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Agenda

The 2021 agenda featured speakers from Intertek, Aspen Research, Becton Dickinson, PPD, AstraZeneca, and more, discussing industry-leading topics, such as materials contributions, analytical challenges, case studies, and much more.

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Masterclass Introduction to Extractables and Leachables
Session I
Additional Presenter: Daniel L. Norwood | Executive Partner, Feinberg Norwood & Associates Pharma Consulting
  • Overview
    • The issue of extractables and leachables
    • Why do we care?
  • History of extractables/leachables concern
    • Pre-1990
    • Post-1990

Paul Cummings | General Manager E&L, Smithers
Lunch Break
Session II
Additional Presenter: Paul Cummings | General Manager E&L, Smithers
  • Who must perform extractables/leachables characterization and testing?
    • Pharmaceutical packaging
    • Medical Devices
    • Single Use System and other manufacturing systems
  • Designs of an Extractables assessment.
    • Risk evaluation
    • Purpose of extractables assessment
    • Safety Thresholds
    • Analytical Laboratory best practices

Daniel L. Norwood | Executive Partner, Feinberg Norwood & Associates Pharma Consulting
Networking Break
Session III
Additional Presenter: Daniel L. Norwood | Executive Partner, Feinberg Norwood & Associates Pharma Consulting
  • Design of a Leachables assessment
    • Drug product matrix assessment
    • Identifying target compounds based on extractables
    • Non-targeted leachables
    • Leachables method validation
    • Actual leachables assessment versus Simulation Study
    • Correlation of extractables and leachables
  • Drug Product Manufacturing Systems (Process Related Leachables)
    • Risk assessment and evaluation
    • Current best practice recommendations
  • FAQs
    • “If my product is a generic using the same packaging as the innovator, can I skip E&L?”
    • “If I do an appropriate risk assessment, can I skip E&L?”
    • “My component provider has given me a potential extractables list.  Can I use that in place of an extractables study?”
    • Additional questions
End of Day
Opening Remarks
Session I: Regulatory Standards for E&L
< Session Description >
This session will feature presentations exploring the ever-changing regulatory landscape in the USA.   Presentations in this session will address updates on regulations ISO standards etc.
Implementing 10993-18: Considerations in Establishing an AET for Chemical Characterization of Medical Devices
This talk will focus on the analytical evaluation threshold (AET), including its purpose and approaches to selecting it.   Of particular importance are the AET components of uncertainty factor (UF) and dose based threshold (DBT).   To this end, the 10993-18 approach to UF will be discussed, along with its limitations and views FDA reviewers have expressed.  Also presented will be the use of multiple orthogonal analytical methods/detectors as a means to potentially reduce the need for large values of UF.  Finally, issues related to setting the DBT will be explored—time permitting.
Attendees should come away from this session with some awareness of the current issues in establishing an AET for chemical characterization of medical devices, as well as a better understanding of possible approaches in this developing field

Ted Heise, PhD, RAC | VP Regulatory and Clinical Services, MED Institute
Physics-based models to predict patient exposure to medical device leachables
Medical device materials contain chemicals that may pose toxicological concern(s) if released in sufficient quantities. Toxicological risk assessment approaches are increasingly being used in lieu of animal testing to address these concerns. Currently, these approaches rely primarily on in vitro extraction testing to estimate the potential for patients to be exposed to chemicals that may possibly leach out of device materials, but the clinical relevance of the test results are often ambiguous. Recent developments suggest physics-based models can be used to provide more clinically relevant exposure estimates. However, the lack of data available to parameterize and validate these models presents a barrier to routine use. This presentation will provide an overview of these approaches, including considerations in developing and parameterizing exposure models, strategies that can be used to address the challenges associated with limited data, and potential future directions and improvements.
David M. Saylor, Ph.D. | Research Materials Engineer, Division of Biology, Chemistry, and Materials Science , US Food and Drug Administration
Speaker Q&A Panel
An in depth Q&A session with the morning’s speakers. Moderated by an advisory board member.
Networking Break
Session II: Overcoming Analytical Challenges
Addressing Unknown Extractables

In order to successfully assess the toxicological risk of an extractable, you first must identify it.  However, it is frequently the case that a definitive identification cannot be made.  In this presentation, defining what is meant by “unknowns”  and strategies for addressing unknowns will be discussed. 


Paul Cummings | General Manager E&L, Smithers
Importance of a High Performing Screening Method for Testing Stability Samples for Leachable Impurities
Leachable testing for finished pharmaceutical products are important part of the regulatory filing and it is under more scrutiny than ever before. Leachable testing for multiple finished drug products such biologics, large volume parenterals and polymer based finished products requires to work on a trace levels with high confident. Working with trace levels (typically 10 parts per billion or below), requires high level of analytical expertise and top of the line analytical instrumentation. Leachable testing ideally should be performed on a targeted list of analytes and a general non-targeted screening fashion, to avoid any unexpected leachables. For targeted screening analytical testing is more straightforward, and usually not an issue to detect the targets even at ppb sub-ppb level. However, for a general screening method this can be difficult, and many times requires special sample preparation combined with high resolution accurate mass detection. Case studies will be presented to show the importance of a high-performance and sensitive screening method, to detect unexpected leachables, and to support related quality investigations

