Extracting the truth: the importance of complete chemical characterisation

Sandi Schaible, senior director of analytical chemistry at WuXi AppTec, shares the importance of complete chemical characterisation.

Plastics are everywhere in medical device manufacturing. Whether we’re talking about a filter, bag, container, delivery system or implantable device, these days, chances are, plastic is part of the equation. While plastics and polymeric materials can enhance performance and pricing, these materials do carry risk of their own. Manufacturers need to understand these risks as they develop their products, plan for production and identify both materials and component suppliers as well as laboratory testing partners to support their submission and lifecycle management of their products. They need to understand the key tenet that not all plastics are created equally.

Plastic and polymeric products, parts and components can include significant numbers of chemical constituents. Some of these constituents are expected, but many are unexpected and can be potentially harmful. Additives, excipients, and release agents along with impurities, can pose significant differences in plastics that, at surface level, appear to be equivalent. It is these chemical constituents that can leach from the products and compromise patient safety. Extractables and leachables (E&L) testing is the most effective way to extract, detect and identify these potentially problematic compounds so that a thorough risk/safety assessment can be conducted to determine the risks.

Extractables testing challenges products using aggressive solvents under exaggerated conditions. The point of extractables testing is to generate “worst-case” data to create a conservative approach to safety. Leachables testing or simulated use extractions investigates compounds that have migrated from a plastic component under clinically relevant or “normal” conditions utilising drug products, placebos, or more clinically relevant extraction solutions.

Regulatory bodies are becoming more and more interested in understanding complete chemical characterisation, looking for extractables and leachables data. Because even common materials or those with a long history of clinical use can contain chemicals of concern. Per ISO 10993-1, most medical devices require extractables or exaggerated extractables studies and a toxicological risk assessment, with potentially additional chemistry to mitigate risks to fulfil materials characterisation endpoints.

For drug manufacturers, the release of USP <1665> and <665> signals a keen interest in the extractables and leachables in the plastic components of the biomanufacturing process in addition to the extractables and leachables work that has been conducted for years with regards to container closure and stability studies.

Shift Your Mindset on E&L Testing

The goal of an E&L study is to detect and identify all the chemical constituents above an analytical threshold, including chemicals that are unexpected. It takes a committed laboratory to do the work needed to identify compounds, a report with “unknowns” can cost delays and require retesting.

Robust, well conducted E&L studies require a commitment by the laboratories to provide complete characterisation; they must identify the unknowns. Many chemistry laboratories advertise E&L capabilities, but a lab designed specifically for them is different. It means building an infrastructure that includes the instrumentation, cross-functional skill sets and staff to generate and interpret the data in meaningful ways.

For example, liquid chromatography-mass spectrometry (LC-MS) is a highly sensitive platform used to detect semi to non-volatile compounds. When it comes to plastic medical products, typically the most chemicals are found using LC-MS. And this is often when chemicals of concern are found. There are no commercial databases of LC-MS compounds, and even the most comprehensive private databases contain only a fraction of possible chemicals derived from E&L studies. So it takes the effort of expert chemists doing compound elucidation to get to identification. But, without the identification, an E&L programme is incomplete and often, unusable for a toxicologist doing a risk/safety assessment.

To reiterate, manufacturers need to know how committed their laboratory testing partners are to identifying all potential hazards. Complete identification is complex and resource intensive. Working with a lab that specialises in complete chemical characterisation will yield the best results.

Ask the Right Questions

Thoroughly vetting potential partners can save manufacturers from unexpected charges and unanticipated problems down the road. Understanding your lab testing partner’s method of identifying chemicals of concern and level of rigor is critical. To this end, manufacturers should

dig deeply into any potential partner’s experience. Helpful questions include:

● How long has the laboratory been conducting E&L studies? How many programmes have you run?

● Can you commit to the elucidation and complete identification of all components?

● Is complete identification included in the price and timeline that you provided? Or is this extra?

Successful partnerships require more than experienced practitioners, so it is essential to also ask about project management and communication. Helpful questions include:

● What is your on-time delivery record? And, when does the clock start? Upon receipt of the test article?

● E&L studies often yield unique situations. Can you commit to proactive communications when these arise?

● What support do you provide after analytical testing concludes? What if regulators have questions?

Finally, manufacturers must understand the services they are purchasing—and those they are not. Some laboratories charge extra for identification or identification beyond what can be found in a commercial database. Other laboratories claim they have the capacity to take on a new E&L programme but fail to deliver on time when the process proves more complex than anticipated. Asking the right questions when vetting partners allows manufacturers to make informed decisions, achieve regulatory success and market safe products.    

A Final Word on E&L Testing

Plastic and polymers have become the dominant materials in medical products, but several factors contribute to their safe use. Manufacturers cannot assume that just because a plastic or polymer has been used before or is commonly used that there will not be potential safety concerns. E&L testing helps manufacturers find the unexpected chemicals that may, or may not, potentially impact safety. A robust E&L programme should detect and identify all chemical constituents and provide a clear picture to assess risk. Manufacturers are right to question any laboratory testing partner that cannot deliver complete data about their container, delivery system or device.