By Louis GarguiloChief Editor, Outsourced Pharma
Follow Me On Twitter @Louis_Garguilo
Let’s look at two practical activities for tech transfer to CDMOs, and two pieces of just as practical advice for working with those service providers, all four to help you increase your Chemistry, Manufacturing and Control (CMC) effectiveness.
The wisdom comes from pharmaceutical industry veteran David Hennings, currently head of CMC and senior director at (San Francisco) Bay Area biotech Cortexyme Inc. Hennings also recently helped out Outsourced Pharma readers with this article: Interdisciplinary CMC: Weaving Your Way To Drug Approval.
Two For Tech Transfer
(A) Be Analytical
Start with this scenario: The first time you are scaling up a lead compound in development. Hennings says what immediately comes to his mind is that just about everybody undershoots the need for analytical support. They underestimate its importance at this stage, and so they don’t want to make what seems like “extra investments” in analytical work. However, says Hennings, at this stage analytical development should be “understood as a requisite activity to better ensure future project success.”
“Analytical finds itself left behind in the discovery stage,” he says. “The medicinal chemistry team has its own goals and timelines, and usually employs only basic analytical techniques. They may use HPLC, but only employing a generic method which doesn’t pull out impurities or provide other valuable information.”
In effect, important analytical work gets pushed to the back of the activity line, and in so doing, contributes to “end-game problems for drug development.” These problems might manifest with the delay of product release, perhaps as a lack of adequate methods development, and negatively impact drug programs in various ways.
“Analytical is a big concern in tech transfer,” adds Hennings, “and one that’s popped up throughout my career … which might mean I should be paying even more attention to it myself!”
(B) Isolate And Purify
Another specific component that is at first underappreciated, and an often-seen irritant to successful tech transfer, is the performance of meaningful isolations and purifications.
Here, it’s most often the drug owners themselves who have failed to address this part of the chemistry, before transferring their processes to CDMOs for continued development.
As we saw above, even when these activities are undertaken, typically they are not well-suited for direct implementation by a CDMO. The techniques used internally in the discovery stage are designed for rapid purification of many compounds, for example by flash chromatography, and are not amenable to production on larger scales. Here’s Hennings chalk talk:
“In the discovery stage, you ‘rotovap’ [a rotary evaporator (or rotavap) is a device used for the efficient removal of solvents] the compound to dryness, get your solid, and you just move on to the next step. You usually can’t do that on any type of larger scale without incurring delays or higher costs. The need for more robust isolations are routinely underestimated. The importance to a successful tech transfer is not only the [chemical] bond making and breaking, but the processing of the material, the isolations, purifications, and the drying. These studies aren’t necessarily omitted from the tech transfer to CDMOs – they simply are not done at all, for various reasons, including lack of resources, time, and/or money. They are, however, absolutely needed for a more successful product development.”
If these activities aren’t performed up to par internally, then this is something the CDMOs should focus on explicitly. But there’s a challenge with this scenario.
“Drug sponsors are always trying to figure out what spend they can delay, right?” recites Hennings. “What costs can you delay is an overriding question. Unfortunately, this is where issues arise, including our earlier discussion on analytical: We’ve got a method, or enough material to work with, so let’s just move forward and address all this later when we have more time and money.”
Hennings says one thing is certain with this approach: It will eventually cost more of that precious time and money, and could derail a successfully advancing project.
Doubly Good Outsourcing
Hennings spent one year of his career working at a contract service provider. When he mixes that side of the industry with his other experiences, he can best sum it up in a word: expectations.
(C) Great Expectations
“Ensure you identify and select service providers that can align with your expectations.”
We’ve all heard that as a primary tenet. Hennings says it’s actually a secondary consideration.
First you must ensure you actually know what your expectations are. They should be clearly defined internally, and depending on the level of outsourcing, everyone from executive management to frontline employees should be on the same page, well before you look to cast expectations on your service provider.
We are not talking about managing expectations, another phrase we hear so often. We are talking about fundamentally understanding what can and should be done, and what needs to be gained and obtained from the services you receive. And then conveying that to your service provider for their mutual buy in, or further discussion.
But what if, in fact, your organization isn’t experienced enough to know what services are indeed necessary, or what can be expected? Drug sponsors are often outsourcing precisely because they don’t have the expertise internally. They are relying on their outsourcing partners, CMC consultants, and other subject matter experts.
Even in this nowadays very common scenario, little changes, perhaps just the order of events and not the substance. Step one now is to come together with your partners first to get on the same page, or better yet, create one.
“For example, there are different levels of development,” says Hennings. “You can over develop, and you can under develop. Don’t let any assumptions be out there, because your CMO might assume you won’t need particular services or data for phase one work, while you do. Again, if you don’t learn and define the proper set of expectations, you’ll run into the most problems with CDMOs ... big problems.”
(D) Project Management
Our final topic is the glue that holds all of the above together, and of course much more.
So let’s start with the three burning questions for project management:
Should you insist your CDMO assign a project manager to your project?
Should you absolutely have an internal project manager to work with the CDMO?
What should the relation look like between the two?
Starting with the second question: In just about all cases, you need internal project management. “Throwing projects or activities over the fence, and hoping for the best, is not a strategy for success,” warns Hennings. “It matters less who you assign – whether a functional lead, or your CMC team leader – but you need an internal project manager.”
On the CDMO side, whether you are assigned a formal project manager or not – and that is most often determined by size and scope of your project(s) – it’s vital to identify upfront who is taking on the project oversight function at your CDMO. For smaller relationships, it might be one of the process chemists on your project. Says Hennings: “You’ll know who to talk to when questions, challenges and opportunities arise. Even if it’s a one-off project, you must have an advocate on that side of the relationship.”
And as far as the two sides working together? The first things they should get together on are these four keys to tech transfer for CMC success.