Ashli Speed, Conference Producer, Smithers  
Paul Cummings, General Manager, Analytical Services Medical Device Testing Smithers

Although the field of Extractables and Leachables has matured considerably, there will always be `new challenges as new regulations and new and more complex pharmaceutical manufacturing and delivery systems are developed.  Regulations continue to evolve such as the new ISO 10993 parts introduced in the past 2 years.  In addition, there ever greater demands being placed on the analytical techniques employed, with lower and lower detection limits required.  And there are ongoing practical issues such as locating, recruiting, and developing the scientific expertise required to successfully perform E&L studies. This presentation is not intended to offer absolute answers to these questions.  Rather the purpose is to engage the knowledge and expertise of the conference delegates in broad ranging discussions around these and any other topics related to the  major changes, challenges, and innovations in the E&L community.
Paul Cummings | Principal Scientist, Smithers

Biological evaluation of medical devices is evolving to make use of non-animal approaches. In 2016, the FDA-CDRH Guidance on “Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" was revised to emphasize the use of a chemical risk assessment approach to address systemic toxicity, genotoxicity, and carcinogenicity. Chemical risk assessment has increasingly become a common approach, in lieu of biological testing, to address systemic toxicity (acute, subacute, subchronic, & chronic), genotoxicity, cancer, and reproductive/developmental toxicity in medical device biocompatibility evaluations. Chemical risk assessment begins with chemical characterization that often produces an extract of numerous and diverse substances, which presents a challenge for the analytical chemist and toxicologist to identify, quantify and evaluate chemical toxicological risks. Application of key toxicological risk assessment principles for meeting this challenge will be presented.
Alan Hood | Research Toxicologist, Center Devices and Radiological Health, Office of Science & Eng. Lab., US Food & Drug Administration

Safety thresholds for E&L in parenteral and ophthalmic drug products (PODP) were proposed in 2013 and published in the PDA Journal of Pharmaceutical Science and Technology.  Since then pharmaceutical and medical device advancements have occurred and influenced the final recommendations.  Extensive reviews of the 2013 E&L proposal culminated in the release of “Safety Thresholds and  Best Demonstrated Practice for Extractables and Leachables in Parenteral Drug Products (PDP).”   The final document is now available at www.PQRI.org.  In this presentation you will learn about the changes that took place, and application of science and risked-based assessments for E&L in  intravenous, subcutaneous, and intramuscular injectable dosage forms. The hazards associated with  biological products will be examined and the E&L challenges related to drug-device combination products will be considered. 
Diane Paskiet | Sr. Director Scientific Affairs, West Pharmaceutical Sciences

The EU Medical Devices Regulation (MDR, Reg. No. 2017/745) has entered into force on May 25, 2017 and is now fully applicable and enforceable by law since May 26, 2021. Compliance with the General Safety and Performance Requirements (GSPR) is the keystone for establishing conformity with the EU MDR. The GSPR, which replace the Essential Requirements from EU MDD, introduce new requirements with regards to the biocompatibility evaluation of medical devices. Especially, GSPR 10.4.1 focuses on carcinogenic, mutagenic or reprotoxic (CMR) and endocrine disrupting (ED) compounds when present at a concentration above 0.1% w/w in high-risk medical devices. This presentation will give an insight of current European Regulation chemical compounds (REACH, CLP) and its link with MDR, and will propose an approach on how to address the presence of CMR and ED compounds in medical devices. In addition, recent feedback from Notified Bodies will be presented. Examples will include deficiencies related to the toxicological risk assessment of CMR/ED compounds, degradation products, and extractables/leachables.
Valériane Levelut, PHARMD, ERT, DABT | Toxicologist, NAMSA

