Biological evaluation of medical devices is a risk-based process intended to determine the potential for adverse biological responses resulting from patient contact with device materials. The framework for this evaluation is defined in ISO 10993-1:2025, which establishes the general principles for assessing biocompatibility based on:
- Nature of body contact
- Type of tissue contacted
- Duration of contact
Among these factors, exposure duration is a critical determinant of the biological endpoints that must be evaluated. Incorrect estimation of exposure duration can lead to:
- Under-testing (regulatory risk)
- Over-testing (unnecessary animal studies)
- Rejection during regulatory review
- Inadequate toxicological risk assessment
Exposure duration classification directly influences the biological endpoint selection table in ISO 10993-1:2025. Incorrect categorization can result in incomplete evaluation or unnecessary testing. Regulatory reviewers frequently assess exposure duration calculation as a critical step during technical documentation review.
Exposure Duration Categories
One of the most critical determinants in biological evaluation is how long the patient is exposed to the medical device materials. ISO 10993-1:2025 does not merely classify devices by their physical design or intended purpose — it categorizes them based on the total exposure period to a single patient.
This classification directly determines:
- The scope of biological endpoints
- The depth of toxicological assessment
- The need for systemic toxicity studies
- The potential requirement for chronic or carcinogenicity data
The standard defines three exposure duration categories:
Limited Exposure (≤ 24 Hours)
A device is considered limited exposure when the total duration of contact with the patient does not exceed 24 hours.
This exposure may occur:
- During a single continuous procedure (e.g., surgical instruments)
- As multiple short exposures within the same 24-hour period
- Through cumulative use that still does not exceed 24 hours total
The defining element is that total exposure time remains within a 24-hour maximum window for a single patient.
Why This Category Matters
Limited exposure devices are typically associated with acute biological risks. The body’s response is generally immediate and localized. Therefore, the evaluation focuses on:
- Cytotoxic potential
- Irritation or intracutaneous reactivity
- Sensitization potential
If the device contacts circulating blood, hemocompatibility endpoints may also apply.
However, ISO 10993-1:2025 makes it clear that even limited exposure devices require a risk-based assessment. Chemical characterization must still be performed to ensure no unexpected systemic risk exists.
Prolonged Exposure (> 24 Hours to 30 Days)
A device falls under prolonged exposure when the total exposure period exceeds 24 hours but does not exceed 30 days.
This duration significantly changes the biological risk profile. Once exposure extends beyond 24 hours, the probability of:
- Systemic absorption of leachables
- Subacute tissue responses
- Cumulative biological effects increases.
Exposure in this category may occur through:
- Continuous contact (e.g., indwelling catheter for 7 days)
- Daily repeated use
- Intermittent contact summed over time
Biological Implications
Prolonged exposure introduces the possibility of systemic toxicity. As a result, in addition to the endpoints required for limited exposure, evaluation may expand to include:
- Subacute toxicity
- Material-mediated pyrogenicity
- Expanded systemic toxicity considerations
- Chemical characterization and toxicological risk assessment
At this stage, ISO 10993-1:2025 strongly emphasizes integration with chemical characterization principles under ISO 10993-18 and application of risk management principles aligned with ISO 14971.
The transition from limited to prolonged exposure is not minor — it fundamentally changes the depth of evaluation required.
Long-Term Exposure (> 30 Days)
Devices are categorized as long-term exposure when total patient contact exceeds 30 days.
This includes:
- Permanent implants
- Long-term indwelling devices
- Devices used daily beyond 30 calendar days
- Chronic therapeutic systems
Why Long-Term Exposure Is Critical
Long-term exposure allows:
- Accumulation of chemical substances
- Chronic tissue responses
- Long biological half-life interactions
- Potential carcinogenic or reproductive effects
The body’s adaptive response over extended periods must be considered.
Therefore, biological endpoints may expand further to include:
- Subchronic or chronic toxicity
- Genotoxicity
- Carcinogenicity (if indicated by risk assessment)
- Reproductive and developmental toxicity
- Implantation studies (for implantable devices)
ISO 10993-1:2025 reinforces that such testing should be performed only when scientifically justified, with preference given to chemical characterization and toxicological risk assessment before initiating animal studies.
Understanding the three duration categories is only the first step. Accurate classification depends on correct calculation of total exposure period, especially for devices with repeated, daily, or intermittent use.
Calculation and Estimation of Exposure Duration
Correct categorization depends not only on understanding the three duration groups but also on accurately calculating the total exposure period in a single patient.
One of the most common regulatory deficiencies arises from miscalculating exposure duration.
ISO 10993-1:2025 clarifies that exposure duration must consider:
- Frequency of use
- Replacement cycles
- Total therapy duration
- Repeated contact patterns
- Bioaccumulation potential
It is not sufficient to rely on single procedure time.
Daily Contact
Daily contact occurs when a device contacts the patient every calendar day for any portion of that day.
Even if the contact is brief (for example, two hours per day), each day counts as one exposure day.
Calculation Principle
For daily contact devices:
The total exposure period equals the number of calendar days from the first to the last use in a single patient, including replacement of identical single-use devices.
This means:
- Five hours per day for 40 days = 40 exposure days
- Two hours per day for 10 days = 10 exposure days
- Lifetime daily therapy = long-term exposure
Why This Rule Exists
Without this clarification, manufacturers might incorrectly classify a device used five hours per day as limited exposure. ISO prevents such underestimation by requiring calculation based on calendar days, not hourly accumulation.
This approach reflects the biological reality that repeated daily exposure enables:
- Chemical accumulation
- Tissue adaptation
- Systemic absorption over time
Intermittent Contact
Intermittent contact occurs when there is a minimum of 24 hours between consecutive tissue contacts.
Examples include:
- Devices used once every three weeks
- Semi-annual therapeutic systems
- Repeated treatment sessions
Calculation Principle
For intermittent contact devices:
The total exposure period is determined by summing the number of contact days from the first to the last use in a single patient.
The length of contact on each day does not affect classification.
For example:
- 10 treatment sessions = 10 exposure days
- 6 treatments over 3 years = 6 exposure days
The elapsed calendar time (months or years) does not determine the category — the total number of contact days does.
Bioaccumulation Considerations
ISO 10993-1:2025 introduces important clarification regarding bioaccumulation.
Regardless of calculated exposure duration:
If a device contains materials known to:
- Persist in human tissue
- Accumulate over time
- Exhibit long biological half-life
Then the device may require classification as long-term exposure, unless scientifically justified otherwise.
This requirement ensures that toxicological risk assessment accounts for chemical persistence, even when apparent exposure duration seems limited or prolonged.
Bioaccumulation assessment should be documented within:
- The Biological Evaluation Plan (BEP)
- Toxicological Risk Assessment
- Risk Management File
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| Exposure Duration Determination Framework as per ISO 10993-1:2025 |
Correct categorization requires:
- Clear understanding of intended use
- Accurate calculation of total exposure period
- Consideration of daily versus intermittent contact
- Inclusion of replacement cycles
- Assessment of bioaccumulation potential
Misclassification can lead to regulatory delays, additional testing requirements, or worst-case, inadequate patient safety evaluation.
ISO 10993-1:2025 reinforces the importance of integrating exposure duration assessment with chemical characterization and toxicological risk assessment before initiating animal studies. This approach supports scientifically justified evaluation while minimizing unnecessary testing.
Ultimately, exposure duration is not merely a regulatory checkbox — it is a foundational element of biological risk assessment and patient safety.
When properly calculated and clearly documented, it strengthens both regulatory acceptance and clinical confidence in medical device safety.
