Waters Still Murky for Omega-3s in NDI Draft Guidance?

Photo © iStockphoto.com/Lisa_16

Omega-3 oils in the dietary supplement industry undergo manufacturing processes that are considered to be standard today, including processes like molecular distillation or filtration to remove unwanted toxins and contaminants from oils. Unfortunately for omega-3 companies, it’s not entirely clear whether those manufacturing processes may now cause FDA to classify their ingredients as new dietary ingredients (NDIs).

According to the Dietary Supplement Health and Education Act of 1994 (DSHEA), supplement firms are required to submit (potentially) costly NDI notifications to FDA unless their ingredients were sold in the U.S. market prior to October 15, 1994. Pre-DSHEA ingredients sold on the market prior to 1994 don’t require NDI notification; NDIs sold on the market after 1994 do require notification.

When FDA released its original July 2011 version of the agency’s NDI draft guidance, omega-3 firms were especially worried about FDA’s stance on ingredient manufacturing and chemical alteration. FDA said that even if an ingredient was on the market prior to 1994, certain manufacturing techniques used today may cause the ingredient to be an NDI requiring FDA notification. That is because the ingredient, thanks to new manufacturing methods, may now be substantially different from the version of the ingredient sold on the market prior to 1994, FDA said.

In August, FDA released its revised version of the NDI draft guidance. Nutritional Outlook interviewed the Global Organization for EPA and DHA Omega-3s (GOED; Salt Lake City) to find out if conditions have improved at all for omega-3 firms under the new draft guidance document.

Esterification

The chemical-alteration portion of the NDI draft guidance stands to impact a broad swath of industry, omega-3 companies included.

One big concern is how FDA regards esterification. A portion of the omega-3 dietary supplements in the market are in the ethyl ester form. Firms use esterification as part of the standard process of concentrating fish oil to yield high levels of omega-3 fatty acids such as DHA and EPA. Following esterification, some firms may go a step further to convert ethyl ester molecules back into their triglyceride form (the natural form in which these fatty acids are found in fish and in nature).

According to GOED’s executive director Adam Ismail, in 2013, ethyl ester omega-3 supplements accounted for 10% of the total global omega-3 dietary supplement market, while in the United States, they accounted for 12% of the omega-3 dietary supplement market.

GOED maintains that ethyl esters have been on the market in the U.S. prior to 1994 and thus are pre-DSHEA ingredients exempt from NDI notification. “GOED has evidence that omega-3 ethyl esters are old dietary ingredients,” says Harry Rice, PhD, GOED’s vice president, regulatory and scientific affairs. However, language in the NDI draft guidance still creates uncertainties over whether FDA would consider esterification to be chemical alteration.

According to FDA in the draft guidance, any process that changes the physicochemical structure of an ingredient-including process that might boost the concentration of active ingredients or even remove impurities-could cause that ingredient to be an NDI. When asked what manufacturing processes do not result in chemical alteration, the agency said this about esterification:

“In general, FDA considers a process that does not result in chemical alteration to mean a process that: (1) involves an ingredient composed of one single raw material, or derived from a single raw material using a manufacturing process that involves only physical steps (e.g., water extraction and condensation); and (2) does not involve attempts to selectively increase the concentration of particular active ingredients or cause a chemical reaction (other than esterification) that would modify the covalent bonds of any substance in the original material. This type of process is unlikely to affect the safety profile of the ingredient in question or of dietary supplements containing the ingredient.”

Rice says GOED takes this to mean that esterification would not be considered a manufacturing process that would result in chemical alteration and require NDI notification. “Given that the revised draft guidance suggests that esterification would not be considered a manufacturing process that results in chemical alteration, GOED is not overly concerned about esterification.” Still, he adds, “we do plan to ask for clarification just to be certain our interpretation is correct.”

Beyond esterification, though, Rice adds, “There are other ways to concentrate fish oils, so this could definitely affect the omega-3 industry. At the same time, if the other methods don’t result in a significantly different product than the ethyl esters, then we may be in a position to ask the Agency to exempt the other methods specific to fish oils.”

Distillation, Filtration

Then there is the matter of distillation and filtration, processing techniques used in the omega-3 industry to remove unwanted impurities from oil, such as toxins, heavy metals, and PCBs. According to the draft guidance, however, these processes might be considered chemical alteration and trigger the requirement for NDI notification.

Following the question of which processes comprise chemical alteration, the guidance reads, “Removal of some components of a tincture or solution in water, which changes the chemical or molecular composition or structure of the mixture. Examples: chromatography, distillation, and filtration.”

