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Australia’s regulatory approach to botanical ingredient changes may inform U.S. companies as they prepare NDI draft guidance comments.
By Ashish R. Talati and Jennifer M. Adams, Amin Talati & Upadhye
As the dust settles on the release of FDA’s revised new dietary ingredient (NDI) draft guidance, dietary supplement companies, whether multinationals or startups, should be preparing their own comments to file with FDA-or at least be working with one of the trade associations on comments the association will file.
Although, on the surface, the 2016 revised draft guidance has made great progress and includes many positives as compared to FDA’s 2011 first draft of the guidance, there are still areas of concern. In particular, the revised sections on manufacturing changes and chemical alteration have a potential to affect every single company in the dietary supplement space.
As currently written, these sections are overly broad and would result in the need for companies to file NDI notifications due to seemingly benign changes in product manufacturing. The industry needs to provide specific, detailed (read: granular), and science-based comments to FDA that both demonstrate why these sections of the guidance are too broad and advise FDA on how these sections should be changed to ensure the guidance can be applied appropriately throughout the industry.
In general, comments relating to manufacturing changes and chemical alteration should address the following:
· Not all changes (manufacturing or chemical alterations) should be considered significant
· Not all significant changes alter an ingredient’s identity from its pre-1994 (pre-DSHEA) identity and therefore should not trigger an NDI notification
· What type of scientific evidence will FDA accept for measuring baseline ingredient identity and any manufacturing changes that take place thereafter?
Ideally, companies should submit science-based comments indicating which processes do and do not result in a “manufacturing change” or “chemical alteration” and trigger an NDI analysis. Making these comments as detailed as possible would help demonstrate to FDA exactly how far-sweeping the guidance is as presently drafted. Additionally, and perhaps more importantly, such comments would provide FDA with a list of examples and explanations to include in future guidance drafts in terms of what is considered a manufacturing change or chemical alteration, and what is not.
But before hauling out the chemistry textbooks in order to draft their NDI comments, companies should first take a moment to review how other countries handle similar regulations. A particularly applicable example is Australia. The Therapeutic Goods Administration (TGA) in the Australian government’s Department of Health and Ageing is tasked with regulating “Complementary Medicines.” Because there is no dietary supplement category in Australia, ingredients such as botanicals, amino acids, and vitamins and minerals are considered to be Complementary Medicines. All Complementary Medicine products are required to either be listed or registered with the TGA.
In particular, TGA’s “Guidance on Equivalence of Herbal Extracts in Complementary Medicines” provides some key instructions to Australian companies on how they should measure the scope of manufacturing changes made to their ingredients. After publishing a draft guidance in 2007 and soliciting comments from industry, TGA finalized its guidance in February 2011. Importantly, the guidance instructs companies on how to determine when an ingredient is altered and when it is not.
What’s covered in this TGA guidance may serve as a roadmap for NDI comments U.S. companies should consider filing with FDA.
The Australian Model
TGA recognized that not all fluctuations in botanical extraction would affect the safety or efficacy profile of an ingredient. These fluctuations could include a change in supplier, natural seasonal changes in the plant, or changes in solvent concentration or type. The TGA guidance addresses when a change in an herbal extract does not trigger a requirement to list or register the product as a separate good with the TGA-or, conversely, when a change alters an ingredient so drastically that it triggers additional regulatory requirements.
The guidance says that by establishing a baseline chromatography profile of an ingredient (before any manufacturing changes or chemical alterations are made), manufacturers can gauge when a subsequent change in a botanical extract is minor enough that the ingredient is essentially considered the same.
TGA’s guidance describes in detail how a baseline chromatogram profile for an ingredient should be developed and curated, and how it should be interpreted. For example, in order to build a comprehensive baseline profile of their ingredient, manufacturers are instructed to experiment with different chromatography techniques (such as gas chromatography or high-pressure liquid chromatography), different solvents, different stationary phases, and different detection techniques when developing profiles. TGA also explains that all of the active constituents in a botanical should be measured. If measurement of a constituent is omitted, companies should include detailed explanation as to why this constituent is deemed to have no effect on the identification of the substance and therefore does not need to be recorded. The guidance also explains that when there is a known possible adulterant, techniques should be incorporated to enable their detection. Additionally, manufacturers are encouraged to maintain ingredient chromatography profiles that account for possible variations in the ingredient, such as different botanical sources and seasonal changes.
Overall, the TGA guidance captures two key points regarding manufacturing changes and chemical alteration that companies can apply to their own FDA NDI comment submissions.
First is the notion of why manufacturers should establish a baseline ingredient profile for their ingredient and how they should do so. Without knowing the starting point of an ingredient (its identity prior to a manufacturing change or chemical alteration), it is impossible to assess whether a chemical alteration or manufacturing change to that ingredient has occurred. Companies should urge FDA to specify which techniques the agency deems acceptable for determining a baseline and for assessing whether a change or alteration has occurred. They should also provide examples to FDA of which manufacturing methods still preserve an ingredient’s baseline identity.
Second, what analysis is required to determine if a manufacturing change or chemical alteration has occurred? Here, it is crucial to outline science-based examples of specific ingredient changes that do not alter the safety profile of an ingredient. This would allow FDA to expand the list of processes that the agency considers not resulting in manufacturing changes or chemical alteration. FDA specifically says in the draft guidance that the agency would consider arguments “supported by science” when assessing these cases.
Much More Clarity Needed
Companies need to seek clarification from FDA of what the agency considers sufficient science to show that the safety or efficacy of an ingredient has not been altered. For example, would providing an expert opinion letter from a toxicologist be persuasive enough in the agency’s eyes? Companies should submit examples of how these evaluations could be performed and explain the scientific basis for that particular approach. Including these details could expedite crucial clarification needed from FDA.
Although progress has been made with the revised draft guidance, the guidance still yields many more questions than answers. The dietary supplement industry as a whole needs to provide a unified, detailed response while the dialogue with FDA is open. By submitting science-based examples, particularly those accepted by other regulatory bodies, industry will likely get feedback from FDA. This dialogue will also give industry more insight on how FDA would conduct NDI analyses. Determining how FDA will treat your product is the first step towards ensuring that it is compliant and that your brand is protected under the NDI regime.
Unless FDA says otherwise, companies must submit their NDI draft guidance comments by October 11, 2016. Comments can be submitted electronically here.
Ashish Talati is a Member at Amin Talati & Upadhye. Mr. Talati has written extensively on topics related to new dietary ingredients (NDI) and has successfully filed many NDI notifications with FDA. Jennifer Adams is an associate attorney at Amin Talati & Upadhye and handles NDI and Generally Recognized as Safe (GRAS) matters.