Borderline Substance-Based Medical Devices

Introduction.

The boundary between a substance based medical device and a medicinal product is extremely thin and often difficult to clearly define. In the practice of designing and developing substance based medical devices, many doubts regarding qualification arise. The similarity in form, and even in intended use, can lead to incorrect decisions as early as the formulation development stage, resulting in serious consequences beyond just regulatory and market issues. The article discusses selected key issues that must be considered to properly establish that a designed product is a medical device.

 

 

Medical device or medicinal product – why is it so easy to make a mistake?

Substance based medical devices, although often similar in form to medicinal products, require a completely different approach to formulation development. This stems from the differing concepts of these products. The action of a medical device often relies on multiple functional ingredients, including substances commonly considered auxiliary or technological. In the case of medicinal products, the foundation is the active substance or substances, while the main role of ancillary substances, in general terms, is to ensure the appropriate form of the product.

The intended action of a medical device may resemble that of a medicinal product. However, the difference is determined by the mechanism of action responsible for the effect.

Medicinal products are characterized by a pharmacological mechanism, expressed through interaction with biological structures of the body or its components and subsequent signal transduction, leading to the intended therapeutic effect. Immunological and metabolic mechanisms constitute specific pharmacological aspects acting at the level of the immune or metabolic system.

Medical devices, on the other hand, are characterized by a primary mechanism of action that is essentially non pharmacological, non immunological, and non metabolic, and they may be assisted by means of a medicinal nature.

 

 

From idea to market - how to design a medical device and avoid the qualification trap?

Designing a substance based borderline medical device requires special attention during the formulation development stage. Correct qualification is crucial for further regulatory and market activities. At the same time, it is a difficult task, posing many questions without obvious answers, which is reflected in the continuous updating of borderline guidelines. From my experience as a technical expert, qualification aspects raise doubts among manufacturers. I understand the anxiety when the discussion on qualification arises after the design process has been completed.

The most common errors observed in this regard in technical documentation include:

·        defining the device action and the function of individual ingredients solely based on the manufacturer intention without support from scientific data,

·        lack of knowledge of the device's mechanism of action or making claims that are not adequately substantiated by data,

·        omitting the pharmacological, immunological, or metabolic properties of substances in accordance with the current state of knowledge, as well as the omission of a scientific justification for the absence of an ancillary action of these substances in the device,

·        using declarations in the labeling and communication of the device regarding the action of substances considered technological.

The design stage is a clash of product formulation visions and marketing strategies with regulatory requirements. Every element is significant and cannot be marginalized if the product is to succeed on the market. The design of every product is a resultant of possibilities and potential, as not every product can be a medical device.

The design strategy for a substance based medical device should verify from the very beginning whether the device meets regulatory requirements based on solid scientific evidence.

The formulation stage, beyond performing laboratory work resulting in a formulation that meets the project's assumptions, should also encompass the qualification issues of the emerging device. When designing a borderline device, the risk that the design outcome will be a product that does not meet the definition of a medical device and requires design in accordance with other regulations should be minimized as much as possible.

Currently, many raw materials are available on the market that can be used at the medical device formulation stage. When selecting raw materials of appropriate quality, beyond verifying them in the formulation, it is extremely important to find answers to key qualification questions:

·        whether the device containing the substances selected during the design process meets the definition of a medical device in terms of the primary physical mechanism of action?

·        whether the primary action is assisted by pharmacological, immunological, or metabolic means?

·        By what mechanism does each substance in the device formulation act if used separately, regardless of the site of administration and the quantity in the device?

·        By what mechanism does each substance in the formulation act, taking into account issues specific to the device?

The device as a whole, as well as each substance individually, must be scrutinized, and technological substances cannot be omitted.

Answers to these questions must be based on solid scientific data and documented in the technical dossier so that the notified body or regulatory authorities have no future doubts regarding the correctness of the qualification.

 

 

Mechanism of action under control: how to avoid a qualification error?

Identification of the device's mechanism of action is key to the regulatory decision regarding the qualification of a substance based borderline medical device. Particular attention should be paid to establishing the primary mechanism of action, as it determines regulatory qualification, especially for devices containing substances with potential medicinal action.

The difference between medical devices and medicinal products is primarily based on the mechanism of action and the link between this mechanism and the product's intended effect. Therefore, it is extremely important that the concept of the mechanism of action is well understood.