Gyorgy Vas | Technical Scientific Liaison, Intertek
The use of Solid Phase MicroExtraction (SPME) in Extractables and Leachables Studies
Common approaches to extractables studies of medical devices or combination products or pharmaceutical closure systems is extraction with a range of solvents (polar, modified polar, and non-polar). Extraction times and temperatures vary but at the end of the extractions one is left with deciding how to analyze the extracts. One of the common analytical techniques is GC/MS for volatile to semi-volatile organics. Often, to reach the desired level of sensitivity, the extracting solvents need to be back extracted (liq/liq extraction) into a different organic solvent which is then volume reduced to concentrate the analytes. An alternative approach is to use Solid Phase MicroExtraction (SPME) and then desorb the SPME fiber via the GC injection port. This has the advantage of not diluting the analytes in a solvent and thus affords superior sensitivity. We have used SPME-GCMS for various projects including, but not limited to, Extractables and Leachables. This presentation will review the SPME techniques, their advantages and disadvantages, and offer some case studies relevant to both extractables and leachables studies.

Roger Pearson, PhD | President Analytical Services, Aspen Research Corporation
Top 10 Mistakes you might be making in E&L
Ionization modes in LC-MS for typical extractables, the value of "exhaustive extraction", extraction time and temperature studies and further exploration of response factor databases in LC-MS.

Alan Hendricker | Manager - Chemical Sciences, Becton Dickinson
Networking Break and Poster Session
Poster Sessions:
  • Leadscope
  • Boston Analytical
  • Intertek
    • ​Anna Michelson, Research Scientist
PANEL: Addressing The Unique Issues That Come With Mass Spec Libraries For LCMS Data.
Panelists:
  • Bryan Kratzenmeyer PhD, Senior Manager Materials Science, Americas Field Marketing, Waters Corporation
  • Andrew Leightner, Market Development Manager, Pharmaceuticals – Americas Field Marketing
  • Jeffrey Dahl Ph.D., Application Scientist, Shimadzu Scientific
  • Tim Stratton, Manager, Library Technologies, Thermofisher Scientific
  • Dr. David Weil, Senior Application Scientist, Extractable and Leachable Analysis Expert, Agilent Technologies
As there have been several developments around LCMS libraries over the past couple of years, the advisory board would like to offer the instrument vendors the opportunity to present your perspectives and status in this area.  How you are addressing the unique issues that come with mass spec libraries for LCMS data? How to search, how reproducible is the data, is it reproducible at all across platforms, interaction with other databases such as NIST and Chemspider, etc.
Session III: Understanding Materials Contributions to Leachable profiles
Primary and Secondary Packaging Materials as potentialsource of Nitrosamines: impact on the design of an Extractable & Leachable

Recently there have been a number of drug product recalls due to the unexpected presence of N-Nitrosamines. While in most of those cases, N-Nitrosamine formation occurred at the level of the drug substance synthesis and stability, it is well known and documented that some materials, used in primary packaging can also be a source for N-Nitrosamine contamination of the packaged drug product (e.g. older grade elastomers and nitrocellulose laminated blister foils). The unanswered question is: do we know everything about the materials of construction of a container closure system and their ability to generate N-Nitrosamines? When looking at the formation mechanism of N-Nitrosamines, it are secondary amines (and potentially tertiary amines) that are a precursor to N-Nitrosamine formation, together with a nitrosating agent (such as e.g. nitrite/nitrous acid). When evaluating the extraction profile of materials of construction, it is clear that secondary amines are often encountered as an extractable being present in the material. Should this raise a “red flag” for those materials in a N-Nitrosamine risk mitigation strategy, as one precursor for N-Nitrosamine formation is obviously present in the material? And what could be the consequence of these findings, both for the design of extractable and leachable studies, as well as in the assessment of the E/L-results? This presentation will give more insights on how an integrated approach for both the E/L-qualification as well as the N-Nitrosamine risk evaluation for a pharmaceutical container closure system could look like.


