. However, if a new impurity develops, that’s a bigger problem. Both from a scale-up and analytical support perspective, timing is everything. Proper judgement needs to be used to make appropriate decisions.

Begin optimization before going into the kilo lab

Expect to spend weeks or months in the optimization phase. The more developed the chemistry when it comes to us – which varies from a molecule on a piece of paper to processes near ready for the GMP suite – taking the time and effort to make sure the process works is warranted. At every stage there’s an investment being made. The more you spend up front at a small scale to understand the chemistry more completely, the more those modest investments up front pay dividends down the road.

For example, it appeared that one of our projects would require two 20 Kg batches to yield the desired amount. Each one of those batches was going to cost $450,000.  But the process wasn’t fully optimized. Working with our customer, we extended the lab time and went $100,000 over budget. But by doing that we achieved a yield of 38 kilos with the first batch, negating the need for a second batch and saving the customer $350,000. It was a win-win all around. Needless to say, the client was overjoyed.

Optimize in the kilo lab

To optimize time in the kilo lab, we want to run processes at the largest appropriate scale.  If the API is headed for the manufacturing plant, we want to run the process at 100 liters (roughly 25 gallons).  We can learn a lot at 100 liters. We also run the process multiple times to check that results are consistent.

What if a process doesn’t scale in the kilo lab?

Much depends on the nature of the problem.  If an impurity crops up at higher levels than was seen at the smaller lab scale, the scientists first need to figure out how and why it was formed.  Once that is understood, they can adjust the process. That may involve taking longer to heat, or longer to cool, or adding more raw materials. 

Another issue we often see is some physical issue with the material. Particles may form, and filtration processes may need to be adjusted, or a second filtration process added.  Usually the problem can be fixed.

A new impurity is more of a problem and the solution not as simple. But in either case, and particularly with GMP materials, it’s far less costly to make process development adjustments in the kilo lab. You want to avoid at all costs doing process development at the manufacturing plant. That entails investigations and a great deal of paperwork.  It’s just too expensive. It causes delays.  It’s avoidable.

Expect the unexpected

Even when we run a process three times in the kilo lab, it doesn’t mean the road forward will be smooth. The stars don’t always align for the repeated outcomes we look for in the kilo lab.  However, at 50-100 kilos much of the heavy lifting has been done and we’re well on our way. But we’ve occasionally seen challenges crop up much later, when we get to higher scale. Chemistry is a funny thing.

Choose a CDMO with multiple sites

Technology transfer causes undue cost and time delays.  If our capacity in the U.S. plant is ever fully utilized, we can transfer projects seamlessly to our larger facilities in Europe. Clients can stay with us through clinical trial Phases I, II, III without any supply interruption.  There are additional advantages of having multiple sites producing materials.  Not only is it extra insurance in the event of a catastrophe (such as the devastating hurricane in Puerto Rico) but also eases compliance with regulatory requirements on different continents. 

For more information about scale-up and kilo labs, check out the following: “4 Ways the Kilo Lab Development Phase of Drug Manufacturing Can Save Time and Money,” “5 Best Ways to Save Money in API Development: Despite the lack of a road map, more than 20 years in the CDMO business has given us a pretty good idea of what it will cost to develop an API,” and “Early and Late Phase Drug Development: The Route Most Likely to Succeed

Understanding Costs of the 5 Stages of API Production.” Please call (978) 462-5555 to ask get more ideas about how to save money getting your API to the clinic.