In order to classify their substance-based medical device as such and not as a medicinal product, manufacturers often have to prove that complex ingredients work primarily through physical mechanisms.
This article provides assistance.
Please read the following article on substance-based medical devices first. This article explains which products are included and which regulatory requirements apply. Another article explains the difference between substance-based medical devices and medicinal products.
1. Complex ingredients: What it’s all about
a. What complex ingredients are
Complex ingredients in substance-based medical devices are components that consist of several chemical compounds and whose composition or mode of action cannot be clearly assigned.
Manuka honey, for example, contains over 14 complex ingredients, such as methylglyoxal, which contribute to honey’s antibacterial and antiseptic effects.
The third chapter presents many examples of medical devices with complex ingredients and how they work.
These complex ingredients can come from natural sources such as plant extracts or animal products or be fully synthesized.
Their complexity arises from the number and type of molecules involved, the spatial structure, and the chemical bonds between these molecules.
2. Challenges with complex ingredients
a. Identify complex ingredients
The first challenge for manufacturers is the determination of the ingredients and their concentration. Otherwise, neither the safety nor the effectiveness of the devices can be verified.
b. Prove physical effectiveness
Even from a regulatory point of view, these complex ingredients cannot always be clearly assigned. Manufacturers must reliably answer several questions:
- Is the main effect only physical?
- Can metabolic reactions be completely ruled out?
- Which analyses can be used to prove this?
- Do the limits of efficacy or the absorption type (local or systemic) play a role?
If metabolic reactions occur, the product falls under pharmaceutical law, not medical device law.
c. Managing regulatory consequences
For example, the pharmacodynamics of multicomponent herbal mixtures are often unknown or cannot be clearly determined. This makes it difficult to determine the main mode of action.
In cases of doubt: Pharmaceuticals
According to MDCG 2022-5, in cases of doubt – i.e., when it is not clear which substance is responsible for the intended main effect of the product – Article 2(2) of Directive 2004/27/EC amending Directive 2001/83/EC shall apply.
This means that the product is considered a medicinal product.
”These comprise substances or preparations made from substances that…are intended for use in or on the human body and are intended for use as remedies with properties for the curing, alleviating or preventing of human diseases or disease symptoms…“
Medicinal Products Act § 2 Section 1 no. 1
Necessity of consultation procedures
For devices that are systemically absorbed to achieve their intended purpose (class III devices according to Annex XIII 7.8 Rule 21 MDR), a consultation procedure with a competent medicinal products authority or the EMA is required in accordance with Section 5.4 of Annex IX of the MDR.
This consultation procedure is also a prerequisite for approving a possible clinical investigation of the device and must be available when submitting it to the ethics committee and the state authority.
No consultation procedure is planned for medical devices composed of substances or combinations of substances intended to be introduced into the human body or applied to the skin. These devices are absorbed by the human body or locally distributed in the body and thus meet the definition of a medical device within the meaning of Article 2 (1) of the MDR.
3. Examples of complex ingredients
There are many examples of ingredients considered complex and whose main effect cannot always be determined beyond doubt.
a. Manuka honey
Manuka honey is often advertised as alleviating inflammation and infections. Due to its high phenolic acid content, it has a natural sweetness with a slightly woody taste and is therefore added as a “flavoring component” to many medical devices.
Chemical characterization shows the complexity of the ingredients and the different active components. The proportions of the active components vary greatly, depending on the honey’s country of origin.
