Identification and quantification of extractables and leachables (E&L)

According to the biocompatibility standard ISO 10993-1, information on the chemical composition must be obtained for all medical devices. As a result, chemical characterization is required for most medical devices, from low-risk products such as plasters or medical spatulas to high-risk products such as implants. Analyzing the chemical substances released from a device into the patient’s body enables the prediction and reduction of potential toxicities.

In the chemical characterization of medical devices according to ISO 10993-18, volatile, semi-volatile and non-volatile organic and inorganic substances are analyzed using various methods and techniques. Using suitable methods these substances are extracted or washed out of the products and provide an overview of potentially undesirable substances released during use. This chemical profile is used to assess the overall risk to the patient or user when using the product.
The analytical methods used for this purpose are high-resolution and sensitive techniques. Depending on the hazard potential of the products, the following methods are usually used:

Calculation of safety margins based on toxicity and concentration of identified extractables

A toxicological risk assessment is a comprehensive safety assessment of a device, based on its composition, the materials used and taking into account the intended use. The detailed scientific report on the toxicological assessment contains all available and relevant information and data on a specific ingredient in relation to the medical device under investigation. This includes the dosage, the concentration and the specific exposure scenario.

The toxicological risk assessment is a scientific evaluation and includes the following activities:

Properly evaluating and assessing the biological and toxicological risks, posed by extractables or chemical residues that may impact patient safety, is one of the more challenging aspects of the chemical characterization process.
To control the risk associated with extractable substances, these substances are identified, the related risks are quantified and exposure to these substances is limited so that acceptable limits are not exceeded.

Risk assessment is an important and essential part of the chemical characterization and biocompatibility testing, since it defines the acceptable limits for extractable and leachable substances.

The ISO 10993 standard series serves as a framework for assessing the biocompatibility of medical devices and the management of biological risks. The specific standards ISO 10993-17 and ISO/TS 21726 regulate the evaluation criteria for the toxicological risk analysis of the components of medical devices and the determination of the acceptable limit values for extractable substances.

Identification of biological effects after exposure

Medical devices often come into direct contact with human body tissue or fluids. It is important to check that the material of the device does not cause harmful reactions such as inflammation, allergies or tissue damage.

For the approval of medical devices and to ensure that the products are safe for human use, biological tests are carried out in addition to the physical/chemical tests. These tests may be decisive not only to confirm the biocompatibility of the individual extractable substances identified, but also to investigate the effect of the extracts as complex mixtures under clinical conditions and thus minimize potential health risks.

There are numerous other testing methods and biological endpoints. All of these tests are part of a comprehensive risk management process and are often carried out in accordance with international standards such as ISO 10993. Ultimately, they serve to protect and ensure the safety of patients and confirm the reliability and effectiveness of medical devices.

Identification of suitable contract research organisations (CROs) and competent study monitoring

In addition to qualified scientific and regulatory advice on the selection of studies and test strategies suitable for your objectives, we also offer the implementation of the studies at one of our laboratory partners. From the time the order is placed, we take over the entire handling and support of the studies for you until the successful completion of the project.

On the client’s side, the study monitor is the essential scientific complement to the study director of the research laboratory (CRO). Only the successful interaction of both positions can ensure that balanced and controlled decisions are made so that data and results meet the requirements of both, the science and the sponsor. Needs-based, results-oriented and scientific study monitoring guarantees the interdisciplinary coordination and assessment of approval-relevant studies for which quality assurance systems such as GLP, GMP and / or ISO are mandatory.

Tools for continuous improvement

Product safety and risk assessment in the pharmaceutical, biopharmaceutical and medical device sectors are aspects that are already of lasting importance in R&D. You will gain efficiency and precision if you consider today what will be required of you by regulations in the future.

Standardized industrial and regulatory quality management systems (GxP, ISO, …) and guidelines (OECD, ICH, …) are used worldwide to ensure the validity and traceability of data, processes and decisions in the life science sector.

In the early R&D phase, these standardized quality assurance systems are not necessarily suitable for promoting creative solutions to problems in research and development – or for developing innovative products. The challenge for quality management in this phase is therefore to create space for creativity and problem solving and yet generate reliable data.

PhaToCon provides tried-and-tested consultancy and management services in all aspects of preclinical toxicology and accompanying quality management. Processes for change control, deviation management, CAPA (corrective and preventive action) or risk management are the tools for your continuous improvement.

If It Wasn’t Documented, It Didn’t Happen … ?

The Biological Evaluation Plan (BEP) describes the strategy for investigating and ensuring the medical risk or biocompatibility of the medical device. The plan should describe and justify the biocompatibility assessment procedure in detail. All available information on the intended use of the device, the device configuration and design, the materials used in the device and in the manufacturing process, the production conditions and, if applicable, existing preclinical and clinical data should be taken into account.

The biological evaluation plan will then identify the gaps in the biocompatibility assessment and, based on ISO 10993-1, provide an expert recommendation on how to close these gaps most efficiently.

The development of a qualified biological assessment plan is expected by the authorizing institutions and authorities. In accordance with ISO 10993-1, it is also expected that all steps of the biocompatibility test in planning, execution, evaluation and documentation are carried out by experts.

Finally, all data are compiled and evaluated by experts and summarized in the Biological Evaluation Report (BER). At the end, a qualified statement on biocompatibility and, if applicable, a biocompatibility certificate should be available as an important part of the authorization documents.