Polymers used in the pharmaceutical industry serving different purposes. They can be used as part of the packaging or delivery systems, part of the manufacturing process, and can be used as a medical device.The performance and the quality of the polymer play important role how those different functions are being fulfilled the expectation of the intended use. They must meet high level of purity standards in order to minimize the probability of harmful chemicals leaching out from the packaging or from the devices. Chemical safety assessment is one of the necessary steps to claim that the polymer is safe to use for pharmaceutical applications. Over the past decade, different standard setting organizations (USP, ISO) made significant efforts to guide the industry how those safety assessments should be performed, supporting higher chemical safety and lower patient exposure to potentially harmful chemicals. The chemical safety assessment should start with proper material characterization, using state of the art analytical methods, including different chromatography techniques hyphenated with mass-spectrometric detection. Since the polymers are mostly not compatible with direct analysis of those chromatography based techniques, an extraction step is required to perform the testing. The extraction can be based on solvent mediated or solventless technique. This paper presenting data sets for 3 different types of polymers (polypropylene, polyisobutylene and a rubber elastomer), using 3 different solvents and 3 different extraction techniques. The extracts were collected at different time points, and analyzed by GC-MS. There are significant differences were observed between the different extraction techniques and the different solvents.
Daniel Norwood, Ph.D. | Principal Consultant, Feinberg Daniel Norwood & Associates Pharma Consulting

The purpose of an exaggerated extraction is to perform an extraction that is intended to result in a greater number/amount of extractables versus that which would be generated under the clinical conditions of use. In order to do this, some extraction solvents are employed which are not realistic in terms of contact with the materials, but instead are designed for the purpose of materials understanding and characterization. There are a number of reasons for this, but ultimately, in order to properly assess risk, one must completely understand the extractables "universe" for any material. However, it is also important to not to "cause deleterious effects to the materials (such as degradation) or the extractables profile" (ISO-10993-18-2020 Annex D). This presentation will explore the relationship of the exaggerated extraction to the clinical use scenario for medical devices, including how extraction conditions dictated in ISO-10993-12 for medical devices can create the possibility of inappropriate extractions and subsequent conclusions during risk assessment. A systematic approach was taken for multiple polymers using different extraction times/temperatures and subsequent analysis of extractables profiles for evidence of species attributed to degradation of materials. Optimal extraction times/temperatures (alternatives to those proposed in ISO-10993-12) will be discussed with the goal of open dialog on the subject. One specific scenario will also be explored regarding the appropriate solvent and extraction scenario to be used in order to simulate blood contact.
Alan Hendricker | Manager - Chemical Sciences, Becton Dickinson

Single-use technologies are increasingly used in biopharmaceutical manufacturing. Despite their advantages, these plastic assemblies draw concern because they are a potential source of contamination due to extractable and leachable compounds (E&Ls). Characterizing E&Ls from such materials is a necessary step in establishing their suitability for use. Therefore, there is an urgent need for sensitive methods to identify and quantitatively assess compounds in plastic materials. Accelerated solvent extraction (ASE) is a powerful technique that can be reliably used for this purpose. In this study, ASE followed by liquid chromatography and Orbitrap-based High Resolution Accurate Mass (HRAM).
Chris Shevlin | Scientific and Educational Affairs Manager, Thermo Fisher Scientific

The concept of the analytical evaluation threshold (AET) provides a rationale for the appropriate reporting threshold for E&L screening while also addressing the uncertainty in the relative response of individual compounds in the identified data set. The uncertainty in the quantification of data generated using screening methods is based on the fact that not all compounds respond the same in a mass spectrometer. The AET calculation accounts for this uncertainty by employing an uncertainty factor (UF) based on a laboratory’s experimental data. Specifically, the UF is based on the relative response factors of authentic reference standards to the assays internal or external standard. In that past few years clients have been conveying to Eurofins that the FDA has recommended multiple reference standards be used for quantification of compounds in the retention time vicinity of said reference standard. This request seems counter to the AET concept and, since the FDA has provided little detail on how to implement this approach, raises a number of questions. 1. How does the AET apply (or not) to reference standards that are not used in the AET calculation itself? 2. Should class of compound be used in applying the different standards to the data set instead of retention time? 3. How does a laboratory treat unknowns or compounds only identified by class? 4. Does the use of multiple reference standards increase the certainty in the data?
Charles E Ducker | Group Leader, Eurofins Medical Device Testing

