Dr Greg Leyer, PhD, chief scientific officer for UAS laboratories, made the presentation behalf of industry at the behest of the International Probiotic Association. Leyer’s presentation honed in on a troublesome point raised by FDA in the recent version of the NDI draft guidance, where the agency laid out its thinking on what kinds of manufacturing changes could spur the need for a new NDI notification on an existing product. The whole NDI process is predicated on proving the safety of new ingredients and does not bear on their efficacy.
Problematic view of fermentation tweaks
The salient paragraphs read like this:
“Examples of processes that do not chemically alter an ingredient are minor loss of volatile components, dehydration, lyophilization, milling, or formation of tincture, aqueous solution, slurry, powder, or solid in suspension. See IV.B.5. Examples of changes that chemically alter an ingredient (see IV .B.4 for more details and additional examples):” under which was included “New manufacturing method (e.g., new agricultural or fermentation conditions) that significantly changes chemical composition.”
The draft guidance also has this to say:
“These processes would also be likely to affect the safety profile of a dietary ingredient” under which can be found this example: “Fermentation using a fermentation medium different from the one used to make conventional foods in the food supply. Example: into dairy products like yogurt or cheese.”
Leyer said thse small sections of the lengthy document (99 pages plus appendices) were viewed as particularly problematic for the probiotic industry because seeking the best fermentation medium is the bread and butter of probiotic manufacture. It goes on all the time.
“These kind of things happen all the time. Companies are looking to improve the products’ performance, or improve the stability of the strain,” Leyer told NutraIngredients-USA. “In our opinion this requirement would create an undue burden.”
Organic chemistry vs fermentation
Leyer said some of the issue concerning the fermentation medium might have arisen because much of the expertise at FDA is chemical in nature. To an organic chemist, changing the inputs for a given reaction—switching feedstocks if you will—by its very nature would result in a different outcome. But the point Leyer said he was trying to make was microorganisms are living things, capable of adapting to different inputs while being cultured in a tank.
“It’s still the same organism if I grew it on lactose or glucose or something else. If I eat sushi or I eat spaghetti I’m still Greg,” he said.
Leyer said he also got some feedback from an audience member in the pharmaceutical industry that could have formed part of the confusion at FDA, with its long history and experience with drugs, especially biologics.
“In the pharma world the process of making the product IS the product and any change in that process makes it a new drug,” Leyer said.
In the case of probiotic organisms, Leyer said there can be slight differences in how the organisms initially appear when grown on different substrates. But that has no bearing on how they’ll perform in the body, nor does it alter their basic identity.
“I acknowledge that when you grow it on lactose or glucose you will get temporary transcriptional changes. Different proteins will be present on the surface of the cell, but it’s not shedding or acquiring genes, it’s just adapting to its environment,” he said.
Absence of genetic drift
Leyer said he was able to present hard data of the virtual absence of genetic drift in the number of generations typically found in a production setting. For UAS Labs, that number is about 29 generations from inoculation of the first tank to the finish of a production batch. In studies that were looking for genetic changes in other organisms Leyer said it took a a couple orders of magnitude greater in the number of generations to begin to find significant changes. In other words, the chance that a change in the substrate will result in a probiotic organism that is different enough from its parent strain so that the safety information on file for the parent strain no longer applies is just about zero.
“I tried to present some data in how the change in fermentation components has no effect in the genetic makeup of the strains. The number of generations needed to see a functional genetic change is much more than we would find in a production setting,” Leyer said.
“As long as you are not adding something that is itself unsafe to the fermentation medium there is no safety concern. That’s especially true when you consider the low mutation rate. We are not stressing these organisms,” he said.
That information rests on the kind of solid quality control that UAS Labs and other reputable probiotic manufacturers employ, Leyer said. All tanks are inoculated from a carefully isolated parent strain. Reputable manufacturers don’t reserve a portion of their fermentate to inoculate subsequent batches, like a home baker might for his or her sourdough starter.
“Every fermentation starts from one seed vial. We are not ‘back slopping’ fermentation sources,” he said.