The preclinical characterization of the formulation of a substance-based Medical Device: a case report

Di Eliana Russo - Head of Regulatory Affairs

When dealing with a substance-based medical device, the starting point for its correct qualification and preclinical evaluation (of biological safety and/or mechanism of action/preclinical efficacy) is represented by the characterisation of the formulation of which the device is made.

Characterizing the formulation of a medical device means both specifying the exact qualitative and quantitative composition of the constituent components (as % w/w), and defining their origin (e.g. synthesis, animal, vegetable, etc.) and the function in the formula (as an active ingredient or as an excipient) of each component.
Based on the formulation, nature and duration of contact of the device with the body, each manufacturer will have to proceed with the biological safety assessment (ISO 10993-1) and the verification of the preclinical efficacy/mechanism of action of the medical device in its entirety.

For medical devices based on substances with complex and "unique" qualitative-quantitative formulations, rich in different active components and/or plant extracts, the analysis of the evidence available from the literature will hardly be considered sufficient and exhaustive in giving evidence and clear proof of the mechanism of action through which the medical device exerts its action.

Therefore, in these cases, it could be useful to be able to develop in vitro efficacy tests to demonstrate the mechanism of action of the medical device in its entirety (considering the synergistic action of the ingredients).

There are no guidelines in which to find standard protocols for this kind of testing. The protocols will have to be developed according to the specific case, they will have to be validated and take into account the intended use of the device. Therefore, the site of application (e.g. skin, ocular mucosa, anorectal etc.), the clinical condition to be treated, the intended use, and the relative dosage. Test results should be reproducible (intralaboratory), repeatable (interlaboratory) and robust.
Below is a case study of a medical device for which it is necessary to demonstrate the mechanism of action considering the possible synergistic action of the ingredients. 
It is a cream for anorectal application composed of different ingredients (functional and non-functional) including a hydroglyceric extract of Ruscus root (Ruscus aculeatus root extract). 
The main mechanism of action declared by the manufacturer towards the medical device is a barrier effect with the creation of a protective film, which promotes physiological hydration and protects the skin and anorectal mucosa from rubbing. The manufacturer attributes a humectant and barrier function to the Ruscus extract.
Apply 5 g of product up to 3-4 times a day to intact skin and mucous membranes.

Looking at the MDGC 2022-5 Guideline, among the examples of herbal medicinal products, Ruscus is cited as "Intrarectal Ointment Composition":
Ruscus aculeatus extract (Butcher’s Broom root). Ruscus aculeatus (butcher’s broom) – it is traditionally used for haemorrhoids, feeling of heaviness in the legs, pruritus and swelling. Supportive therapy for complaints of haemorrhoids, such as itching and burning. 
Claims: Relief of haemorrhoid ailments. Treatment of the varicose haemorrhoidal syndrome (internal and external haemorrhoids) and anal fissures. Prevention of perianal irritation and congestion, providing relief from local pain, pruritus and burning sensations.

Lo stesso per l’Hamamelis:
Hamamelis virginiana L., cortex (hamamelis bark). Hamamelis preparations have been traditionally used as an astringent and anti-inflammatory for mild skin injuries, haemorrhoids, varicose veins and local inflammations of the skin and mucous membranes. 
Claims: Relief of symptoms associated with haemorrhoids, such as itching, burning sensation.

Therefore, in order to proceed with the correct characterization of the above-mentioned extract and to demonstrate its function in the medical device, it is useful to start from the chemical characterization of the same. This will make it possible to identify the main chemical components of the extract to which potential pharmacological actions could be attributed.

The qualitative and quantitative composition of the main chemical components of an extract (biological markers) is in some cases already clearly indicated in the supplier's technical and safety data sheets (TDS and/or MSDS). If this is not the case, it may be useful to add an in vitro test to the analysis of the scientific literature, aimed at searching for information on the components of the extract.
Another fundamental aspect to clarify the function of the extract and avoid potential pharmacological actions is that, based on the percentage of extract present in the formula (%w/w), to identify the amount available on the human body, based on the expected dosage.

