Extractables and Leachables 2020 is focusing on finding solutions to questions currently facing the industry. Session topics include a Global E&L Landscape, Safety Assessment Strategies, Analytical Challenges in E&L Profiling: Quantitation and Identification, Regulatory Update, The Role of Chemical Characterization in Establishing the Biocompatibility of Medical Devices, Analytical Advances, and Case Studies. Included networking breaks, networking lunch, and an evening network reception encouraged discussion and connection in a sociable environment.

The pre-conference Masterclass, guided by industry experts Dr. Daniel L. Norwood and Mr. Paul Cummings, will explore E&L concepts and outline best practices.

The Poster Session provides the opportunity for industry and academic experts to share their technical research, testing results, and latest case studies with an audience of E&L professionals from across the supply chain.


Extractables and Leachables Master Class
Event Agenda

Introduction and History

  • History of the FDA
  • Why does the FDA act the way they do

Regulations and Standards

  • US regulatory policy
  • Standards setting in the US
  • International considerations

Manufacturing Systems – Risk Assessment

  • Why the interest in manufacturing systems
  • What is a risk assessment
  • What a risk assessment is not
  • Example based on USP proposals

Extractable Elements

  • ICH Q3D and USP<232>
  • Are extractable elements a regulatory requirement

Laboratory Assessment of Extractables and Leachables

  • USP<1663> and USP<1664>
  • Best practices for assessment of extractables
  • Best practices for assessment of leachables
  • Combination drug products.  Here comes ISO and CDRH!!!!
Presenter: Dr. Daniel L. Norwood, Senior Independent Consultant for Smithers
Presenter: Mr. Paul Cummings, General Manager – Smithers Akron E&L Laboratory
End of Workshop
Registration and Welcome
Registration and Continental Breakfast
Welcome and Opening Remarks
Ashli Speed, Conference Producer, Smithers
Paul Cummings, General Manager, Analytical Services, Materials Science and Engineering


Session I: Global E&L Landscape
Materials Quality Regulation in China: New Developments and a Look Ahead
China is deep into implementing reforms to its regulatory framework for reviewing and approving pharmaceuticals, biopharmaceuticals and medical devices.  In the past two years, the health authority has restructured and is now called the National Medical Products Administration.  The government has revised its overarching Drug Administration Law.  Further, various agencies within the administration are producing draft guidelines, pharmacopoeial documents, and other regulatory tools, including those relevant to packaging and device components, and the related supply chain.  Concurrently, agencies are participating in and integrating information from international groups and regulations.  This presentation will highlight some of these new developments, focusing on recent regulatory output with respect to container closure system and device materials, and will provide some thoughts on the future.
Lee M. Nagao, Ph.D. | Senior Director, Science, Regulation & Policy, ELSIE
Session Description
In this session, the speakers will offer an overview of the current regulatory climate in various international jurisdictions.  While not detailed explanations of the regulations, these presentations will give attendees insight into the current status of regulations and the direction of different regulatory agencies around the world
Update On Brazil
This presentation will focus on the discussion of Brazilian’s scenario regarding E&L. How is this topic been discussed in Brazil by ANVISA and pharmaceutical companies; what are they doing; how are the companies conducting the studies; what are ANVISA’s expectations; what are the main doubts.
Mariah Ultramari, PhD | Founder and Toxicologist Consultant, Spektra Consulting
Challenges Facing ICH Q3E
ICH made a decision to proceed with the development of a new chapter ICH Q3E Guideline Impurity: Assessment and Control of Extractables and Leachables for Pharmaceuticals and Biologics.  This task faces many challenges from development, acceptance to delivery. ELSIE has established a Working Group in support of PhRMA. An update in the activities of ELSIE will be presented as well as a discussions of challenges ahead.

