Can you start by sharing the significance of Jordi Labs being one of only two laboratories invited to present at the recent FDA meeting? What does this recognition mean for your team?
Our chemists work hard every day to ensure that the analytical chemistry performed is of the highest level of excellence. Their commitment goes beyond simply generating results; they embrace the harder path because it leads to the best results. Their dedication to innovation and efficiency drives our team to deliver conservative yet reliable analyses, setting the highest standard for the industry. Having the opportunity to showcase their work to the FDA and other industry leaders is a tremendous honor.
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How has Jordi Labs’ methodology evolved over the past decade to align more closely with FDA expectations? Could you provide examples of the specific advancements or shifts in your approach?
Our team has been determined to recognize and address potential errors and inaccuracies in extractables and leachables analysis. This commitment is directly related to our focus on improving patient outcomes, both in ensuring the safety of medical devices and drug products and ensuring these life-saving technologies are efficiently made available to those that need them.
This overall approach, one that ensures errors are recognized and addressed even when it is difficult to do so, has not changed over the last decade. However, the details of the methodology used are being constantly evaluated, refined, improved, and verified.
of extractables. This also extends to our collaboration with the FDA, highlighting the importance of incorporating chemicals with a wide range of physicochemical properties to ensure thorough method coverage. Using a coverage map approach, laboratories can assess how well their methods detect extractables, even when accounting for specific uncertainty factors.
How does this methodological evolution impact the groundbreaking 2020 work by Jordi Labs, which introduced the multi-detector approach?
The multi-detector approach was an important stepping-stone for our current methods. The work highlighted the importance and impact of the use of orthogonal detection methodologies on a lab’s ability to ensure the detection of extractable chemicals. This work also demonstrated the ability of additional orthogonal methods to reduce the required uncertainty factor (UF).
Building from this foundation, our current coverage-map-based process demonstrates the ability of all applied methods to provide positive detection of extractables. In modern E&L analysis, laboratories must use fairly large databases of chemicals to evaluate methods and ensure the quality of the data generated. We have simplified this process by considering the physicochemical properties of these chemicals instead of their identity when evaluating database quality.
If adopted more widely, a focus on properties would allow laboratories performing E&L testing to use a more flexible and easily achievable metric.
Can you elaborate on the challenges Jordi Labs faced in communicating the efficacy of the multi-detector approach to regulators?
The multidetector approach builds on the standard methods that labs have long used for E&L testing. Of course, there were some truly important and innovative technical breakthroughs by our chemists to make this approach possible, but the foundation is those tried-and-true techniques.
Individually, these methods are subject to the same problems the industry has been working through over the past 10 or more years. Despite this, it has been difficult to separate the technical advancements from the fundamentals of the methodology. I think that this fact led to a misunderstanding that the multidetector approach represented something very different and, therefore, potentially less well understood.
Instead, the methods being used are very well understood, and the multidetector approach simply represents a different way of thinking and applying those methods. Thinking differently and integrating some very important technical achievements has meant that Jordi Labs has a better understanding of the methods' capabilities, which in turn means less risk of missed or ignored extractables.
Despite any misunderstandings, we have remained enthusiastic about sharing our work with the industry, including our multidetector approach. We strongly believe that collaboration within the industry drives innovation and ultimately improves patient outcomes. Throughout this journey, we have continuously refined and advanced our methods.
As our approach has matured, we recognize that effectively communicating its advantages now requires updated terminology. We have recently shifted our focus to highlighting the method’s coverage and the properties of the database employed in method evaluation. We hope that this makes it clearer that the database and uncertainty determination differ from the analytical methods used.
E&L testing is a core focus for Jordi Labs. Could you discuss the unique aspects of your coverage-map-based approach and how it meets or exceeds industry needs?