Let's continue with the characterization of the Ruscus extract:

  • The raw material is added in the formula as Glycerin-Aqua extract, obtained from the root of the plant (as per TDS the extract contains between 50% and 75% glycerol, 50-25% water, 1-2% plant extract).
  • %w/w of the extract in the formula: 0.09000 of which only 1-2% is plant extract (0.0018%).
  • The amount of hydroglyceric extract to which the user is exposed daily according to the dosage indicated by the manufacturer is equal to 0.2 g (of which only 0.008 g of plant extract).

Based on these data, a comparison with the official EMA monograph of Ruscus shows that the extract contained in the medical device is of a different chemical nature than the extracts recorded in the monograph, which can be aqueous, or 80% or 96% ethanol.
In addition, the pharmaceutical form and route of administration indicated in the monograph for the therapeutic use of Ruscus extract (symptomatic treatment of hemorrhoids) are solid preparations for oral use.

In more detail, for the extract contained in the medical device under evaluation to be comparable to the Ruscus extract in the monograph, and therefore qualify as an herbal medicinal extract, it should be an aqueous or ethanol extract (80% v/v or 96% v/v), used in solid preparations for systemic (oral) use, and should be taken at a daily dosage of 0.450 g (for the ethanol extract 80% v/v)1, which far exceeds the amount of extract to which a user of the medical device could be exposed as a result of daily use of the device, following the dosage indicated by the manufacturer (0.008 g). Especially if we consider that the route of administration of the device is a different route of administration (topical, anorectal) than that of the monograph (systemic, oral).

In summary:

The analysis just carried out allows us to conclude that the function to be attributed to Ruscus extract in the medical device is to be attributed to the predominant hydroglyceric component of the extract and that it cannot be qualified as a herbal medicinal product. This confirms the function declared by the manufacturer and the absence of ancillary actions attributable to the extract.

In the face of the information collected to support the function attributed to all the individual ingredients of the medical device, proceeding with an approach similar to the one described above for Ruscus, the questions to be asked are:

  • Is it necessary to perform in vitro tests to verify the mechanism of action of the entire medical device? YES 
  • Is the evidence on the non-FIM mechanism of action of the entire medical device sufficient? NO

It will therefore be necessary to:

  • Define an in vitro efficacy testing protocol to demonstrate the barrier effect of the medical device in its entirety.
  • Evaluate the absorption profile of the medical device (on a bibliographic basis or by testing) to confirm the localized action at the application site.
  • Define an in vitro test protocol to confirm the absence of pharmacological, immunological and metabolic (FIM) actions of the medical device in its entirety. 

As far as the in vitro efficacy test is concerned, this could be designed to verify the barrier and protective effect of the medical device when applied to in vitro reconstructed tissue of intestinal epithelium, with an insult by an irritant. 
Regarding the in vitro test protocol to avert FIM action, this could be based on the in vitro evaluation of possible metabolic or pharmacological effects of the device. For example, evaluation of anti-inflammatory action by direct inhibition of the release of pro-inflammatory cytokines; re-epithelializing action by direct modulation of growth factors; modulation of the redox state mediated by activation of antioxidant enzymes, etc.

In this specific case, the results of the above-mentioned tests provided evidence of the absence of the above-mentioned FIM activities and confirmed the main mechanism of action of the medical device declared by the manufacturer (barrier, protective effect). 
It can therefore be reasonably concluded that the scientific evidence produced is sufficient to demonstrate the mechanism of action and preclinical efficacy of the product in its entirety, the absence of ancillary actions attributable to the hydroglyceric extract of Ruscus, as well as the qualification of the product as a medical device.  

1.    European Union herbal monograph on Ruscus aculeatus L., rhizoma.