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.