Atish Sen, PhD | Staff Scientist Analytical Sciences Inhalation Product Development, AstraZeneca
Networking Break
Session II: Safety Assessment Strategies
PQRI Best Practices: Use of a Classification Strategy to Develop Safety Thresholds for Leachables in Parenteral Drug Products
Contemporary parenteral drug products make use of the advantages of the materials and designs that modern container closure systems (CCS) offer. Despite these advantages, these systems also present the potential for introducing leachable impurities into the drug product. Unlike process-related impurities, leachables typically exhibit structural distinction from each other and the drug itself, increasing the likelihood of multiple and differing toxicity profiles. Thus, unlike managing process related impurities which have been addressed in ICH guidance documents, the qualification of leachables can present both analytical and safety evaluation challenges in the risk assessment process. From a toxicology perspective, with some leachables safety data may already exist in the published literature, while with others additional in vitro and/or in vivo studies may need to be conducted to assess potential risk. In recognition of the challenges that the qualification of these specific impurities present, the Product Quality Research Institute (PQRI) Parenteral and Ophthalmic Drug Product (PODP) work team developed a process leading to the development of both analytical and safety thresholds for CCS-derived impurities to help ensure both the quality and safety of parenteral products. An update on the acceptability of this strategy based on regulatory review of the PQRI recommendations will be provided.

Douglas J. Ball, MS, DABT | Managing Partner and Toxicology Consultant, D&B ChemTox, LLC
Session Description
Safety assessment may be performed on extractables or leachables. Evaluation employing the use of thresholds commonly considers the endpoint of mutagenicity. This session will explore approaches that include other endpoints that must also be considered in a comprehensive assessment.
Appropriate Scientifically-Defensible Approaches to Assessing the Toxicity of Extractables and Leachables in Drug Products: Using All the Tools Available
It is quite a challenge to digest all the analytical data developed from extractable and leachable studies just from the analytical side.  But what do you do with these data, once you have the information?  The FDA and other regulatory bodies and the drug, device, or supplier manufacturer want to ensure that those materials identified do not change the quality of the product or cause toxicity themselves.   A risk assessment of the extractables and leachables is needed that will provide scientific support to the safety of the product.  This presentation will provide approaches on what analytical data needs to be assessed, what toxicity data needs to be assessed, and how to conduct an appropriate and scientifically-defensible toxicological risk assessment for extractables and leachables into drug products for biopharmaceutical and small molecule products.

Allan W. Ader, Ph.D., DABT | Co-Founder and Principal Toxicologist, SafeBridge Consultants, Inc.
Session III: Analytical Challenges in E&L Profiling: Quantitation
Extractables & Leachables: Importance of Sample Preparation, Data Collaboration and Interpretation
Extractables and Leachables (E&L) studies require a carefully planned design for extraction and data interpretation due to the complex nature of the materials, manufacturing processes, storage of medical devices along with their intended use.  However, E&L studies are often treated as routine tasks assigned to laboratory technicians trained in routine sample preparation with limited knowledge investigating complex extractables and leachables issues, data interpretation and correlation. Preparation of sample extracts is a very important process for trace level analysis of unknown components in complex matrices. Preparation and analysis of extracts require profound knowledge of sample handling, chemistry, chromatography, spectroscopy, technical skills, laboratory equipment along with, extensive training in data acquisition, molecular structure identification and confirmation and data interpretation. Identification relying solely on search libraries or databases as is generally followed and practiced in most laboratories, may lead to misidentification and mischaracterization of analytes.  Furthermore, quantification using relative response factors of representative standard compounds can swing the results by many fold either way.

