FDA released a pre-publication version of its long-awaited New Dietary Ingredients guidance today, and early industry reactions have pinpointed four particular areas of concern: sections of the document dealing with the use of solvents in extracts (especially supercritical CO2 fluid extraction), nanotechnology, the status of synthetic botanicals and a provision that could result in multiple NDI filings were cited.
"Welcome to the brave new world of real dietary supplement ingredients," said Michael McGuffin, president of the American Herbal Products Association (AHPA). "I'm not going to pretend I've read every word, but it's an interesting combination of what we've thought all along. It provides true guidance."
The United Natural Products Alliance noted a few examples of the "big issues arising out of this watershed document":
- Many common manufacturing changes to existing NDIs or ODIs trigger a new NDI status.
- Changing solvents will usually trigger NDI status.
- Synthetic dietary ingredients are not dietary supplements at all. They have been kicked out of the dietary supplement category.
- You must describe how the combination of all the ingredients in your formula relate to the history of safe use of the dietary supplement.
- You should address bioavailability of the ingredients as formulated.
The issues with supercritical extraction
One of industry's greatest concerns leading up to the publication of this document was whether new technologies, in particular the modern use of supercritical CO2 fluid extraction in the creation of botanical extracts, would mean that old, presumably grandfathered botanicals would be subject to an NDI filing.
The document reads that use of water or aqueous ethanol as a solvent does not constitute chemical alteration, but does call into question other solvents commonly used in the market today such as hexane or supercritical CO2.
"We've kind of known this for a while, that using CO2 would constitute chemical alteration from FDA's point of view. From our standpoint, it's just a cleaner technology," said Shaheen Majeed, marketing director for Sabinsa Corp., which runs a supercritical fluid extraction facility in India.
Supercritical fluid extraction combines the feedstock to be extracted with carbon dioxide in a vessel under very high pressure and temperature. The gas enters a phase that is somewhere between a fluid and a gas.
"The first result is an oil," Majeed said. "That first phase of oil is really pure. From there you can take your extract into a gooey, gummy stage." Both of these work well in softgel products, Majeed said.
"But if you want to get to a powder [from the gooey stage]," he said, "most likely you would have to take it back through an alcohol extraction."
So does starting with CO2 in a supercritical facility amount to chemical alteration? In Majeed's view, it merely results in a cleaner, purer feedstock for subsequent manufacturing or extraction. "It's going to be something that has to be discussed (with FDA)," Majeed said.
"We'll push back on this," McGuffin said. "We'll need to show that the use of that technology doesn't chemically alter it. "
Nanotech is new, according to guidance
Under the same section of the document dealing with what constitutes chemical alteration of an ingredient (IV-B-4), FDA says that "application of nanotechnology that results in new or altered chemical properties of the ingredient" is cause for an NDI filing. The document subscribes to the industry standard for nanotech as being anything reduced in size to between 1 and 100 nanometers.
"They mention nanotechnology a couple of times," McGuffin said. "Because there is little safety data on nano, we recommend manufacturers call FDA first."
Synthetic and "nature identical" ingredients
According to the Dietary Supplement Health and Education Act (DSHEA), classes of ingredients that qualify as dietary supplements include vitamins, minerals, botanicals, amino acids and any constituents or metabolites thereof. However, the NDI guidance document seems to separate synthesized versions of botanicals from the rest.
"It seems to be accepting synthesis for some ingredients but not for others," McGuffin said. "It specifically mentions taurine as a metabolite of an amino acid. What FDA is saying is that cysteine is an amino acid, taurine is a metabolite of cysteine, and we don't care how you get it.
"But constituents of botanicals can only be from the natural product, not synthesis," he said. A synthesized botanical, in other words, likely would be subject to an NDI filing. Examples that come to mind are synthetic versions of polyphenols such as pterostilbene and resveratrol.
Possible multiple NDI filings
Another area of concern revolves around a provision that could result in burdensome, multiple NDI filings, in McGuffin's view. He laid out a hypothetical case in which a company was marketing a garcinia extract alone and in combination with vitamin C and with chamomile, both grandfathered ingredients. "There's nothing in DSHEA that says that's three NDIs," he said. "The NDI is for an ingredient, and should only be for garcinia. You don't need one for vitamin C or for chamomile. FDA is point blank saying that there should be three separate NDI notifications. I think they're wrong."
The industry has 90 days in which to comment on the draft filing. Go to www.regulations.gov to submit comments online. Written comments can be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administraion, 5630 Fishers Lane, RM. 1061, Rockville, MD 20852.
Industry associations quick to react
Industry associations have been quick to react with services for members (and nonmembers) to help them deal with this change to the regulatory landscape. The Amercian Herbal Products Association, which has the industry's most complete, up-to-date database of NDI filings available on a subsciption basis, is planning a webinar on the issue to be scheduled soon.
The Natural Products Association is conducting a webinar, "NDI Guidance: What You Need to Know" on Monday, July 11 at 3:30pm Eastern time.
The United Natural Products Alliance is holding a two-day conference on the ramifications of the NDI guidance document, July 26-27 in Salt Lake City.