At the US RAPRA 2021 conference, we explained the extractable profiles of LDPE, HDPE, polypropylene and ABS based on the polymerization reaction chemistry of these materials. In this presentation, we are going to explore the extractables profiles of other commonly used polymer materials in drug product packaging and manufacturing components, including butyl rubber, silicone rubber, PET, PBT and polycarbonate. We will provide the typical extractable compounds from those materials and explain how they are formed from their polymerization chemistry.
Benton Cartledge, Ph.D. | Senior Scientist, PPD Laboratories

A filter is used close to the end of the manufacturing process to sterilise the drug product (DP) before filling into syringes. An Extractable and Leachable (E&L) risk assessment was performed, and the filter was scored as a potential high risk of leachables ending up in the DP due to the large contact surface area and no potential of reduction. In general, filters need to be flushed to remove leachables and highest levels of leachables are expected to leach from the filter in the first millilitres. An appropriate volume of DP to flush through the filter prior to the start of the filling process and restarting the filling process after a hold period, needs to be established but also optimised to ensure both patient safety and waste minimisation. To get an understanding of the leachable profile and levels of leachables in the syringes, filter flush studies were carried out, followed by Total Organic Carbon (TOC) analysis and GC-MS analysis. TOC analysis provides an indication of the total amount of substances that can leach, and screening for volatile and semi-volatile substances by GC-MS provides the identity and levels of individual substances which can leach from the material. Whilst levels of potential leachables, from the non-specific TOC analysis, were greater than the calculated safety threshold in cumulative fractions after all the holds, levels of individual substances, as measured by GC-MS were not greater than this threshold. Therefore, the potential safety risk of leachables from the filter in combination with the filter flush protocol for the manufacturing process is demonstrated to be low and the minimum volume of filter flush determined to ensure process optimisation.
Jéssica Marques | Trace Analysics and E&L Scientist, , GSK

Factors as a Means to Account for Response Factor (RF) Variation: A Case Study
a new case study will be presented using the multidetector approach to AET evaluation contrasted with the use of the recommended UF of 4 and 10 for a model polymer system. The multidetector approach leverages the independence of the response factors for a given compound obtained on different detectors and chromatographic systems to overcome potential weak signals on any one detector and thus reduces the reliance of the method on UF to overcome response variation. The multidetector approach was summarized in two recent publications (Jordi, et al. J. Pharm. Biomed. Anal.  2020, 186, 1-14 and Jordi, et al. PDA Journal, vol. 75, No. 2 2021, pg. 289-301). The effectiveness of using a combination of triple detection Liquid Chromatography Mass Spectrometry (LCMS) with Ultraviolet (UV) and Charged aerosol detection (CAD) as well as Gas Chromatography Mass Spectrometry (GCMS) will be presented. Quantitation for a series of reference compounds characteristic of the polymer systems will be used to gauge the potential for false positives using the different AET approaches. Finally, the benefits of this approach for detection of compounds with little to no mass spectrometry response will be highlighted.
 
Kevin Rowland | Lab Manager, Jordi Labs

With the publication of ISO 10993-18:2020 and refreshed scrutiny of medical device extractables methodology, the diligence, transparency, and burden of these studies has increased tremendously. Laboratories are producing more, and better, data that needs to be evaluated for toxicological risk; it is not uncommon for some devices to produce several hundred or even thousands of compounds requiring assessment. Most typically, the majority of these compounds are at or near the TTC and it is not uncommon for them to lack full identification. This presentation proposes a risk-based approach to toxicological assessment of medical device leachables, focusing on those compounds with imperfect identification and concentrations near the TTC.
Dr. Matthew Jorgensen | Senior Extractables and Leachables Expert, Nelson Laboratories