This presentation will highlight critical issues facing not only analytical chemists but toxicologists, consultants, manufacturers and suppliers.  We hope to provide scientific guidance and principles for harmonization of E&L investigations. Specifically, we will focus on the following points:
1. Optimization of data acquisition using selective instrumentation based on the rule of solubility that “like dissolves like”
2. Contradictions, vagueness, confusion and controversy of regulatory guidance documents, FDA feedback and reviews
3. Pros and cons of use of the non-polar solvent (hexane) relative to its effect on device integrity prompting calls for its elimination during recent   E&L conference
4. Presentation of data highlighting shortfalls of Artificial Intelligence/Library Search for compound identification
5. Emphasis on training and qualification of analytical investigators and technical reviewers
Mourad Rahi, PhD | Director, Analytical Services, American Preclinical Services, LLC
The Multidetector Strategy for Reducing Response Factor (RF) Variation in E&L Analysis
Chemical characterization per ISO 10993 has become an important component of biocompatibility testing of medical devices. Similarly, pharmaceutical packaging is characterized for extractables and leachables to verify the safety of drug products per USP <1663> and <1664>.  A major concern regarding the accuracy of extractables and leachables studies is quantitative error due to response factor (RF) variation. This error occurs because many extractables do not have commercially available standards and equal concentrations of different extractables give different signal responses using mass spectrometry detectors. Recent publications have highlighted the risks posed by RF variation for both LCMS (Jordi et al. Journal of Pharmaceutical and Biomedical Analysis 150 (2018) 368–376) and GCMS (Jenke and Odufu, Journal of Chromatographic Science 2012;50:206–212). The importance of this issue has been recognized by the FDA resulting in the addition of an uncertainty factor (UF) in the calculation of the analytical evaluation threshold (AET). While this aids in mitigating the risks of under reporting of extractables, the resulting revised AET creates significant analytical challenges often exceeding the limit of detection (LOD) of current mass spectrometry instrumentation and requiring sample concentration. It also creates questions as to the validity of risk assessments based on relative quantitation values and is one of the key issues at the root of poor reproducibility in recent high profile interlaboratory studies. It is therefore strongly desirable to define improved methods for quantitation with more universal RFs which mitigate the need for UFs. In this presentation, an alternative strategy for quantitation using a multidetector strategy including a liquid chromatography system with mass spectroscopy (LCMS),  ultraviolet (UV) and charged aerosol detection (CAD) as well as a Gas Chromatography system using mass spectroscopy (MS) and Flame Ionization Detection (FID) will be presented. Data comparing the response factors for more than 200 extractables by UV, LCMS, GMCS, FID and CAD will be presented demonstrating an approach to reduce overall RF variation. This reduced the associated need for UFs and increases confidence in the resulting risk assessments.

Mark Jordi | President, Jordi Labs
Networking Lunch
“Top 5” mistakes you might be making in E&L (Case Studies)
Best practice documents for the characterization of E&Ls as well as other regulatory documents are well established for a variety of pharmaceutical systems, container closures and devices. However, as the industry evolves some non-optimal practices have begun to creep into the E&L thought pool that reminds us to reiterate/revisit tenets of the best practices and how we should approach certain aspects of E&L testing. This talk focuses on the author’s “Top 5” mistakes you might be making in E&L and will discuss reasoning behind a more optimal practice for each, including: 1) Performing toxicological risk assessments on organic/non-realistic solvent extractables quantitative (or semiquantitative) data 2) Expecting extractables characterization methods to be validated 3) Trying to quantitate HPLC-UV-MS data without authentic reference standards 4) Thinking that one set of extraction parameter variables is always better than another. 5) Thinking that replicate testing during extractables characterization studies is of large value added in all circumstances Multiple case studies will be presented showing experimental details in support of the best practice

Alan Hendricker | Manager - Chemical Sciences, Becton Dickinson
Session IV: Analytical Challenges in E&L Profiling: Identification
Networking Reception & Poster Sessions
Poster Sessions Description
During a designated time in the networking reception experts will discuss their poster boards, creating the opportunity for discussion.
Effect of Mobile Phase Composition on Relative Quantitation of E &L Compounds using ELSD, Mass Spectrometry and UV Detection
The objective of E/L analysis is to accurately identify E/L compounds above the analytical evaluation threshold (AET) and safety concern threshold (SCT). It is well documented that changes in mobile phase composition (buffers, organic solvent, pH) can dramatically effect response of E/L compounds.  The use of Universal detectors such as Evaporative Light Scattering Detection (ELSD) and Corona Discharge Detection (CAD) are commonly used in series with MS Detection. Certain classes of compounds such as Parabens and Phthalates, due to volatile nature of the compounds don’t work as well using ELSD/CAD.  The poster will explore the impact organic solvent composition has on the relative responses and baselines of the various system then using standard reverse phase gradients versus using a make-up flow pump to keep mobile phase composition constant at 50/50 Water/Organic solvent.