Chemical characterization testing is a very challenging version of ‘non-targeted analysis’ (NTA). In NTA, it is critical that methods can detect the chemicals of interest. In extractable testing, especially for medical devices that frequently contain a wide variety of materials, there is a very wide range of possible extractables. This is often referred to as the ‘universe of extractable.’ Because of this, the analytical methods used for chemical characterization need to be broad and effectively address problems associated with response factor variation.
The approach Jordi Labs uses acknowledges and addresses these problems. The coverage-map approach uses a database constructed of a wide range of chemicals to evaluate the set of methods to be applied. This database could not contain all of the chemicals that one might possibly encounter as extractables, so our approach ensures that a reduced set of chemicals to be used is sufficient. The way to do this is to evaluate the chemicals based on their physicochemical properties, as these properties determine the chemical’s response to a given analytical method.
What are the primary benefits of your evolved methodology for clients in regulated industries? How do these align with FDA priorities?
There are many advantages to this approach, but the most significant ones are its ability to enhance accuracy and efficiency when compared to other data processing and thresholding methods.
The use of a well-constructed database to evaluate the methods used allows us to use the proper uncertainty factor (UF is applied to ensure low-responding compounds are appropriately included in a study).
Other approaches may seek to be as conservative as possible for UF. As long as proper compound-finding approaches are being used, the result of this conservatism is a large amount of false positives. A significant amount of effort is required to evaluate these false positives, which ultimately is a wasted effort because these false positives are below the AET and will be removed during the quantification phase of the study. A well-established database from a coverage-map-based approach allows the UF to be set at the proper value to generate the correct level of coverage. This means that the majority of false positives are correctly screened out prior to identification.
The approach also establishes the distribution of response factors across the different methods being used, which can be used to evaluate expected accuracy. Provided that the right physicochemical properties are included, the distribution of response factors can be established.
From this information, we can assess the expected accuracy of each method. Our research clearly shows that the distribution of response factors for LCMS methods is unlikely to provide accurate semi-quantitative results. This is due to the tendency for compounds to cluster at the extremes of the response factor distribution, which itself is quite broad. As a result, we avoid using this detector for quantity estimates, as the potential for significant error is much higher.
In what ways does your work in E&L testing contribute to broader industry advancements or standard setting?
Since sharing our groundbreaking work on the multidetector approach, we have seen other laboratories follow and use additional detectors. As a lab that is focused on getting safe medical devices onto the market, we hope this trend continues.
In addition to sharing our research with other industry colleagues, we have also tried to collaborate with regulators whenever possible. The goal of this open collaboration is to ensure transparency regarding the potential shortcomings of the methods used, to share findings on potential solutions, and to openly discuss the benefits and risks of those solutions. The same open approach is applied in our efforts to aid in drafting updated industry standards.
As a recognized thought leader, what future trends do you anticipate in this area?
I think that we will continue to improve our understanding of the physicochemical properties of extractables and their relationship with responses from modern detectors. This can lead to improved efficiency (by continuing to reduce applied uncertainty factors) and improve quantitative accuracy. We will also continue to build on the connection between the analytical chemistry performed and the toxicological assessment following. A better understanding of the process and challenges of these parts of the chemical characterization process will enable improved patient outcomes. Jordi Labs is dedicated to this pursuit; our toxicologists and analytical chemists work closely together to ensure each extractable is as well evaluated as possible.
About Kevin Rowland
Kevin Rowland is the Executive Vice President and General Manager at Jordi Labs, where his leadership focuses on pioneering solutions and achieving analytical excellence to meet the most demanding challenges. Kevin has been a
integral part of Jordi Labs for 15 years, contributing in various capacities with a focus on high-resolution mass spectrometry, method development, and extractables and leachables testing. Collaborating with Dr. Mark Jordi, he has co-authored several influential papers that have advanced the field of extractables and leachables analysis.
About Jordi Labs
Jordi Labs, an RQM+ company, provides the highest quality contract analytical services to some of the world’s leading consumer products, polymers, pharmaceutical and medical device manufacturers. Our team of PhD analytical chemists specialize in chemical identification. One of core competencies is Extractables & Leachables testing.