The workshop, which took place on November 2 at the College Park Marriott Hotel & Conference Center in Hyattsville, MD, also explored an array of cutting-edge analytical techniques.
Here were the big takeaways:
The market
1. The total probiotic market in food and yogurt is growing at a CAGR of 8%, according to Euromonitor data, and will be worth $50 billion by 2021
2. The market for probiotic dietary supplements is growing at a CAGR of 11% and Euromonitor estimates it will be worth $5 billion globally by 2021. “The market was $4.3 billion in 2016,” noted IPA Executive President George Paraskevakos, “so I expect we’ll hit $5 billion before 2021”
3. The US is the leading market for probiotic dietary supplements, worth $1.9 billion in 2016.
Analytical insights
4. Developed at the start of the 20th Century, plate counts are the gold standard for quantifying viable cells and give the colony forming units (CFU) measure, but at the current time only a few ISO methods have been published and these are related to dairy products, said Dr Marco Pane from Probiotical.
5. Flow cytometry methods (which were developed about 25 years but companies only started using this in the last 7-8 years) measures AFUs (active fluorescent units), which are considered viable cells. While the method is accurate and universal, it is not an alternative to Plate Counts, said Dr Pane.
6. FDA wants your help! Dr Chris Elkins, Director of the Division of Molecular Biology at the FDA’s Center for Food Safety and Applied Nutrition (CFSAN), is working on genomic & phenotypic database of microbes commonly found in dietary supplements, and would welcome industry input. The database would allow for three things: 1) to give scientists an idea of what is currently commercially available, 2) it could facilitate the review of NDIs (identity, safety, history of use via molecular sleuthing), and 3) it could help with product development.
7. FDA’s GutProbe, which is a custom DNA microarray that provides a ‘quick, more accurate, and inexpensive’ method for identifying microbials and probiotics in dietary supplements, could help with GMP monitoring.
8. DNA testing is the future for probiotics, but 16S rDNA sequencing is not the way to go with multi-strain formulations. This method tests for the 16S gene and only works when you have individual, isolated strains, explained Dr Buffy Stahl, R&D Leader at DuPont. For multi-species products, DuPont is proposing a PCR (polymerase chain reaction)-based solution that focuses on the phosphoglucose isomerase (PGI) gene. The pgi-mPCR method can quickly detect up to 20 common species and sub-species in a blend of probiotics, she said.
DuPont has validated the method with 52 commercial products, but added that it’s an identity test and not quantitative. For more information on this method:
Frontiers in Microbiology, doi: 10.3389/fmicb.2016.01747
"Genotyping by PCR and High-Throughput Sequencing of Commercial Probiotic Products Reveals Composition Biases"
Authors: W. Morovic et al.
The NDI issue
9. The success rate for microbial NDIs (new dietary ingredients) is better than other categories. Dr Cara Welch, Senior Advisor for the Office of Dietary Supplements at the FDA, explained that in the 20+ years that the NDI requirement has been in place, the agency has received 37 microbial notifications, of which 20 were unique. Of those, about 50% received an acknowledgement letter. About 30% received an inadequate letter, about 10% received an incomplete letter, and the rest received a “not a dietary ingredient” letter.
10. The revised NDI draft guidance published August 12 and open for comments until December 12 will, the agency hopes, result in more NDINs than FDA has historically seen.
11. The NDI draft guidance poses some challenges to probiotics, said Solange Henoud, Regulatory Affairs Director at Lallemand. First up, ‘probiotics’ are not defined by FDA. Secondly, there is the species vs strain issue: Labeling of the microorganisms has often been at the species level, and not the strain level, so there’s a challenge with establishing presence in the food supply over time. Thirdly, it is not clear what ‘chemically altered’ means for live microorganisms. For example, what is the manufacturing process that would sufficiently change the strain identity to affect its safety profile? IPA is finalizing its comments on the draft guidance and will submit before the Dec 12 deadline.
12. Changes in the fermentation media should not trigger an NDI for probiotics, said Dr Greg Leyer from UAS Labs, because the processes are designed to minimize genetic drift. Also, changing the media is a common practice in the historic production of probiotics as producers improve yield or activity, remove allergens from the media, improve stability, and so on. Each fermentation starts with an isolated seed vial that has been purified, is genetically identical to the next seed vial, and has been stored cryogenically, he explained.
Changing the media may temporarily change the gene expression in a microbe, but results in no permanent changed to the genetic code, he said..
Studies have shown no genetic changes over thousands of generations, said Dr Leyer, before noting that a typical fermentation process from initial seed to final fermentation harvesting is about 29 generations.
“The concept that routine fermentation changes would trigger an NDIN deserves discussion,” said Dr Leyer.
And the FTC’s views
13. The Bayer case did not change anything for the Federal Trade Commission, said Rich Cleland, FTC’s assistant director of the Division of Advertising Practices. “One district court judge’s decision is not the decision of a Supreme Court Justice and not the law of the land,” he said. The commission continues to expect RCTs to support claims made in advertising, he said, and dismissed the idea that this is holding the industry to a drug standard. “An RCT with 100 people is not a drug standard,” he said. “That is not the standard required for you to get approval as a new drug.”
On the topic of experts, Cleland noted that the FTC primarily looks for experts in the condition that is being talked about in the claims, so in a case about a dietary supplement product making constipation claims, for example, the FTC would look first for an expert in constipation or a gastroenterologist, and not necessarily an expert in dietary supplements or probiotics.