Dr. David Weil | Senior Application Scientist, Agilent Technologies
Efficient Management of Extractable & Leachable Data in Process Development
Analytical and numerical data collected and compiled for Extractable and Leachable (E&L) studies is often scattered among a variety of systems including email, Microsoft applications (e.g. Excel) and electronic notebooks, to name a few. While scientists have developed practices and processes to compile E&L data to help make decisions, it remains a tedious manual process where simple questions such as “what extractables have been found from material x?” are not easy to answer. In this poster, we introduce Luminata®—a CMC decision support application that helps project teams address the challenge of effective data management across product development. Luminata enables scientists investigating drug products and enclosure systems to create E&L study maps from data processed in the software of their choice. E&L study data may be assembled from various systems, connecting analytical data with study conditions and observations, in a single software for easy sharing, streamlined access, and effective decision-support. The ability to store E&L study data in one searchable location facilitates risk-assessment of product enclosure materials in drug product development.

Joe DiMartino | Luminata Solution Manager, ACD/Labs
Evaluation and Comparison of Sample Preparation Techniques and Analytical Instrumentation for Extractable Testing
Anna Michelson Ph.D., Gyorgy Vas Ph.D., Louis Fleck, John Duett, Nan Zhang, Jacquelyn Cali

Intertek Pharmaceutical Services, Whitehouse NJ

Choice of extraction technique is often critical for the outcome of an extractable study. Chromatographic profiles for various extraction techniques (closed pressurized vessel (CPV), temperature controlled orbital shaker, accelerated solvent extraction (ASE), reflux) are compared.

In addition, importance of high resolution instrumentation for proper identification is highlighted for GC-MS and LC-MS data.
Anna Michelson, Ph.D. | Scientist in Trace Organic Labs, Intertek
In silico methods to assess the toxicity of extractables, leachables and degradants
Candice Johnson, Dave Bower, Kevin Cross, Scott Miller, Glenn Myatt

Leadscope, Inc. 1393 Dublin Rd, Columbus, OH 43215, USA

(Q)SAR modeling can be used in the absence of empirical data to assess the genotoxic potential of extractables, leachables and degradants. In this poster we demonstrate how in silico tools are used to make predictions of genetic toxicity using principles that are in line with ICH M7 guidelines. Several case studies will highlight the implementation of in silico tools with focus on the transparency and interpretation of the results. Additional models and databases to support hazard assessment for endpoints such as skin sensitization and irritation/corrosion will also be discussed.

Candice Johnson, Ph.D. | Research Scientist, Leadscope, Inc.
Response Factor Variation Study of Internal Standard for Semi-Quantitation of Extractables and Leachables Using LC-MS
Substances leached from pharmaceutical manufacturing components, package systems, and medical devices under laboratory conditions have been increasingly emphasized by regulatory bodies such as the US Food and Drug Administration (FDA) and The European Medicines Agency (EMA). The safety impact of the leached substances on patients depends on the discovery, identity and amount. Currently, the concentration of the leached substances above the Analytical Evaluation Threshold (AET) is frequently quantitated using an internal standard assuming equivalent response factors. Such an approach is accurate only if the responses of the internal standard and the leached compound are similar. However, the extractables profile always results in a wide variety of compounds. Therefore, not all internal standards are suited for concentration estimation. Herein, to establish accuracy of the internal standard approach, a comprehensive response factor variation study for semi-quantitation of extractables and leachables is reported. The results will be given for selecting the suitable non-volatile internal standards to semi-quantitate the extractables and leachables to its greatest possible value.

Bullet Points: Internal Standard Selection Non-volatiles Extract Analysis LC-MS Q-TOF Compound Analysis and Quantitation Mass Spec Response Factor Comparisons Extractables Compound Identification and Quantitation

Eric Hill | Director, Extractables & Leachables Services, Boston Analytical
Sources of Interlab Variation in Medical Device Extraction Studies
The top several potential causes of iterlab and intralab variation have been identified and will be discussed. The single most significant causes relate to details of the extraction of the medical device and handling of extract liquids prior to instrumental analysis. This presentation will discuss these causes of variation and their potential consequences on toxicological risk assessment.

