3 Common Deficiencies in Biological Evaluations of Medical Devices

Biological evaluation of medical devices is crucial for ensuring that the device´s contact with the human body is safe, guided by ISO 10993 standards. However, many manufacturers encounter challenges that lead to deficiencies, potentially delaying regulatory approvals. This article explores three common deficiencies raised by notified bodies and how to address them to meet regulatory requirements and ensure patient safety.

1. Lack of Physical and Chemical Characterization: Missing or Incomplete Data

One of the most frequent deficiencies encountered in biological evaluations is the absence of proper chemical characterization. The ISO 10993 specifically requires manufacturers to characterize the chemical composition of all materials that come into contact with patients. This includes both direct contact materials and indirect contact materials, such as packaging materials that could leach substances into the medical device.

Understanding the chemical composition of materials is essential for identifying potential risks, such as toxic substances that could affect patients‘ health. This characterization forms the basis for further risk assessments, including cytotoxicity, genotoxicity, and sensitization studies.

Manufacturers often fail to provide a comprehensive chemical characterization, particularly when dealing with complex or proprietary materials from third-party suppliers. Even if the exact composition of raw materials is available, the manufacturing process, which might impact the material, is often not taken into account. This oversight can result in major setbacks during the regulatory review process. Notified Bodies in Europe may reject the submission outright or request additional information, delaying the time to market.

Justification necessary for waiving studies

To avoid this deficiency, manufacturers should work closely with their suppliers to obtain complete and accurate chemical composition data. If certain materials‘ compositions are unknown or proprietary, alternatives may need to be considered, or detailed toxicological justifications should be prepared.

Advanced analytical techniques, such as gas chromatography-mass spectrometry (GC-MS), high-performance liquid chromatography (HPLC) and inductively coupled plasma mass spectrometry (ICP-MS) can provide the leachable and extractables profile.

These extraction tests should be performed on the finished device (and not the raw materials) to take into account the effects of manufacturing processes. Ideally, a device stored in its packaging for the intended shelf-life and under appropriate storage conditions should be extracted to also consider potential degradation products and effects of the packaging. A proper extraction medium must be chosen to mimic the contact with the respective human tissue or fluid.

Additionally, it’s crucial to ensure that this chemical characterization is performed in line with the latest version of ISO 10993. Regular updates to the standard could mean that older tests may no longer be valid without justification (see Point 3).

We can support you.

Do you need advice on choosing the right laboratory and required tests for your devices?

2. Overlooking Relevant Data

Manufacturers are required to conduct thorough reviews of toxicological data for all materials and components used in their devices, including packaging materials. This literature search should cover scientific studies, regulatory databases, and other sources of toxicological data to ensure that all known safety concerns related to the device’s materials are considered during the risk assessment process. Without this step, manufacturers may overlook critical information, such as previously identified toxicological hazards or known interactions between certain materials. This can lead to an incomplete risk assessment and, ultimately, regulatory non-compliance.

In many cases, manufacturers fail to conduct a comprehensive literature review, focusing only on easily accessible or well-known sources. This approach can result in missed safety concerns, especially for newer materials or components that may not have been extensively studied. In addition, failing to consider packaging materials and their potential to leach harmful substances into the device can lead to overlooked hazards.

Literature Search for Safety

Manufacturers should take a systematic approach to their literature search, covering all relevant databases and sources. This includes toxicology databases such as ECHA (European Chemicals Agency) and CompTox Chemical Dashboard, further literature databases such as PubMed as well as industry-specific databases that may contain valuable information on material safety. When searching for data, it is essential to consider both direct contact materials and indirect contact materials, such as adhesives, coatings, and packaging materials.

Moreover, a detailed search strategy should be documented, showing how the literature review was conducted and the sources consulted. This transparency will help regulatory bodies to evaluate the thoroughness of the search and reduce the likelihood of requests for additional information.

3. Justification of Expired Standards

A third common deficiency is the failure to justify the use of data from extraction tests that were collected under outdated or expired standards. As ISO standards evolve, the requirements for biological evaluations change, meaning that data collected under previous versions of the standard may no longer be acceptable.

The goal of an update of an ISO standard is to reflect the latest scientific knowledge and best practices in the field. Extraction data that were considered adequate under a previous version may not meet the requirements of the updated standard, particularly if new risks or testing methods have been introduced.

Some manufacturers assume that data collected under previous ISO standards will be automatically accepted by regulators, leading to non-compliance issues when newer standards are applied during the review process.

How to Adress it

To avoid this pitfall, manufacturers should conduct a gap analysis whenever an ISO standard is updated. This analysis involves comparing the requirements of the old standard with those of the new version and identifying any areas where additional testing or justification is needed. If older data is still being used, a robust scientific rationale must be provided, explaining why the data remains valid and how it meets the updated standard’s requirements.

our task

We help you to launch your medical devices and IVDs quickly and efficiently.

Closing Gaps

To ensure compliance, manufacturers should perform a comprehensive material characterization, conduct a thorough literature search across relevant databases, and perform an in-depth gap analysis when standards are updated. By taking these steps, you’ll not only meet regulatory requirements but also contribute to the safety and well-being of patients who rely on your medical devices.