Avoiding and Addressing Surprises in the API Manufacturing Process

Starting Early: How to Ease the Process of a New Drug Application
September 16, 2021

Avoiding and Addressing Surprises in the API Manufacturing Process

When you’re developing and manufacturing your active pharmaceutical ingredients, the last thing you want to deal with is surprises. Unfortunately, even with the soundest methods, processes, and strategies, problems occur in manufacturing.

From his experience in the days before modern good manufacturing practice (cGMP ), Dave Adams, senior drug substance consultant at DSI, a ProductLife Group company, quickly learned the importance of understanding the plant and how the equipment and the processes work when putting an API into production.

That means involving the operators, listening to them, and working with them to troubleshoot a problem.

“For many years at one of the companies I worked for, we operated a plant by having a team with one member from each department: QC, purchasing, warehousing, etc.,” Dave says. “There were maybe eight people on a process team, and this team would have full responsibility for running a batch, a campaign. We also included operators on the team, and they provided invaluable input on managing processes in cheaper, faster, and safer ways.”

Developing your API

Before companies take their molecule into manufacturing, they need to prepare pilot batches and scale up, and that’s where you need to involve someone with plant or development experience. That’s because, while a filtration or distillation might take minutes in a laboratory, it could take several hours in a plant.

“In production, time is money. The longer it takes to run the process, the more it’s going to cost your company, while the faster something is produced, the lower the cost,” Dave says. “As soon as you see a distillation, an engineer can calculate how many hours of work that’s going to be, and what that is going to do to cycle time.”

Ideally, your development chemist should have plant experience so they can develop the simplest process for any plant. “Make a process that separates well and doesn’t need conductivity sensors or that filters well and has good crystallization,” Dave adds. “Another consideration is your choice of solvent. Pick a solvent that boils easily or works well for your process so the engineer won’t have too many difficulties putting it into the plant.”

Another key point is to make sure your development chemist pays attention to anything they observe in development, documents any issues, and investigates them further. This can avoid costly issues from escalating further down the track.

Bringing in the regulatory experts

With the advent of cGMP and quality by design (QBD) approaches to development, there has been a move to bring regulatory and quality assurance people in when defining a process and designating the raw materials. This viewpoint is key because of the need to define potential impurities in your filings.

You also need to define very specifically what you expect from your supplier during the agreement phase so you aren’t left with surprises from the raw material.

“If you’re worried about heavy metals, if you’re worried about sand or two by fours, you need to spell that out,” Dave says. “You need to be very careful and do an audit to ensure that they’re not going to give you surprises.”

The cost of those surprises can be high – from damage to your reactors if sand gets into the product, to failed batches that can massively set back your development program.

Penny-wise, pound-foolish

A common concern for companies with the development process is cost. Never scrimp on the time and testing it takes to develop your product because you cannot anticipate how long development is going to take.

“One very important thing I’ve asked every time I’m involved with a new project is, ‘Did you try it on the plant time cycle? Did you hold it?’,” Dave notes. “One client intentionally held each step for 12 or 14 hours just to stress test it, they went purposely slow at each step, including a filtration step that could be done in half an hour. They wanted to prove that it was going to work.

“Another client wanted us to heat a batch with sodium hydroxide and water so it boils at 100. When the sample was ready, it was already overcooked and degrading. On the second batch I asked the operator to take a sample before they heated it up, and it was already done. The reaction was that fast in the plant that they didn’t need to heat and hold for an hour. By following their process, they were degrading the sample. So yes, you need to investigate every parameter during development, and some of them might lead to surprises.”

These are important considerations as you develop your validation protocols. Identify your critical process parameters and build in safety factors for a robust development process.

Working with partners

One key consideration when working with contract manufacturers is how experienced they are. Often the only way to know that is to have some insight or experience in the manufacturing process before contracting a CMO. Also, be aware that if the contract you sign with a CMO doesn’t specify cycle time and batch quality you can end up losing money.

“It helps to have somebody on your side who understands production and knows when you’re being taken advantage of, even up front when you’re signing your contracts,” Dave says.

Building a relationship between the sponsor and the CMO to ensure that connection with production, engineering and quality control ensures a far more seamless process than just having someone in the CMO blindly read a document. When clear communication channels are established, the sponsor has regular updates about the production process rather than waiting weeks or months to find out what’s happening.

When managing the technology transfer between the sponsor and CMO it’s important to have standard operating procedures in place. Document what you want to transfer, who’s going to be responsible for what, who’s going to supply samples, references, test procedures, and what’s going to be developed at which site.

“It’s important to connect people on both sides – the analysts, the engineers, the chemists, and so on,” Dave says. “They need to follow SOPs and document everything they’re doing. They sign it every time a method is transferred or batch record goes back and forth for approvals and revisions until both sides agree that it’s transferred correctly.”

Selecting a champion

At the top of the pyramid, it helps to have a process champion, someone who owns the process and who is an overall subject matter expert. He or she is the person who makes the bigger decision, such as increasing production or moving to a different site or placing orders. “It’s very important to have one process owner or process champion, one person who represents the process,” Dave says. “It’s this person who deals with scheduling issues at different plants, ensuring production at one site is ready in time for delivery to another site and that the overall plan is working.”