Bullet Points: Sources of Interlab Variation for Medical Device Extractables Critical Extraction and Sampling Parameters Toxicological Risk Assessment of Medical Devices

Dr. Matthew Jorgensen | Senior Extractables and Leachables Expert, Nelson Laboratories
End of Day One
Registration and Welcome
Registration Opens and Continental Breakfast
Opening Remarks From The Chair
Session V: Regulatory Update
Session Description
This session will feature presentations exploring the ever-changing regulatory landscape in the USA and abroad. Presentations in this session will address the disparities that exist in guidelines. 
Update on USP L&E Chapters
Leachables and extractables have been a major focus of the  USP initiatives for standards modernization.  Chapters on packaging components and systems have been overhauled to build upon the physicochemical evaluations including recommendations for best practices.  There are several chapters currently undergoing revision or plans to be revised in the upcoming cycle.  For example, the elastomers chapter has been revised, along with other elastomer chapters being developed.  This presentation will provide an update on USP’s efforts related to L&E and future outlook.
Diane Paskiet | Sr. Director Scientific Affairs, West Pharmaceutical Sciences
CDRH Scientific Perspective on Analytical Testing and Toxicological Risk Assessment for Medical Devices’
Networking Break
Session VI: The Role of Chemical Characterization in Establishing the Biocompatibility of Medical Devices
Chemical Characterization: Overview of the Revised ISO 10993 Part 18
The ISO 10993 series of standards on biological evaluation of medical devices continues to evolve, working to keep up with progress in knowledge of related subject matters. In keeping with this progress, an update of ISO 10993-1 (the top-level standard for medical devices) was published in 2018. A key change in this revised document was the addition of a more explicit and exacting requirement for chemical characterization of all device types—regardless of the nature and duration of patient contact. To meet the heightened focus on chemical characterization, and to update the existing standard, a major revision of ISO 10993-18 “Chemical characterization of medical device materials within a risk management process” was undertaken. The revised document was published earlier in 2020. This presentation will focus on the key parts of the newly published document, including a discussion of experiences during, and lessons learned from, the multi-stakeholder development of the final standard.
Dennis Jenke | Chief Executive Scientist, Triad Scientific Solutions, UK
Session Description
The process by which the biocompatibility of medical devices is evaluated is undergoing an exciting change; transitioning from an approach that largely relied on animal testing to a method that is increasingly based on the safety assessment of extractable and leachable (E&L) compounds released from the device.  The two cornerstones of this approach are the ISO 10993-18 standard on chemical characterization and the ISO 10993-17 standard on the toxicological risk assessment of medical device constituents.  These standards are currently undergoing revision and this session will provide the latest updates on the new concepts that are being considered for incorporation into the revised standards.  
Establishing a Standard Approach for Assessing Toxicological Risk of Medical Device Constituents
The topics to be covered include the following:
  • The development/content of ISO TS 21726:2019 on the application of threshold of toxicological concern for medical device
  • The future direction of ISO 10993-17