| Active Ingredient | Ratio | Function, Effect |
| Methylglyoxal (MGO) | 300–1.200 mg/kg | Strong antibacterial effect, effective against many bacterial strains including MRSA and VRE; anti-inflammatory; antioxidant |
| Dihydroxyaceton (DHA) | Variable | Precursor of MGO; converted to MGO during honey ripening |
| Hydrogen Peroxide | Low | Antiseptic effect; helps wounds to heal |
| Leptosperin | Unspecified | Bioactive substance; contributes to the health-promoting effect |
| Phenolic Compounds (Caffeic Acid, Ferulic Acid, Syringic Acid, Quercetin, Isorhamnetin, Luteolin) | Unspecified | Antioxidant effect; support antibacterial activity |
| 3-Phenyllactic Acid | Unspecified | Antifungal and antibacterial effect |
| Sugar (Glucose, Fructose) | Main Component | Energy provider; osmotic effect |
| Minerals (e.g., Calcium, Potassium, Magnesium) | Trace Elements | Supports skin regeneration and metabolic processes; important for cell and nerve function |
| Vitamin B1 (Thiamine) | Trace Elements | Supports energy metabolism and nerve function |
| Vitamin B2 (Riboflavin) | Trace Elements | Important for cell growth and energy production |
| Vitamin B6 (Pyridoxin) | Trace Elements | Involved in protein metabolism and immune function |
| Biotin | Trace Elements | Supports skin and hair health |
| Nicotinamide (Niacin) | Trace Elements | Important for energy metabolism and DNA repair |
| Enzymes (e.g., Glucose Oxidase) | Unspecified | Catalyze the formation of hydrogen peroxide |
b. Iceland moss (cetraria islandica)
The therapeutic effect of Icelandic moss is based on the interaction of many of its ingredients, in particular, the mucus-forming polysaccharides and lichen acids. It is traditionally used to relieve dry coughs, inflammations in the mouth and throat, and temporary loss of appetite.
| Ingredient | Ratio | Function |
| Polysaccharides (Lichenin and Isolichenin) | ~50 % | Forms a protective film on mucous membranes; relieves irritation and inflammation |
| Proteins (Raw Protein) | ~24,8 % | Nutritional value, structure formation |
| Lignified Acids (Mainly Fumarprotocetraric Acid) | 2–3 % | Antibacterial effect, bitter substance |
| Raw Fiber | ~4,6 % | Digestive |
| Usnic Acid | Traces | Antibiotic effect |
| Fatty Acids (Rocellic and Lichesteric Acid) | Low | Antimicrobial effect |
| Vitamin A | Low | Antioxidant; important for vision and immune system |
| Vitamin B1 | Low | Supports energy metabolism and nerve function |
| Vitamin B12 | Low | Important for blood formation and the nervous system |
| Iodine | Low | Supports thyroid function |
| Silicic Acid | Low | Strengthens connective tissue and bones |
| Bitter Substances | Low | Appetizing, digestive |
| Water | Variable | Structure preservation, depending on the degree of drying |
c. Healing earth
Healing earth is a natural product mainly consisting of finely ground loam, loess, clay, or moor soil, predominantly of minerals such as silicate, calcite, three-layer clay minerals, feldspar, and dolomite.
Healing earth as a medicinal product
Healing earth is approved as a medicinal product in Germany because specific therapeutic effects (neutralization of gastric acid) can be demonstrated, especially in treating gastrointestinal complaints such as heartburn, acid-related stomach complaints, and diarrhea.
This approval is based on its traditional use and documented effectiveness over decades. According to regulatory requirements, it is sufficient for the manufacturer to prove that the device has been used safely and effectively for at least 30 years to receive approval as a traditional medicine.
Healing earth as a medical device
However, healing earth is also available as a substance-based medical device. One example is Luvos® healing earth microfine, which is used, among other things, to bind cholesterol and fats from food, support intestinal cleansing, and relieve gastrointestinal complaints.
In this case, the healing earth’s effect is based on its high adsorption capacity. It binds excess acids, toxins, bacteria, and fats in the digestive tract and thus helps to alleviate discomfort. This effect occurs locally in the gastrointestinal tract without systemic absorption, distinguishing it from pharmacologically active medicinal products.
The grain (available surface) and the aggregate state are decisive for classifying as medicinal products or medical devices!
d. Other devices with complex ingredients
Further examples of complex herbal active ingredient components in substance-based medical devices are listed in the guideline MDCG 2022-5.
The ingredients would be considered medicinal products in their own right and can, therefore, if they are contained in a medical device, lead to a classification as a class III medical device in accordance with rule 14 of Annex VIII of Regulation (EU) 2017/745.
In such cases, the manufacturer must prove that the active ingredients used have an ancillary effect besides the device’s main effect.
