NDI Guidance Comments Get Specific on Chemical Alteration

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When FDA first issued its revised new dietary ingredient (NDI) draft guidance back in August, the agency said it welcomed public opinion about which manufacturing processes might-or might not-chemically alter a dietary ingredient. If a manufacturing process caused an ingredient to change significantly from the version of the ingredient that existed on the market prior to October 15, 1994 (the cut-off date separating grandfathered ingredients and new dietary ingredients), then the ingredient might considered a new dietary ingredient and require a firm to submit an NDI notification to FDA.

FDA said it wanted industry input, and it looks like stakeholders have delivered. Many of the draft guidance comments sent to FDA this week either mention specific examples of processes that may (or may not) result in chemical alteration.

First and foremost, however, many comments emphasized that the type of manufacturing process used should not be FDA’s primary focus; rather, the main concern should be the end product and whether the manufacturing process actually altered the identity of the ingredient-or not.

In the August draft guidance, FDA had stated that an NDI notification would be needed if changes to an ingredient’s manufacture altered the “physicochemical structure or properties, purity and impurities, or biological properties (such as bioavailability or toxicity) of the ingredient.”

In its December 12 comments this week, the Council for Responsible Nutrition (CRN; Washington, DC) praised this approach, stating: “CRN...appreciates that FDA recognizes it is more efficient and effective from a regulatory and public safety policy standpoint for FDA to focus on the chemical identity and safety of the dietary ingredient, as opposed to the process by which the dietary ingredient is manufactured.”

Many of the commenters mentioned in this story maintain that creating an all-inclusive list of acceptable manufacturing processes may not be ideal; rather, they say, FDA should recognize that a manufacturing process may not necessarily always substantially change the identity of an ingredient and thus the agency should consider chemical alteration on a “case-by-case” basis.

The American Botanical Council (ABC; Austin, TX) stated in its comments submitted to FDA on December 12 that “ABC contends that this analysis should be done by the manufacturer (or the agency when evaluating a product, e.g., during an inspection or review of an NDI notification [NDIN]) on a case-by-case basis, and based on the chemical composition of the ingredient rather than the choice of a particular manufacturing process.”

“A change in a manufacturing process may not necessarily, in and of itself, be a trigger that would create an NDI,” ABC continued. “The critical considerations are the chemical composition and safety profile of the ingredient.”

CRN likewise emphasized the need for case-by-case consideration over the need for a predetermined list of processes. “CRN recognizes that it would not be effective for the supplement industry to provide examples of manufacturing steps or processes that would cause an existing dietary ingredient to be 'chemically altered' within the meaning of Section 413(a)(1) and, conversely, of manufacturing steps or processes that would not constitute chemical alteration," the association wrote. "Each manufacturing scenario is unique to the ingredient and should be evaluated case-by-case.”

Getting Specific

Despite advocating for a case-by-case approach, many of the comments do provide specific, science-based examples of what types of processes could change an ingredient’s identity versus those that would not.

ABC, for instance, provided these examples as what kinds of manufacturing changes should not be considered as chemically altering an ingredient:

• A change in the blending ratio of raw materials. Due to variation in growing conditions, for example, lot-to-lot variations in contents of a particular constituent or constituent group may be balanced by mixing the lots at various ratios. This type of mixing is widely used to provide ingredients with a defined content of specific constituents (e.g., the standardization of ginkgo [Ginkgo biloba] leaf extracts to comprise 24% flavonol glycosides and 6% terpene lactones), and is not a manufacturing process change that impacts the safety of the finished ingredient or product.
• The addition of a step exposing an ingredient to dry heat over a short period of time may not alter the identity of an ingredient but may make it safer due to the reduction of the microbial load.
• The addition of an approved antioxidant such as ascorbic acid or tocopherol is not likely to alter the chemical composition of the dietary ingredient but may extend its shelf-life.