Alan Hood | Research Toxicologist, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, U.S. Foo
Q&A: Practical Implications of Chemical Characterization of Medical Devices
Networking Lunch
Session VII: Analytical Advances
Is the E&L community ready to move away from conventional large volume Liq/Liq Extraction & Solvent Evaporation?
Sample preparation is a critical step during the analysis of Semi-Volatile Organic Compounds (SVOCs) in aqueous samples using direct injection Gas Chromatography (GC) coupled to a Mass Spectrometer (MS) and/or Flame Ionization Detector (FID). By far the most common approach for the analysis of semi-volatile Extractables in aqueous solvent extracts of pharmaceutical container closure systems, or medical device components, is conventional liq/liq extraction using large solvent volumes and a separatory funnel followed by solvent evaporation. The main drawback of this approach is how labor intensive it is, especially if pH adjustment and derivatization is incorporated into the sample preparation. The advances in novel sample preparation and automation have provided the trace analytical community with an opportunity to embrace more efficient means to conduct these analyses. Baxter has developed and qualified a highly automated and cost-effective GC-MS/FID analytical method using the Gerstel Robotic Platform. It is based on the concepts of Dispersive Liquid/Liquid Micro-Extraction and incorporates pH adjustment & derivatization to achieve exceptional precision and incredibly low detection limits required to satisfactorily address toxicological significance
Mike Hodgson | Global Extractables & Leachables Senior Manager, Baxter International Inc
Advancing E&L Analysis Through Sample Pre-Concentration
Updated regulations around the world highlight the need to understand chemicals, such as residual solvents, monomers, off-odors, and additives, that are released from products/materials. Chemical biocompatibility assessments are often constrained by the analytical limit of detection (LOD). The current industry procedure for quantitation of volatile organic compounds (VOCs) and semi-volatile organic compounds (SVOCs) is by headspace and liquid-injection GC–MS analysis. Increasing the sensitivity of GC–MS analytical procedures can often be very challenging, even when using sample preparation/concentration techniques such as liquid-liquid extraction, solid-phase extraction, etc. The presentation explores solvent-free preconcentration techniques to achieve lower detection limits for the analysis of extractables and leachables.
Dr. Nikhil Sahotra | Materials Emission Market Specialist, Markes International, UK
Migration Kinetics 2: Continued Study on Extractables Migration from Container/Closure Systems
As a continuation of a study performed using bromobutyl rubber stoppers (previously presented at Smithers Rapra E&L USA 2019), polypropylene bottles were extracted using two different solvents across numerous time points. The goal of this study was to apply the kinetic models developed using the rubber stoppers and investigate the applicability of these models on a different container/closure system with different target analytes. Polypropylene bottles were extracted in IPA and ACN at 5, 25, 40, 50, and 60 °C over the course of various timepoints ranging from 4 hours to 180 days. HPLC was utilized to analyze for Irganox 1010, Irgafos 168, and related degradants. The concentration of each target compound (µg/bottle) was calculated and plotted against time. The results of the analyses showed similar trends between target analytes with a logarithmic increase in concentration with increasing time. Additionally, larger concentrations of target compounds were observed with higher extraction temperature. Finally, these data were evaluated against previously developed kinetics models.
Benton Cartledge, Ph.D. | Senior Scientist, PPD Laboratories
Session VIII: Case Studies
Challenges in Leachable Method Development and Validation
Development and validation of robust analytical methods for leachables present challenges that are unique.  Every combination of analyte and drug product is unique and can often present unexpected problems throughout the MD/MV process.  Deciding when a method is ready for validation is not always apparent and moving to validation too quickly can result in many unforeseen difficulties and ultimately extend the time required to achieve a successful validation.  This talk will present some examples of validation that did not proceed as planned and discuss some strategies to increase the probability of success. 
Paul Cummings | General Manager E&L, Smithers
Session Description
This session is focused on the real-world application of extractable and leachable principles and guidelines – putting the theory into practice. It focuses on the different approaches taken by companies to understand the risk to patients.  
Effect of the Terminal Sterilization for the Quality and Performance of Medical Devices; Delivery and Storage Systems
Radiation and ethylene oxide terminal sterilization are the two most frequently used processes in the pharmaceutical industry. They are efficacious, safe, to manufacture of sterile products. Terminal sterilization is routinely applied to a wide variety of commodity healthcare products, implantable medical devices (stents, heart valves, etc.) along with products used during implantation procedures (catheters, guidewires, etc.). Terminal sterilization is also routinely used for processing combination products where devices, drugs, and/or biologics are combined on a single product. All medical, ophthalmic and parenteral equipment are sterilized in batches, and usually sterilized using one of the methods of sterilization. As sterilization involving exposure to chemicals and elevated temperature or radiation dose, material compatibility is very important to understand, and should be studied before the sterilization process is finalized. Case studies will be presented covering the following topics: • Impurities related to ethylene oxide sterilization • Radiation induced degradation products for common antioxidants • Radiation effect on the drug delivery performance of combination de
Gyorgy Vas | Technical Scientific Liaison, Intertek
Extractables from Single-Use Systems (Bioreactors) and the Impact on Cell Culture Performance
As the biopharmaceutical industry increasingly moves its manufacturing platform into single-use systems, more awareness of potential impact of extractables and leachables from single-use polymeric materials leads to increasingly stringent scrutiny. In this presentation, considerations on how to perform extractables and leachables studies including extraction conditions, analytical techniques and workflows, and data interpretation will be first discussed. A case study on single-use bioreactors will be followed to demonstrate that an appropriate extraction condition is crucial for the extractables profiles to be predictive of leachables. An extractables compound from the case study proved to be a leachables in a root-cause investigation when an adverse cell culture growth performance was observed. Details of the impact from the extractables and its cytotoxic effect on cell growth will be discussed towards the end.

Yanxin Luo, PhD | Scientist of Process Development, Amgen
Panel: Future Direction of E&L
Paul Cummings

Douglas Keihl, Eli Lilly, Research Advisor
End of Day Two