The primary mechanism of action is the way in which the device achieves its primary intended action, referring to both the place and the mode of action of the device and its components, as well as their interaction with the body or it components. The effect described as therapeutic is the result of the product's action after application.

It should be noted, however, that there is no universally accepted definition of "non-pharmacological" mechanisms of action. In practice, these mechanisms are generally equated with physical mechanisms. Regulatory guidance identifies physical interactions such as mechanical action, formation of a physical barrier, lubrication, hydration or dehydration, and pH modification.

The scientific literature also presents expert concepts explaining this notion, according to which a physical mechanism of action is understood as an interaction between substances contained in the device and other substances present in the body, with the sole purpose of modifying the surrounding environment or matter.

What is important, the device's mechanism of action should be objective and based on the latest scientific evidence, taking into account current knowledge of the device, its constituents, and its manufacturing process. Any claims regarding the mechanism of action should be supported by robust scientific evidence and a critical scientific assessment. Sources of evidence may include:

·        published scientific literature,

·        pharmacological and toxicological data on the substances,

·        results of experimental laboratory studies,

·        clinical data.

All gathered evidence may be used in a complementary manner. If the product under development is intended to meet the definition of a medical device, the answer to the key design research question—"Is the principal intended action of the product achieved by pharmacological, immunological, or metabolic means?"—should be no.

 

 

Substances in Medical Devices – When Detailed Analysis Determines Success

A thorough evaluation of the available scientific knowledge relating to each individual substance, together with an assessment of the device as a whole, enables the correct determination of the function and role of every substance in achieving the device's intended purpose. This also provides the basis for answering further qualification-related questions concerning the presence or absence of an ancillary action of substances that may themselves meet the definition of a medicinal product.

Rule 14 of the classification rules set out in Annex VIII of the MDR effectively requires every substance incorporated into a device to be assessed from two perspectives:

·        whether the substance may be considered a medicinal product within the meaning of Article 1(2) of Directive 2001/83/EC; and

·        whether the action of the substance is ancillary to that of the medical device.

This analysis is frequently omitted from classification protocols. However, a comprehensive understanding of the behaviour of each substance - both when used independently, regardless of dose or route of administration, and when incorporated into the device - is fundamental not only for correct qualification and classification but also for innovation. The guidance documents emphasize the need for an individual assessment and scientific justification of the mechanism of action of every substance, irrespective of the purpose for which the manufacturer incorporated it into the device during the design process.

The assessment of technological substances remains a subject of considerable discussion and may appear to represent a return to the "stone age" because of the widespread tendency to apply medicinal product design paradigms to medical devices by default. In medicinal products, pharmacologically active substances are responsible for the therapeutic effect, while excipients primarily serve to create the pharmaceutical dosage form and generally do not produce therapeutic effects. In contrast, in a medical device, every constituent may contribute to achieving the device's intended purpose.

Many technological substances (e.g. flavouring agents, colourants, antioxidants, or chelating agents) may possess the potential for pharmacological activity. In such cases, the solution is to demonstrate either that the substance is not available to the human body or its constituents, or that it is available only in quantities insufficient to exert any effect on the human body or its constituents. Where the manufacturer demonstrates, on the basis of robust scientific evidence, that the substance is not available to the body, it is equally important that no clinical benefits attributable to that substance are claimed in the device's labelling, instructions for use, or promotional communications.

 

Designing in the Absence of Data – How to Address Scientific Uncertainty

It is also possible, particularly in the case of devices incorporating innovative substances, that no data on the mechanism of action are available.

Among the many possible approaches to addressing such knowledge gaps, systems biology and in vitro mechanism-of-action studies deserve particular attention. These rapidly evolving fields support both device development and the generation of evidence substantiating the mechanism of action, thereby facilitating the correct regulatory qualification of the product. The literature describes several examples in which a non-pharmacological mechanism of action has been demonstrated for devices containing substances with pharmacological potential. Although these emerging methodologies are promising, manufacturers should carefully consider the reliability of the data generated and the associated validation requirements before relying on them during device development.

 

Conclusion

The correct qualification of substance-based medical devices requires a detailed analysis of both the mechanism of action and the function of all constituent substances. Errors made during the design phase may have significant regulatory and commercial consequences. Success depends on robust scientific evidence, close collaboration with experts and constructive dialogue with regulatory authorities. Only such an approach can minimize qualification errors and support the successful placement of medical devices on the market.