Active pharmaceutical ingredients (APIs) which are comprised of biomolecules are being increasingly used as therapeutics. The novel application of such APIs has led to an emerging regulatory question concerning the potential interaction of biomolecule APIs with leachables. To address this question, experimental and computational approaches could be used within a framework which relies on the rapid and conservative screening potential of in silico methods upfront, followed by a more extensive evaluation of any concerning signals from the computational methods. To this end, a biomolecule reactivity in silico workflow was developed which presents the necessary stages for assessing the reactivity of a small molecule leachable with a biomolecule. In silico models which are relevant to the assessment of peptides, proteins and mAbs include a statistical model which predicts the reactivity classes of the Direct Peptide Reactivity Assay (DPRA) and a profiler which characterizes the potential interaction of the chemical with a nucleophile into different chemical domains (e.g., Michael acceptor, aromatic nucleophilic substitution, bimolecular aliphatic nucleophilic substitution, Schiff base, acyl transfer, and nonreactive. Assessment of the reactivity of leachables with nucleotide containing APIs can be supported by the application of direct acting mutagenicity alerts that were derived from an analysis of AMES data and an expert review.
Candice Johnson, Ph.D. | Research Scientist, Instem

There is a recognised need to assess the sensitisation potential of extractable and leachable compounds, alongside other toxicological endpoints of concern. This study sought to investigate the role that existing data and in silico models, including expert systems and machine learning algorithms, could play in predicting dermal and respiratory sensitisation as part of a wider extractable and leachable safety assessment. A novel workflow will be presented, which has the potential to be used to predict the dermal sensitisation potency of extractables and leachables as part of a pragmatic safety assessment. This workflow has been assessed against those chemicals in the ELSIE safety information database which have a known dermal sensitisation potency, and the results show that an in silico approach is both applicable and protective of human health.
 
Dr. Martyn Chilton | Principal Scientist, Lhasa Limited

• Overview of ELSIE Framework for Sensitization Assessment of E&Ls
• ELSIE database analysis of known strong/extreme skin sensitizers
• Proposed Decision Tree and Case Study

Patricia Parris | Global Risk Assessment Services Toxicologist, Drug Safety Research & Development, Pfizer

The extractables and leachables, E&L, literature is now replete with several examples of unplanned sources of leachables in drug products. From pesticide treated shipping pallets to printed unit cartons of ophthalmic products, there are leachables migrating into drug products from unplanned sources. Typical E&L risk assessment focuses on the primary container closure or drug delivery system. Other potential sources have expanded to include secondary packaging for dosage forms such as eye care where the primary package is semi-permeable. USP <665> (draft) has attempted to expand the risk assessment process into both the bulk active and final dosage form manufacturing stages to identify & control potential sources of leachables. This talk will discuss application of a single risk assessment framework and several case studies to refine and simplify the framework.
Robert E. Malick | Principal Research Scientist II, Combination Products, Operations Science & Technology, Abbvie

Complete Chemical Characterization as part of managing the risk in of your materials has taken front stage in recent years. Ever increasing expectations continue to drive regulatory questions. Anticipating these regulatory questions before you initiate your chemical characterization study is key to maximizing for success. With this presentation we will discuss the evolving expectations for chemical characterization studies to meet regulatory expectations and what you need to do to get it right the first time. The crucial elements for success we will cover are these: 1. Robust Study Design: Anticipate and address expectations from the start. 2. Instrumentation: Picking the right tools for the job. 3. Data Analysis: Putting in the time upfront means time saved in the end. 4. Expert Assessment: When assessing risk, experience matters.
Sandi Schaible | Senior Director, Analytical Chemistry, WuXi AppTec

Since the AET concept was introduced to the analytical testing of extractables and leachables, the analytical test methods required to have detection capability below to that limit. It was not a challenging task when the AET levels were at or above 100 ppb level, which can be achieved by any laboratories. When the industry moved to lower detection requirements related to large volume parenteral products the laboratories faced more challenges. For the E&L data packages, US FDA requires evidence for the performance of the analytical methods used for the testing, and one of the most critical performance parameter is the limit of detection (or LOQ). The ICH method validation guidance (Q2B (R1)), providing guidance for calculating the limit of detection, however does not providing examples in details how to execute those calculations. The most common method for LOD assessment is determined by a signal-to-noise calculation, however this approach has significant flaws. Examples related to E&L studies with different AET levels, will be presented to show how an LOD of an analytical method can be appropriately assessed.
Gyorgy Vas | Technical Scientific Liaison, Intertek