If these processes improve the safety of oils, it’s hard to imagine that they should be penalized by FDA under the NDI framework. In its “The GOED Current” newsletter, GOED said, “Distillation and filtration are two common processing steps for omega-3 rich oils. GOED does not believe the use of distillation and filtration in the processing of omega-3–rich oils should make the ingredient an NDI, so GOED will seek clarification.”

According to Rice, “GOED will seek clarification on this issue, particularly since manufacturing changes don’t necessarily mean a change in the safety profile…These manufacturing changes don’t yield unwanted substances, so we may ask for an exemption.”

Fatty Acid Profile

Another, newer concern with the draft guidance relates to an oil’s fatty acid profile.

STORY CONTINUES ON PAGE 2

FDA’s new draft guidance says that if an oil, such as a plant oil or a fish oil, requires an NDI, firms may be able to ease the regulatory load by partially relying on data showing that those fatty acids in the oil are already consumed safely at higher levels in the food supply (such as in fish eaten for meals).

This is what the draft guidance says: “[I]f your NDI is an oil made from a plant or fish and you can show that the oil consists only of a mixture of fatty acids, each of which you can identify and demonstrate to be widely consumed at higher levels in conventional foods, you may be able to conclude that the dietary supplement containing the NDI will reasonably be expected to be safe based on compositional information alone.”

According to Rice, “While we were concerned initially, this may be to the industry’s advantage if an omega-3 company is permitted to submit (as substantiation of safe use) a simple dossier on safe history of use if the fatty acids can be found in the diet at higher levels, for instance in a piece of salmon or a can of tuna.”

Questions persist, however. For instance, how would firms establish baseline “compositional information" of an oil's fatty acids (in order to do a comparison with the fatty acid profile of a food)? This is especially complicated because fatty acid profiles can fluctuate from oil to oil.

In its draft guidance comments back in July 2011, GOED explained the nature of these fatty acid fluctuations. “The Guidance further states that changes to the chemical composition of the ingredient would require a NDIN. We feel the FDA has failed to recognize that natural products like edible oils and herbal extracts often contain a large number of unique chemical substances, and that the ratios of each substance can vary significantly as a result of environmental and seasonal influences. For example, the fatty acid profile of oils derived from edible marine species can change significantly due to environmental influences (e.g. water temperature, etc.), effects of diet and seasonal variation (e.g. migration). These changes in chemical composition can be experienced lot‐to‐lot and season‐to‐season.”

Because those fatty acid levels can range, would FDA consider an ingredient an NDI any time fatty acid levels strayed from baseline compositional data? Or, as GOED said in its 2011 comments, “The Guidance can be interpreted to mean that such changes require lot‐by‐lot notification to the FDA.”

According to GOED, FDA’s statements surrounding fatty acid content need clarifying. "In the past, FDA has only been concerned with EPA/DHA content, but this raises questions about the full fatty acid profile that will need to be clarified,” “The GOED Current” stated. Also, it added, "questions need to be answered about whether ethyl ester fatty acids can be compared to sources of triglyceride or phospholipid fatty acids in the normal diet.”

Rice also points out that non-fish omega-3 ingredients may be more likely to require notification. “It is more likely that 'non fish' omega-3 ingredients will require NDINs, and in fact, many companies marketing these types of ingredients have submitted NDINs,” he says.

Still Questions

Finally, one thing to remember is that most of the omega-3 drugs in the market are in the ethyl ester form. John Endres, ND, chief science officer for regulatory consultant AIBMR Life Sciences (Seattle, WA), says he wonders, if FDA were to consider dietary supplement ethyl esters to be NDIs, would the agency also feel the need to address ethyl esters in the drug market?

To date, he says, he hasn’t seen anyone get an FDA warning letter just because they are selling ethyl esters. “They could decide to crack down on it possibly, but I haven’t heard anything about that,” he says.

Regarding the NDI draft guidance, GOED’s Rice says,“Absolutely, the omega-3 industry has many critical unanswered questions, but we are confident that in time they will be answered. The reality is that omega-3–rich ingredients have a long history of safe use. While I’m not suggesting that the GOED membership try to fly under the radar, the reality is that the FDA has much bigger fish to fry.”

Also read:

Which Ingredient Categories Would Be Hit Hardest by FDA’s NDI Draft Guidance?

Would FDA’s NDI Guidance Really Cost Industry Billions of Dollars?

Company Submits First NDI Master File to FDA. Plus, Will Master Files and Piggybacking Really Be Useful in Practice?

Jennifer Grebow
Editor-in-Chief
Nutritional Outlook magazine
jennifer.grebow@ubm.com