The American Herbal Products Association (AHPA; Silver Spring, MD) provided its own comments on December 12 that expanded the list of manufacturing process FDA had said would not be considered as creating an NDI. The association stated that, “In order to focus attention on ingredients that are truly novel and therefore merit additional scrutiny as NDIs, FDA should accept the ODI [old dietary ingredient] status of ingredients processed by these methods”:

• Minor loss of volatile components;
• Drying, lyophilization, or other removal of moisture or other solvents;
• Reducing the size as necessary, e.g., by milling, chopping, cutting, or grinding;
• Extraction (including tinctures) by soaking, steeping, infusing, macerating, percolating, or steaming in or with water; wine, liquor, ethanol, or hydroethanolic mixture; vinegar; glycerin; honey; a food oil; or other suitable liquid which is itself a food, at suitable conditions of temperature, pressure, and agitation; 

• Solution in water, slurry, powder or solid in suspension; 

• Fermentation or other microbiological processes alone or in combination with 
other food ingredients, using wild inoculations or specific, traditionally cultivated strains of microorganisms; 

• Heating, cooking, baking, frying, pressure cooking, roasting, grilling, steaming, 
smoking, cooling, refrigerating, freezing, or otherwise applying wet or dry heat or cold in any manner and in any combination with other food ingredients, at suitable conditions of temperature, pressure, and agitation; 

• Straining, filtering, pressing, or squeezing; 

• Peeling
• Coating
• Curing
• Distilling or rectifying
• Evaporating
• Mixing, combining, or emulsifying with other food ingredients by stirring, shaking, or other means.

AHPA also emphasized that FDA should maintain its stance that any such list is not all-inclusive.

The Natural Products Association (NPA; Washington, DC) also shared a few examples of processes that wouldn’t trigger the NDI requirement:

• Addition of ester groups through esterification, phosphodiester bonds, α- (1→ 4) glycosidic bonds, α-(1→ 6) glycosidic bonds, and β-(1→ 4) glycosidic bonds, for example, would be examples of chemical changes that would not result in chemical alteration because they can be readily cleaved in the human body.
• Concentrating through extraction would be another process NPA would like to see added to the list of processes which do not chemically alter a dietary ingredient.
• Bonds that are easily cleaved in the human body should be allowed for developing novel dietary ingredients.

Extraction Solvents

Solvents used in botanical extraction are a key focal point in the NDI draft guidance. FDA has stated that ingredient extracts and tinctures might require an NDI notification if they are created using any other solvents other than water or aqueous ethanol. This would put in jeopardy such widely used modern extraction methods like supercritical fluid extraction.

In its comments, NPA stated its opinion that “regardless of the solvent, extraction of botanicals should not require an NDI notification as they are just concentrated constituents found in foods.”

ABC addressed the issue of extraction solvents and supercritical fluid extraction in its comments. ABC said that supercritical carbon dioxide should not be expected to drastically alter an ingredient’s identity; moreover, it said that some newer solvents might actually create fewer changes to an ingredient compared to changes that would occur if one were to use higher amounts of some of the solvents FDA already considers exempt from NDI status. ABC outlined these two examples below:

• The impact on the chemical composition based on changes in the extraction solvent should be evaluated by the brand holder of the product on a case-by-case basis. Manufacturers may have switched from ethanol to methanol to save costs, e.g., from 70% aqueous ethanol to 50-60% aqueous methanol, without a substantial change (although there will always be some difference) in the chemical composition of the ingredient. Such a change is less likely to affect the ingredient than the environmental conditions in which the plant is grown, and will be less of a change than switching from 40% aqueous ethanol to 70% aqueous ethanol, which is a manufacturing change that is acceptable without triggering a new NDI submission according to the draft guidelines.
• Switching from hexane to supercritical carbon dioxide would not only be beneficial with regard to the ingredient safety (with respect to residual solvent issues), but will likely not change the chemical profile dramatically.

ABC also said it believes that other solvents besides water and ethanol were used in botanical extraction prior to the NDI cut-off date (October 15, 1994) and thus should not be considered as creating an NDI. Similarly, AHPA claimed that supercritical fluid extracts should be grandfathered, stating that “commercial availability of supercritical extracts of a variety of food ingredients is recorded at least as early as 1989, including, for example, basil, ginger, pepper, and others.”

