The Peril Of Analytical Methods Transfer

By Matthew Pillar, Editor, Bioprocess Online

What do people working in each of these scenarios have in common?

• A graduate student working with her professor on an academic molecular development exercise that has biotech formation potential
• A pre-IND biotech doing R&D work on a promising molecule
• A clinical-stage biotech readying its candidate for human trials
• A late-stage biotech preparing to contract with a commercial-scale CDMO
• A biotech positioning itself for partnership with a biopharma company to further develop and manufacture its molecule
• A biopharma or biotech company on a drug acquisition mission

Of course, there are potentially several correct answers to the question. Ambition. Altruism. Risk tolerance. Exhaustion. The need for more funding.

But as it relates specifically to the long and arduous journey of bioprocess development, there’s also absolute certainty that the people behind each of these intentions will, likely at multiple points on that journey, be responsible for the transfer of analytical methods that could make or break a candidate’s potential at every ensuing step.

Scale-up in all its iterations from bench to commercial readiness, tech transfer to an outsourced manufacturing partner, product acquisition, manufacturing equipment or consumables change, even process development personnel turnover are just a handful of the certainties that place analytical decisions made early on under a microscope. When comparative testing reveals that the assays that informed your IND no longer translate at clinical scale or beyond, for whichever of those reasons, both money and the even more precious resource measured by the clock are lost.

The Lena Tholen quote I referenced in last week’s column should strike fear in any process developer’s soul. “In the past year, more often than not, I’ve seen companies that already have a product in phase II clinical studies coming back to us when they’re ready to jump into phase III, and they’re realizing their productivity is still too low for commercial viability," she said. It’s the words “more often than not” that don’t get talked about enough.

For this and other mid-to late-stage development woes, a poorly designed or translated assay from the start could be to blame. Failure to perform those assays at the proper cadence (pool, clone, scale-up, etc.) could also be to blame. But often, it’s the unforeseen variables that influence comparability study outcomes that set development plans off course and create unwelcome surprises down the line.

What Puts Analytical Method Transfer In Peril?

Any number of missteps can jeopardize an analytical method transfer, some, like poorly-defined acceptance criteria, more obvious than others. Here are a few of those “others,” all of which underscore the point that there’s no such thing as “too nitpicky” in method transfer.

• Lack of method clarity/poor translation during transfer. Here’s where that personnel change introduces risk to assay execution. Human beings, and in this case, the way human beings interpret and execute a seemingly straightforward test, can introduce variability. In analytical methods, uninvited variables almost always spell trouble. Speaking of translation, the transfer of analytical methods to foreign contractors, or even in-country contract development specialists who speak a different language, should be handled with microscopic oversight. Language barriers can have big consequences in biotech. Document everything meticulously, and don’t rely on Google Translate to convey the nuance of said documentation.
• Equipment/consumables changes. Even something as seemingly innocuous as single-use tubing can impact method transfer. Leachates in the plumbing of one laboratory can throw off results obtained in another. A reagent procured from one vendor can have different attributes than the “same” reagent obtained from another. Even equipment of the same make and model has been documented as the root cause of analytical method transfer failure, due to equipment modifications (at the vendor’s behest or otherwise), miscalibration, or improper qualification.
• Environmental factors. Temperature is the must-control variable here. Even slight temperature differences alter chemical reactions, potentially affecting some of the key attributes being measured, such as solubility and diffusion rate. Analyte degradation or changes in reaction kinetics will yield non-comparable outcomes. If you’re on the receiving end of an analytical method transfer, it’s best to go full-on meteorologist when documenting the ambient conditions of prior assays.

In biotech as in football and relay races, the handoff is among the riskiest moves to execute. A couple of months from now, on December 3 at 11 AM ET, Bioprocess Online Live will bring you a live hour of discussion and Q&A on the relationship between analytical method design and transfer. Our panel of experts will share best practices on designing robust assays that travel, and how to manage the transfer of those methods whether you’re handing off or receiving. Keep it locked on Bioprocess Online for details.