Clinical, Medical & Diagnostic Products


Navigating the Complexities of E&L Analysis in Medical Devices Baljit Bains, Advanced Chemistry Development, Inc


The growing complexity and diversity of medical devices have increased the demand for advanced and specialised testing to ensure the safety of medical devices. Chemical characterisation of product materials (polymers, metals, ceramics) and extractables and leachables (E&Ls) is crucial in assessing the potential impact of the medical device’s biocompatibility and the associated toxicological risk.


Medical devices should not release chemicals that can accumulate or leach into the human body in amounts signifi cant enough to pose a risk of toxicity or impact its stability and effectiveness. Throughout the lifecycle of a medical device, from manufacturing to storage, there can be intentional or unintentional addition of compounds. E&L analysis is performed on all medical devices from simple tongue depressors to more advanced pacemakers to identify potentially toxic chemical compounds present in the device. Given the diverse chemical structures and additives that can leach out of manufacturing or packaging components, it is increasingly challenging to identify and precisely quantify E&Ls accurately.


Challenges of E&L Analysis


Accurate identifi cation of E&L compounds is essential to ensure the safety of medical devices. However, there are many challenges to understanding E&L information.


Processing and Data Management Different solvent and extraction conditions must be used for each sample, and it can take a long time to process, analyse, and report these studies. This also generates a signifi cant amount of data which must be appropriately managed and stored.


Detection and Identifi cation


The complexity of materials used makes identifi cation challenging, as E&Ls are often unfamiliar compounds lacking available reference standards. Detection can be masked due to extremely low concentrations of leachables, or secondary degradants can form over time making identifi cation diffi cult. It is important to determine correct dose-based thresholds, this usually requires toxicologist input.


Ambiguity in Guidelines


While there are existing guidelines for E&L analysis, they can be ambiguous - leaving scientists uncertain about whether they have fulfi lled all the necessary regulatory requirements. Scientists do the most they can, in the allocated time, but are often left feeling that it’s not enough for regulatory approval.


Regulatory and Advisory Guidelines


In recent years, regulatory and advisory bodies have signifi cantly increased their attention to the characterisation of chemicals and their focus on quality control. While there is some ambiguity, there are consistent guidelines for all medical devices. The ISO10993-18:2020 guidelines are a set of standards that guide the process of characterisation for medical devices. These guidelines cover the identifi cation of the materials of construction, clarify extraction procedures and analytical techniques to be used in E&L testing, and have an annex dedicated to the analytical evaluation threshold (AET). The AET is calculated based on the dosage and the route of administration. Chemical species detected at or above this threshold need to be identifi ed, quantifi ed, and reported for possible toxicological assessment. Setting and meeting the AET is an important part of the regulatory submission process.


Analysis of E&Ls


The presence of E&Ls in medical devices after the manufacturing, packaging, or storage process is unavoidable. E&L analysis is crucial for evaluating the potential toxicological risks these E&Ls may pose to human health. E&L studies require careful design and must consider factors such as the device’s classifi cation, intended use, and duration of contact. The setup of a chemical characterisation study can be summarised in three steps - extraction, detection, and identifi cation and quantifi cation.


It is also important to consider how the analytical technique will be applied and decide whether to take a screening approach (screen for every potential compound present in the extract) or a targeted approach (detect what is known with a low limit of quantifi cation (LOQ) and high accuracy). To ensure all compound classes and ionisable species are covered, it may be necessary to use multiple analytical techniques (including high-sensitivity instruments).


Identifi cation and Quantitation


Targeting methods and real-use conditions indicate true concentration exposure, allowing toxicological assessment on realistic values—testing the actual impact and the products. Compounds detected at or above their toxicological thresholds are targeted for identifi cation and quantifi cation.


Identifying every analyte is not always possible, and consideration must be given to unknown compounds. These unknown compounds have the potential to impact the safety of the medical device. Furthermore, it is not possible to confi rm every single identifi cation with authentic reference sources. To suffi ciently identify and report E&Ls, it is necessary to establish and utilise levels of confi dence.


Software programs like ACD/Labs’ MS Structure ID Suite analyse and process xC/ UV/MS data and store the knowledge in searchable databases. MS Structure ID Suite uses analytical chemistry to identify and quantify E&Ls - enabling confi dent identifi cation of ions present in the spectra, assisting with fragment assignment, and quantifying these analytes.


Extraction


Compound discovery and identifi cation are performed to extract the largest amount of extractable for identifi cation. The type of extraction (exaggerated, exhaustive, or simulated use) and the conditions (extraction solvent, temperature, and time) selected depend on the type of medical device to be tested.


Detection


There are different techniques to use for the chemical characterisation of E&Ls. To choose the correct technique for analysis, it must be clear which compounds will be analysed. Compounds that can potentially be harmful and the tests required for analysis are shown.


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40