Processes that Do Alter Ingredient Identity

On the flip side, ABC also provided examples of manufacturing process that could alter an ingredient’s identity:

• Manufacturing changes in which the polarity of the solvent changed substantially (e.g., a 
change from hexane to 70% ethanol, or from pure acetone to 40% aqueous acetone) will generally result in a significant change in chemical profile and thus create a new dietary ingredient.
• Substantial changes in the extraction temperature and pressure under which the extraction is performed may lead to a significantly different chemical composition.
• The use of purification steps, such as column chromatography or precipitation/crystallization methods, to obtain highly purified ingredients (e.g., 98% pure apigenin obtained from parsley). 


Don’t Punish Higher Purity

Industry leaders also argued that FDA should not penalize firms-by way of requiring NDI notifications-for modern-day manufacturing processes that actually improve the purity or safety of an ingredient. AHPA’s examples of such cases were if “the levels of residual solvent in [a] product can be reduced through adjustments to the drying process,” or if a supplier "finds that by adjusting its sourcing of the herbal raw material it can lower the specifications for a naturally occurring undesirable constituent in its product...”

“These types of adjustments will not make the ingredient less safe, so there is no reason they require additional safety review by FDA,” AHPA stated. “Furthermore, industry should not be disincentivized from making these changes by the onerous prospect of an NDI filing requirement.”

Streamline Process for Minor Changes

Some manufacturing processes will inevitably alter an ingredient, but if those changes are minor and unlikely to alter the safety of the ingredient, CRN suggested that FDA could instate a shorter, more streamlined process for notifying the agency. In its comments, the association proposed the concept of an “abbreviated NDI notification” by which firms could notify FDA of any minor changes.

AHPA also pointed out the economic costs if FDA were to require NDI notifications due to even the smallest manufacturing changes. “AHPA notes it is in no one’s interest for NDI notice requirements to be triggered on the basis of trivial or immaterial manufacturing changes,” the association said. “The NDI notice requirements outlined by FDA will impose extreme costs on industry, requiring perhaps tens of thousands of dollars to prepare a notice where safety is established on the basis of historical use and up to several millions of dollars where formal safety studies are required. If these notice requirements are applied broadly or indiscriminately, as FDA may intend based on this draft guidance, consumers will lose access to many or even most dietary ingredients currently available."

More Work Needed

Many industry members are still very worried that FDA will establish a list of “positive” manufacturing processes that don’t require NDI notification and that will, by default, become an all-inclusive list, leaving everything not on the list subject to NDI status.

Groups like CRN hint that perhaps FDA should not create a list at all. “It would not be effective, or even possible, for CRN to provide specific examples of manufacturing changes or processes that would cause or not cause a pre-DSHEA dietary ingredient to become an NDI. Each scenario is entirely unique to both the ingredient and manufacturing change. Likewise, it would be difficult to provide examples and data to cover the many different types of dietary ingredients and manufacturing innovations that have occurred over the past two decades. Rather, each manufacturing change must be evaluated by the manufacturer case by case. It is far more efficient and effective from a regulatory and public health standpoint for FDA to focus on the resulting chemical identity and safety of the finished dietary ingredient, as opposed to the process by which the dietary ingredient is manufactured.”

Given the complexity of this topic, in its December 12 comments, NPA said it “would like to see an open comment period specifically addressing processes that would not chemically alter ingredients.”

Also read:

For a more comprehensive look at industry’s key objections to the NDI draft guidance, check out Nutritional Outlook’s recent eBook on the topic here.

Top Critiques of FDA’s NDI Draft Guidance in Industry Comments

Chemical Alteration in FDA's NDI Guidance “Will Impact Everyone”: Takeaways from Natural Products Association’s NDI Webinar

Botanical Ingredient Suppliers Brace for Impact of NDI Guidance: SupplySide West Report

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