Additional Presenter: Erica Dahl, Ph.D., DABT, Managing Toxicologist, SafeBridge Consultants, Inc. now doing business as SafeBridge Regulatory & Life Sciences Group

A Permitted Daily Exposure (PDE) is defined in guidance by the European Medicines Agency (EMA) and the International Conference on Harmonisation (ICH), as a health-based limit and represents a dose (either oral, IV, or otherwise specified) that is unlikely to cause an adverse effect if an individual is exposed, by that route, at or below this dose every day for a lifetime.  PDEs are used to define acceptable levels of residual solvents in drug products [in ICH Q3(C)], elemental impurities including metals [in ICH Q3(D)], and the EMA guideline for protecting drug products from cross-contamination (residual carry-over of active pharmaceutical ingredients in multi-purpose plants).  As specific guidance for determining acceptable amounts of leachables into drug products has not been defined, a robust scientific approach is needed.  Therefore, the use of PDEs using health-based risk assessment approaches has been applied and is acceptable to submit to regulatory agencies as part of the “toxicological evaluation” of leachables into drug product.  The basis of the PDE determination, when in the extractable and leachable process to develop PDEs, what to do with drugs given on a less than daily basis and why significant scientific judgment and experience to derive these values will be discussed.  A case study of how a particularly difficult leachable compound without available data and how to derive a PDE for it will be provided to demonstrate how structural similarity to compounds with data can be used to derive acceptable levels for patient safety purposes.
Allan W. Ader, Ph.D., DABT | Co-Founder and Principal Toxicologist, SafeBridge Consultants, Inc.

The field of Extractables and Leachables (E&L) is at a threshold for significant changes to its paradigm and execution. Some of current standard practices will have to be revisited and updated in view of developments over the past few years. This presentation will summarize the current state of the art and then discuss future developments in E&L. Issues such as what extractions and leachables stand for, AET and relative response, leachate modelling, etc. that will shape the field will be presented.
Atish Sen, PhD | Staff Scientist Analytical Sciences Inhalation Product Development, AstraZeneca

The latest update of ISO 10993-18 (Chemical characterization of medical device materials within a risk management process) has led to requests from regulatory agencies and notified bodies for information relating to the qualification of extractable and leachable methods. In some regions this has included requests for accreditation under ISO 17025. The varied nature of non-targeted methods can make it challenging to add some extractable & leachable methods to an analytical labs scope of accreditation.
This presentation highlights aspects of method qualification as per ISO 10993-18 (2020), requirements for accrediting E&L methods as per ISO 17025, some of the challenges with adding E&L methods to a labs scope of accreditation.
Nick Morley | Principal Scientist, Hall Analytical Laboratories

Additional Presenter: Ron Brown, Director and Principal Toxicologist, Risk Science Consortium, LLC

Factors as a Means to Account for Response Factor (RF) Variation: A Case Study
a new case study will be presented using the multidetector approach to AET evaluation contrasted with the use of the recommended UF of 4 and 10 for a model polymer system. The multidetector approach leverages the independence of the response factors for a given compound obtained on different detectors and chromatographic systems to overcome potential weak signals on any one detector and thus reduces the reliance of the method on UF to overcome response variation. The multidetector approach was summarized in two recent publications (Jordi, et al. J. Pharm. Biomed. Anal.  2020, 186, 1-14 and Jordi, et al. PDA Journal, vol. 75, No. 2 2021, pg. 289-301). The effectiveness of using a combination of triple detection Liquid Chromatography Mass Spectrometry (LCMS) with Ultraviolet (UV) and Charged aerosol detection (CAD) as well as Gas Chromatography Mass Spectrometry (GCMS) will be presented. Quantitation for a series of reference compounds characteristic of the polymer systems will be used to gauge the potential for false positives using the different AET approaches. Finally, the benefits of this approach for detection of compounds with little to no mass spectrometry response will be highlighted.
Dr. Cheryl Stults | Principal, C&M Technical Consulting