The medical device manufacturing industry is heavily regulated. Every country and jurisdiction have their own set of rules and regulations to govern the medical device industry, the manufacturing of the medical devices, their marketing, their clinical implications, etc.
Although medical device regulations can be tailored and adapted according to the preferences of individual countries, some standards do exist that
- Cover multiple jurisdictions, or
- Have global implications.
ISO 10993-17 is an example of one such standard having global implications. Developed by the International Organization for Standardization, ISO 10993 presents requirements to define the toxicological risk assessment of constituents in medical devices. However, as of now; the new ISO 10993-17:2023 is not yet accepted in the US.
The complete name of the standard is ISO 10993-17:2023. Biological evaluation of medical devices Part 17: Toxicological risk assessment of medical device constituents.
Toxicological Risk Assessment in ISO 10993-17
ISO 10993 is meant for toxicological risk assessment for medical devices’ components and constituents. The document and its requirements are meant for toxicologists or other professionals who are qualified enough to make informed decisions by evaluating scientific data and using their knowledge of medical devices.
Here, it is pertinent to mention that the toxicological risk assessment being performed in the biological evaluation is based on:
- Exposure dose estimation,
- Derivation of tolerable intake or a tolerable contact level,
- Derivation of an MoS,
- Selecting a threshold of toxicological concern,
- Toxicological information about constituents explains the potential harms and the circumstances in which these harms can occur.
ISO 10993-17: Navigating the Recent Changes
ISO 10993 got a recent upgrade in 2023. This has been the first major revision in twenty years. A lot of changes have been introduced to the standard so that it can become compatible with the modern dynamics of the medical device industry.
Here, we are listing some of the major changes introduced in the recent upgrade of ISO 10993-17:
- It specifies the circumstances in which a toxicological risk assessment may be required.
- It explains the calculation of the worst-case estimated exposure dose of a constituent of the medical device.
- It has introduced novel concepts regarding hazard assessment, such as methods to address the additivity of harm, in silico methods, and read-across.
- It has also explained the way of calculating the probability of the occurrence of harm to health using other means. Examples of these means include:
- Frequency-based dose response
- Biological testing and
- Probabilistic dose response
A major consideration in ISO 10933-17:2023 has been given to hazard identification and risk estimation on the basis of TI (Tolerable Intake), TCL (Tolerable Contact Level), EDDmax (Worst-case Estimated Exposure Dose), Tolerable Contact Level (TCL), and Margin of Safety (MoS). Let’s break down each of these terms below:
Tolerable Intake (TI)
It is an assessment of the daily exposure of a recognized component for a designated duration. This daily exposure does not lead to a significant risk to health and is calculated in terms of body weight. To find the TI value, toxicologists first do a full toxicological analysis of the identified component in order to define its toxicological profile and then pick the most relevant data as starting point (POD) for the derivation of the TI. Besides determining the POD, uncertainty factors are incorporated to account for variability. The revised standard also offers additional guidance in this regard.
EDDmax (worst-case Estimated Exposure Dose)
EEDmax incorporates the worst-case assumptions regarding chemical release and device operation. It is the maximum value for a particular clinical-use scenario.
Tolerable Contact Level (TCL):
It refers to an approximation of the level of surface-contact exposure to a specific constituent that does not cause noticeable irritation. ISO 10993-17 provides guidance to manufacturers regarding the implementation of uncertainty factors that require consideration.
Margin of Safety (MoS)
It is the ratio of TI to EEDmax. If EEDmax is greater than the TI, then MoS will be less than 1. This implies that the exposure can be harmful. However, if MoS is greater than 1, then risk control, risk evaluation, and additional risk analysis are required.
Circumstances where Requirements of ISO 10993 are not Applicable
Processes described in ISO 10993 are not meant to apply to the circumstances where the toxicological risk has been calculated in other ways, such as
- Components found in (or extracted from) a medical device in a quantity that accurately represents patient exposure but falls below a reporting threshold established by toxicology (refer to the relevant specifications in ISO 10993-18:2020, Annex E and ISO/TS 21726 for details). However, this does not include chemicals that are already excluded or belong to a cohort of concern.
- A medical device (either new or changed) for which biological or chemical equivalence has been determined with an existing clinically accomplished or biochemically compatible medical device.
- Medical device constituents not coming in body contact, such as in-vitro diagnostics.
- Biological risks having physical interactions of the body and the medical device such that there are no changes in the chemical exposure. Examples of physical interactions include energy, surface morphology, and application of mechanical forces.
- Any active pharmaceutical ingredients of products with device-drug combination.
- Any biological components of device-biological combination products.
- Getting exposed to a specific constituent arising from sources other than the device itself, such as water, air, or food.
What has Been Removed from ISO 10993-17:2023?
Compared to its 2002 counterpart, some concepts are not the part of ISO 10933-17:2023 anymore. These include:
- Benefit factor
- Utilization factor
- Allowable limit
- Proportional exposure factor, and
- Tolerable exposure.
How Should Manufacturers React?
With its upgrade, ISO 10993-17:2023 presents several new requirements for medical device manufacturers. The standard contains extensive guidance on performing risk assessments for medical devices. This risk assessment will improve the consistency of medical devices, and thus, manufacturers will be able to penetrate more markets and build their trust.
How can TSQ&E help you?
TSQ&E has long-term experience working in the medical device sector. We have consultants and European registered Toxicologists that are well-versed in the requirements of various standards, such as EU MDR and ISO 10993-17. Now a registered toxicologist is required to do the TRA (Toxicology risk assessment) and we can help you in that. If you are a medical device manufacturer who wants to show compliance with the requirements of upgraded ISO 10993-17, contact us today. We will offer you extensive information regarding the risk assessment process and help you fulfill all the new requirements of ISO 10993-17:2023.