| Ingredient | Inteded Purpose, Effect |
| Yerba Santa (Eriodictyon Californicum) | Oral for asthma, bronchitis, laryngitis, sinusitis, and hay fever |
| Clove Oil (Caryophylli Aetheroleum) | Antiseptic, analgesic, and soothing properties |
| Mallow (Malva Silvestris) | Anti-inflammatory properties |
| Marigold (Calendula Officinalis) | Anti-inflammatory and antiseptic properties |
| Lavender (Lavandula Angustifolia) | Antiseptic properties |
| Chamomile (Chamomilla Recutita) | Anti-inflammatory, antiseptic, and antispasmodic effect, pain relief |
| Butcher’s Broom (Ruscus Aculeatus Root) | For the treatment of hemorrhoids; inhibits inflammation and is used as a laxative |
| St. John’s Wort (Hypericum Perforatum) | Anti-inflammatory, antiseptic, and analgesic properties |
| Lady’s Mantle (Alchemilla Vulgaris) | Anti-inflammatory and astringent properties |
| Santacraut (Eriodictyon Crassifolium) | Promotes saliva production; used for lung ailments and to stop bleeding |
| Thyme (Thymus Vulgaris) | Disinfecting, antiseptic, and expectorant properties |
| Fennel (Foeniculum Vulgaris) | Various medical applications |
| Sage (Salvia Officinalis) | Antibiotic and antifungal properties |
| Marshmallow Root (Althaea Officinalis) | Soothing effect on mucous membranes (moisturizing) |
| Willow Bark Extract (Salix Alba) | Keratolytic, anti-inflammatory, and analgesic |
| Tea Tree Oil (Melaleuca Alternifolia) | Antiseptic, antimicrobial, and anti-inflammatory properties |
| Lavender Oil (Lavandula Angustifolia) | Calming, anxiolytic, and mood-enhancing |
| Peppermint Oil (Mentha Piperita) | Relief for gastrointestinal diseases |
| Turmeric (Curcuma Longa) | Anti-inflammatory effect |
| Ginger (Zingiber Officinale) | Effect on nausea and vomiting |
When using these complex ingredients in substance-based medical devices, it is important to document the exact mechanism of action and ensure that the main effect is based on physical or physicochemical effects and not on pharmacological, immunological, or metabolic effects. This is crucial for the correct classification and regulation of the device.
4. Overcoming challenges
a. Identify complex ingredients
Analysis and characterization of complex ingredients are an important part of product development and quality assurance.
All substances/active ingredients used in the product must be carefully documented, and their modes of action must be analyzed. For this purpose, extractions are carried out in various solvents (e.g., hexane, ethanol, water).
This is followed by analysis using
- gas or high-performance liquid chromatography
- mass spectrometry, and
- nuclear magnetic resonance spectroscopy.
The objective of these analyses is the determination of
- each individual component,
- their respective structures,
- impurities, and
- degradation products.
b. Ensure product purity
VDI 2083 Part 21 guideline is useful as a generally applicable, overarching standard for demonstrating the purity of medical devices in the manufacturing process.
It contains a structured approach and helps to decide whether acceptance criteria for product purity are necessary and, if so, how these can be derived.
In addition, it presents suitable and meaningful analytical methods for the various types of contamination – biological, chemical, or particulate.
Despite this guideline, determining acceptance criteria based on risk remains a challenge in medical technology because of the lack of normative specifications. Rather, it is the responsibility of the manufacturer or assembler to determine these as part of a risk evaluation.
The initial and reprocessing of medical devices by the user and the assessment of the biological compatibility of medical devices (biocompatibility according to the standards in the ISO 10993 series) are not covered by this guideline.
c. Verify physical mode of action
Special care is required with complex ingredients that contain components with a fundamental pharmacological, immunological, or metabolic effect.
Exclude non-physical modes of action
Among other things, the manufacturer must scientifically prove that such accompanying substances do not play a significant role in fulfilling the intended principal effect of the device.
Determination of physical and chemical properties
An analysis of the physical and chemical properties is required to characterize the consistency of a substance-based medical device.
This begins with determining the state of aggregation. Then, density, viscosity, thermal properties, electrical conductivity, and optical and mechanical characteristics are examined to understand the material’s behavior.
Chemical analyses include solubility, reactivity, antimicrobial effect, and acid/base resistance, which provide information on bioavailability and stability.
This comprehensive characterization is crucial for the technical documentation, risk evaluation, and classification of the device in accordance with the Medical Device Regulation. The data obtained influences the classification as a medical device or a medicinal product and determines the scope of additional clinical investigations.
Conclusion: A thorough characterization of the consistency is essential for a successful approval process and for demonstrating the safety and effectiveness of the device.
Select the appropriate concentration
To ensure differentiation from medicinal products, the concentration of active ingredients must be chosen so that the effect remains primarily physical/chemical (e.g., change in pH value, barrier function).
