THE DO’S AND DON’TS OF SELECTING A CONTRACT MANUFACTURER

The medical chemistry process early on involves just a few kilograms of product as most drugs don't make it into the clinic. But if all goes well, and the drug makes it to that stage, suddenly the quantities become metric tons or more, and the manufacturing and safety processes become quite different.

For emerging biotech companies that might have used a small med-chem contractor to handle limited-scale active pharmaceutical ingredient (API) development, that often means finding a new vendor, and that can be a difficult move for a company that has no experience with contract manufacturers and may just be looking to go as far as Phase II.

Asking the Right Questions

Rick Offerman, Ph.D., Senior Project Management Consultant at DSI, a ProductLife Group company, said it’s important to initiate discussions with several CMOs and pose key questions to their team, such as: “Have you taken a number of Phase I processes and converted them to commercial manufacturing?” Then, ask them to review your process and tell you about pitfalls. If you’re using techniques that won’t translate to large-scale manufacturing, ask what they would do in its place. Let them tell you what their plans are, and then assess what they’re telling you.

In early med-chem, the type of solvent you use is largely irrelevant. But as you move into Phase II and beyond, you have to consider issues such as whether the solvent is toxic, hard to dispose of or if there are environmental limits on how much of the solvent can be used in a facility, as well as cost of the solvent.

“When you go to a competent CMO, they'll start screening a lot of solvents, and they will propose simple screening experiments to determine yields and impurity profile,” Offerman said. “Cost is always a factor, but it's not the major one. The bigger priorities in manufacturing are using a minimum number of solvents, readily available solvents, and solvents that are easily disposed of. Most important is a solvent that won’t change your product profile.”

When selecting a CMO, you also want to know their experience with a solvent, and if they can handle it in bulk. “Also, get a sense of how many processes have been taken through to commercial because that's why you're going to a CMO,” he says. “You’re paying for expertise when you go to a CMO, and that expertise includes manufacturing, engineering, and troubleshooting.”

Another key consideration is the regulatory record of any particular site. When was their last inspection? What was the outcome? Did they get any warning letters?

A Holistic Process

As the sponsor company moves to a new site and process, there are several steps that need to be undertaken. Comparability protocols will need to be undertaken to ensure you're getting the same impurities. If those impurities are different, work will need to be done to identify what effect they might have on the drug or in the body.

“It's a big regulatory exercise to demonstrate that the new process is producing a comparable product to the old process,” Offerman said. However, since CMOs typically don’t have many regulatory people on site, a small biotech company might need to bring in outside expertise to support those processes. You also want to bring in formulation people to address potential problems when switching solvents. It’s important to have an integrated approach through the system to understand the API, the impurity profile and justify differences that arise through the regulatory chain.

There will always be problems when scaling up in manufacturing: heat histories are different and the time the API in the reactor is different. Bringing experts together to discuss issues and propose solutions drives greater efficiency and helps to solve more problems.

When selecting a CMO, there are three key considerations: quality, regulatory history and cost. Quality and regulatory expertise are worth paying more for, Offerman says, because if a cheap CMO has a major regulatory problem, you may never get your product out of the facility.

“Recently, there has been a lot in the news about nitrosamine contamination in drugs and it appears that there were process changes that were being carried out by CMOs that were never approved or documented,” Offerman said. “They decided it was cheaper to go with another solvent, but they didn't look at the ramifications. Whether you're a big drug company or a small biotech company, if you've got a drug that's contaminated with nitrosamine you have to pull your product off the market. It's a bad situation to be in cost-wise.”

While trust in the CMO and their ability to deliver and meet timelines is key, it’s still important to have a project manager reviewing the timeline or Gantt chart on a weekly basis with a team or processes may slip.

There are many key considerations when choosing a manufacturing partner. You need to ask the right questions of CMOs, ensure your processes are lined up – for example, that your raw materials supplier can be trusted to deliver on time so you don’t miss your manufacturing slot – and ensure your CMO has the right experience and knows how to recognize and react to a problem. Make sure you collaborate and have continuous oversight of the project and do your homework on the CMO. Cost matters, but quality and regulatory history should always be the bigger priorities.