As sponsors have started to shift more and more of their manufacturing to outsourcing partners, relationship building has become an even greater priority. This is where the person-in-plant becomes an invaluable source for building a more trusting relationship with the contract research manufacturer (CMO). Essentially, a person-in-plant is a sponsor employee or, more often, a third-party expert consultant who is present at the contract manufacturing site to observe, support, and provide feedback to all stakeholders.
As a process chemist with an extensive background in process development and contract manufacturing, Dr. Daniel Torok, senior drug substance consultant at DSI, a ProductLife Group company, is able to offer a deep and broad perspective with production floor problem solving.
“When it comes time to go into a plant, either for a client who just wants somebody to watch over a registration campaign or validation campaign, or that time when the client calls on a Friday afternoon with a crisis because the batch is going up in smoke and they need someone there to help fix it, the 20 plus years I’ve spent in production facilities can provide a different and valuable perspective,” Dan says.
Why Bring in a Person-in-Plant?
Having that external oversight has a twofold advantage. First, there is the white coat effect, which tends to shift the level of attention given to a project. That’s important, Dan says, because CMOs’ profit margins depend on full, or close-to-full, occupancy, which means there aren’t additional engineers available simply to observe critical points in a validation campaign.
“Having a person-in-plant go and represent you covers that lack of additional attention during a time of need,” he says. “The key is you need to have the right person, and you need to start by building trust.”
An experienced person-in-plant knows what’s going on in a manufacturing facility and what to look for. In large API facilities, for example, operations might take place over multiple different plant levels, and a batch might move through all these levels within an afternoon. A good person-in-plant will work with the head of the facility in a collaborative way, demonstrating respect for that individual’s expertise and convincing them that you are there to help.
“Once you build that level of trust, they will begin to go to you with problems, which brings significant value to the sponsor,” Dan says. “After years of working in plants, I know almost every piece of equipment and can quickly tell if something isn’t right. For example, prior to the transfer of a validation batch, I noticed the operator didn’t have the cam lock properly fashioned onto the bottom valve, and they were about to try to transfer a batch. When that happens, it means losing the batch. I told him to check the cam lock on the bottom of the reactor, and after checking it he thanked me.”
The fact is, even if the batch uses cheap raw materials, rescheduling it or having a delay in a clinical trial is incredibly expensive. Having an experienced set of eyes to help you get it right the first time is a huge money saver.
Budget and Planning
For smaller biotech companies operating on a limited budget, the decision to bring in a person-in-plant should be carefully planned to determine where an expert set of eyes would be most valuable. Look at the risks involved with the type of production and decide whether there is a benefit. Putting together a simple drug substance probably doesn’t require that oversight, but if it’s a process such as crystallization or filtration with several days of heavy product manipulation, it often pays to have that outside perspective.
“When it comes to things like launching stock material, process validation, or critical clinical batch manufacture, where enormous oversight is needed, having a person-in-plant should be worked into the budget,” says Brian Lihou, head of operations at DSI.
Planning is important to managing the budget, Dan says. Decide when you want that oversight on-site and what you want to see. Your external person-in-plant consultant might fly to a site, but during that time they could be working on other projects if key processes are well spaced out, and that can save the client a lot of money.
The role of the person-in-plant goes beyond providing oversight at the manufacturing site. An experienced drug substance consultant can also provide a point of view on physical chemistry processes taking place – both the good and the bad.
“When I’m returning from a site visit, I start to document observations while they are fresh in my mind,” Dan says. “That might be concerns I have about batches I observed that weren’t a problem at the time, but could become a problem in the future, such as slower-than-expected filtration or product consistency, and to recommend some change control or remediation steps.”
Brian adds that it’s also important to highlight what worked well. For example, there might be a facilities mechanic who goes above and beyond to keep the process moving forward. “These are all things that have to be in a well-rounded site wrap-up report,” Brian notes.
One important consideration for any observer is to recognize that processes might not always be the same for every production cycle.
“I was watching a validation campaign once where the operators from one night to the next did the batch transfer completely differently through the same equipment,” Dan says. “My jaw dropped and we had some talks with the plant later about the pros and cons, but it made me realize that things aren’t always the same every time you go into production. It’s important to be cognizant of that, but also to realize that the folks on the floor who are running the process, the person who’s writing your batch record, and the analyst handling your in-process controls all want to do a good job. So as an observer, it’s important to treat them well. If you have to reprimand anyone, blame the plant manager, never the person who is turning the wrench for you at 3 a.m.”
Understanding the challenges plant operators face, being empathetic to what they often have to sacrifice to get the production process done on schedule, and developing mutual understanding is all part of building an effective, long-lasting, and trusted relationship with the CMO.