Dear colleagues of the Nitrosamine Exchange Forum,
I would like to create discussion topic regarding the risk analysis of colorants and flavorings in pharmaceutical formulation. As we are all aware, ensuring the safety and quality of pharmaceutical products is of paramount importance to both the pharmaceutical industry and regulatory bodies. Analyzing the risk associated with colorants and flavorings is a crucial step in the manufacturing process.
I would like to invite all participants to share their experiences and insights on how their respective scientific communities and pharmaceutical industries are addressing this issue. Specifically, I am interested in learning about the strategies, methodologies, and best practices employed in the risk analysis of colorants and flavorings. Additionally, any regulatory guidelines or requirements set forth by organizations such as the FDA and different pharmacopoeias would be valuable to consider.
Some key questions to kick-start the discussion are:
- How do you approach the risk analysis of colorants and flavorings in pharmaceutical formulations?
- What methodologies or analytical techniques do you employ to assess the potential risks?
- Are there specific guidelines or regulatory requirements that you follow in your respective regions?
- How do you determine the potential impact on patient safety when these substances are present in minimal amounts?
I look forward to an engaging and insightful discussion that will contribute to our collective knowledge in addressing the risk analysis of colorants and flavorings in pharmaceutical manufacturing. Thank you for your participation.
From a nitrosamines perspective Christian?
Thank you for your response. My question indeed revolves around the approach to risk assessment of colorants and flavors, particularly in cases where the exact structure or composition is not always known. In situations where the structure is available and contains an amine moiety, I am curious to understand how the justification is made for considering it of low risk, especially when it is used at low concentrations within the formulation.
For dyes, generally the structure is known, and so an assessment can be carried out, and the suppliers are willing to provide a reasonable amount of data, or have so far. Although there are certain dyes where there is the possibility for a large % of “unknowns” to be present.
Flavours are more tricky. Generally, the exact composition is proprietary information of the flavour house and getting an precise break down of the composition can be very difficult, depending upon your relationship with the flavour house. As safety concerns have come more and more to the fore over the past decade the flavour houses have become more forthcoming with information. Probably won’t provide an exact breakdown of everything that is present in terms of % w/w, but they have been providing compositions with ranges when asked e.g. molecule x 40-60%, molecule y 5-10% molecule z 0.5-1.0% etc. It is then a case of assessing the structures of each of these components for the presence of any secondary or tertiary amine groups. It may be that from the % of flavour in the formulation and then the % of any amine within the flavour that the level of amine becomes too low to be considered a risk, but when we are talking about ng/day for nitrosamines that chance is unfortunately low.
Also need to consider the nitrite levels in both the dyes or flavours, as potential contributors to the overall nitrite level in the product - and both have proven to be tricky to analyse so far - depending on the nature of the dye (cold water soluble versus aluminium lake etc.) and the exact composition of the flavour, in conjunction with the analytical technique being used.
In regard to flavors- Based on my experience with several human health risk assessment conducted for flavors and fragrances for international regulatory.
I am in opinion, yes we can definitely take leverage of low exposure.
However, in the context of nitrosamines with current lens of guilty towards them- Regulators may ask more data to prove their innocence’s even at low exposures!
In our experience, flavours manufacturers do not disclose easily the qualitative composition; in some cases we obtained it only after an authority request.
They NEVER disclose the QUANTITATIVE formulation (not even as a range).
However, nearly all the flavour substances are alcohols or esters;; I never found any kind of amine. So, in my opinion, flavours are not relevant in the nitrosamine risk assessment. The formal assessment through the IPEC questionnaire should be sufficient.
@MarkS, @Pradpharma @paliog
Thank you for taking the time to contribute to the discussion on the risk analysis of colorants and flavorings in pharmaceutical formulations. Your insights and expertise are greatly appreciated.
It is evident from your responses that the assessment of colorants and flavors poses unique challenges, especially when considering the precise composition, potential presence of amines and nitrosating agents. I appreciate your insights, which have provided me with valuable guidance and a pathway to further establish the risk associated with these additives within formulations.
Thank you once again for your valuable input, and I look forward to further engaging with you and other members of the forum.
Here is an example of an amine-containing flavour compound: methyl N-methylanthranilate.
Indeed - there are some - every flavour composition needs to be looked at as closely as the suppliers will inform. This looks to be present in grape flavours - so Kool-Aid drinkers beware.
This has already had a limit set by Europe for cosmetics in topical products precisely because of nitrosamine formation.
Of course, some exceptions may exist. However this is a very rare case.
On January 31, 2022, the European Commission released Regulation (EU) 2022/135, restricting the use of methyl-N-methylanthranilate (M-N-MA) in cosmetic products under Annex III of (EC) 1223/2009.
The Regulation has been effective from February 21, 2022.
From August 21, 2022: cosmetic products containing this substance and not complying with the restrictions shall not be placed on the Union market
From November 21, 2022: cosmetic products containing this substance and not complying with the restrictions shall not be made available on the Union market.
Even if the cosmetic regulation formally does not apply to pharmaceutical fragrances, Methyl-N-methylanthranilate is phototoxic, as demonstrated by both in vivo and in vitro experiments:
If it is still used, it should be removed from pharmaceutical products for safety reasons, regardless of the nitrosamines problem.