Conducting in vitro experiments
In vitro experiments with titration and dilution series with synthetically produced different active agent concentrations can exclude pharmacological effects on test organisms and thus avoid a medicinal product classification.
In topical preparations (creams), the determination of the concentration and galenic formulation is whether the active ingredient acts only superficially (physically) or systemically (pharmacologically). However, conducting these experiments remains difficult, and the systemic effect on the body remains unclear in most cases.
d. Prove biological safety
Manufacturers must evaluate the selection and compatibility of the materials and substances used (in accordance with ISO 10993), in particular with regard to toxicity and compatibility between the materials used and biological tissues, cells, and body fluids.
This is followed by verification of all chemical and/or physical specifications defined for the device (by means of in vitro or in vivo studies).
e. Choose alternative ingredients
Manufacturers increasingly focus on using simple, clearly defined substances whose physical or chemical mode of action can be easily demonstrated. Examples include:
- Salt solutions: Sodium chloride-based products for nasal sprays or irrigation solutions whose effect is based on osmotic principles
- Surface-active substances: Use of substances such as Simeticon or polyethylene glycols, whose defoaming effect is based on purely physical properties
- Development of hydrogels with defined physical properties for wound dressings or moisturizing products
- Use of microemulsions to improve the barrier function of skin care products
- Research on osmotic laxatives that have no pharmacological effect
- Development of products for normalizing pH, e.g., in vaginal creams or gastric acid neutralizers
- Development of inert polymers for artificial tears or mucous membrane lubrication
- Use of chemically modified natural substances that have lost their pharmacological activity
These research approaches aim to develop substance-based medical devices whose main effect is clearly based on physical or chemical mechanisms. This allows manufacturers to ensure a clear distinction from medicinal products and to meet regulatory requirements.
5. Tips
Tip 1: Analyze the mechanism in detail
The manufacturer must thoroughly examine and document the main effect of the device. That requires objective and scientifically sound evidence that the main effect is achieved by physical or physicochemical means.
Tip 2: Run specific tests
Suitable in vitro and in vivo tests must be carried out to prove the physical mode of action and exclude pharmacological, immunological, or metabolic effects. Clinical investigations are often unavoidable for substance-based medical devices that come into contact with the body or are invasive.
Tip 3: Keep records of evidence
All test results and scientific evidence must be carefully documented to confirm the main physical mode of action.
Tip 4: Use MDCG 2022-5
The decision tree provided in the MDCG 2022-5 document should be used to ensure the correct qualification of the device.
Tip 5: Get expert opinion
You should seek independent expert advice to qualify the device and review the evidence if unsure.
Tip 6: Perform qualification and classification at an early stage
It is important to start this process early to avoid possible classification errors and prevent legal disputes and enormous costs.
Tip 7: Seek dialog with notified bodies at an early stage
Seek to engage with your notified body as early as possible. Use a “structured dialog” to ask for specific procedural details and regulatory aspects for your substance-based medical device.
The notified bodies formulate their offer as follows:
“The purpose of a structured dialogue prior to lodging a formal MDR application with TÜV SÜD is to clarify the timing, procedural, and regulatory aspects of the application process and forms, and the submission documents.“ (TÜV SÜD)
“The structured dialogue is the formal process that allows manufacturers to clarify, in advance, procedural details, timelines, and regulatory aspects relevant to the certification process, based on the type, risk class, and specific characteristics of the medical device to be certified under the MDR.” (ECM)
6. Conclusion and summary
For many substance-based medical devices with complex ingredients, it is difficult to prove that
- they are actually medical devices and
- they meet the requirements of the MDR.
However, for many challenges, there are solutions that need to be scientifically evaluated.
The Johner Institute’s clinical and safety affairs experts help manufacturers meet the challenges at every step of the product approval process:
- Determining the qualification and classification of the product as a (substance-based) medical device in collaboration with the medical device experts
- Analysis of the mechanism of action of the ingredients to ensure a correct distinction from medicinal products and to avoid an unintentional classification in class III (clinical strategy/biocompatibility analyses)
- Documentation for conformity assessment procedures: Creating the complete clinical evaluation file, preparing the necessary analyses and studies to demonstrate the mode of action, and systematic literature research on your state of the art
- Interpretation of requirements and feedback from the notified bodies, as well as support in communication with the notified bodies
- Elimination of regulatory deviations
- Acting as EU representative if the company is located outside the EU (PRRC/QMS)