Ward D’Autry, PhD | Study Director , Nelson Labs Europe
Understanding Extractables Profile from Polymerization Chemistry
Why the extractables profiles of low density polyethylene (LDPE) component and high density polyethylene (HDPE) component are so much different although both LDPE and HDPE are polyethylene? Why the extractables profile of polypropylene component are so much more complicate than polyethylene component although both are simple polyolefin material? This presentation explores the extractables profile of some common polymer materials and explains the extractables profiles from the polymerization chemistry.
Benton Cartledge, Ph.D. | Senior Scientist, PPD Laboratories
Nitrosamines: Current Regulatory and Testing Status
A review of the current regulatory expectations of heath authorities will be reviewed. The disconnects within various guidelines will be discussed. Different testing method from heath authorities and in public literature will be presented. Testing strategies based on risk management will be discussed along with the current status of E&L testing for nitrosamines
Atish Sen, PhD | Staff Scientist Analytical Sciences Inhalation Product Development, AstraZeneca
Moving towards near perfect extractable study: Novel approach to justify model solvents and new screening tools for extractables.
End of Day One
Session IV: Case Studies
< 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. 
What can the ELSIE Database tell us about the Safety of E&L Substances
 In the absence of harmonized regulatory guidance, identification of appropriate safety thresholds can present a challenge. This session will focus on how working groups within ELSIE are using the E&L Safety Database to address areas of uncertainty in the current risk assessment process. Two use cases will be presented to introduce different applications for the ELSIE Safety Database to address potential uncertainty through an analysis of relevant E&L chemical space to derive a science based qualification threshold and general recommendations for safety assessment of sensitization potential in parenteral drug products. A brief update on the next phase of the ELSIE Database, the ELSIE Knowledge Base, will also be provided.
Brad Stanard, PhD, DABT | Director, EHS Product Stewardship, Ultragenyx Pharmaceutical Inc.
Extractables & Leachables Studies of Electronic Nicotine Delivery Systems
The FDA’s Pre-Market Tobacco Applications (PMTA) for electronic nicotine delivery systems (ENDS) requires extractables and leachables (E&L) studies. We will discuss the approach to E&L testing on vaping devices for E-Liquids, which presents unique challenges in E&L design. Data from multiple different devices for which these studies were performed in support of a PMTA application will be presented. 
Emma Leishman, Ph. D. | Manager, Advanced Analytics, Avomeen
Extractables and Leachables in Biologics – Lessons Learned from the past 10 years
This presentation will focus on the most prominent lessons learned in relation to the assessment of extractables / leachables in biological drug products in the past 10 years, including the importance to identify clearance steps, to design extraction protocols that are well-adjusted to the actual application, and to mind scaling factors during extrapolation of extractables in the drug product, for instance. Special focus will be put on extractables and therefore, potential leachables derived from chromatography resins and leachables in solvents that are used for lyophilized drug products. Despite best efforts, an E&L assessment for biologics may still contain uncertainty. Therefore, it is important to understand the uncertainty factors that are inherent to materials, extractable testing and toxicological threshold values and to balance any remaining risk with expert judgment, data from clinical studies and pharmacovigilance and ultimately, the benefit from the treatment with the biological drug product.
Alicja Sobańtka, PhD | Corporate Operational Excellence and Support, Octapharma
Comparative Study of the Efficiency of Binary Solvent Mixtures vs Blood to Simulate the Use Condition for Medical Devices.
A significant difference in the leachables analysis of medical devices as compared to pharmaceutical packaging is the ability to utilize the actual use condition (drug product) for the analysis of pharmaceutical packaging. The use condition for many medical devices (biological environment) is difficult to simulate and therefore it has been common practice to use binary solvent mixtures (alcohol/water) to simulate the leachables condition. Recently, a number of potential concerns have been raised about the use of binary solvent mixtures such as preferential absorption of the more hydrophobic component of the solvent by the medical device. In this talk, we will review the issues related to the use of binary solvents as well as relay results showing a comparison of the extraction power of blood contrasted with saline and water/alcohol mixtures for a series of analytes relevant to blood contacting medical devices. In addition, a brief update will also be provided on the latest work on mitigating the need for uncertainty factors through a multidetector strategy as recently publications in a work entitled “An Analytical Strategy Based on Multiple Complementary and Orthogonal Chromatographic and Detection Methods (Multidetector Approach) to Effectively Manage the Analytical Evaluation Threshold (AET)
Kevin Rowland | Lab Manager, Jordi Labs
Networking Break
Session V: ISO 10993
Analytical Considerations in Extractable and Leachable Studies of Medical Devices per ISO 10993-18:2020
Chemical characterization (Extractable and Leachable Studies) per ISO 10993 has become an important component of biocompatibility testing for medical devices. A major revision of ISO 10993-18 “Chemical characterization of medical device materials within a risk management process” was recently published in the beginning of 2020. This presentation will focus on the analytical considerations of medical device extractable and leachable (E&L) studies per the new ISO 10993-18 chapter. Topics to be covered will include: 1. Understand the analytical testing requirements per the new ISO 10993-18. 2. How to design an extractable study of medical devices in terms of solvent selection, extraction conditions, setting the suitable analytical evaluation threshold (AET), etc. 3. Analytical case studies per common regulatory deficiency points on medical device E&L studies, including requirements on reference standards during semi-quantitation, spiked recovery, LC-MS ionization modes, analytical uncertainty factor, compound identification status, etc.
Dujuan Lu, Ph.D. | Manager/Global Leader-E&L, SGS
Factors to consider for extractable and leachable testing for medicinal products and medical devices
It has now been over a year since the revised ISO10993-18 guidance came out. This presentation covers the similarities and more significantly the differences between medicinal products and medical devices for chemical characterisation /extractable leachable testing. Key areas will be around limits and the design of extractable studies.
Dr. Andrew Feilden | European E&L Strategic Director, Hall Analytical
Networking Break
Session VI: E&L and COVID Lessons Learned
Living in Uncertain Times: Ultra Rapid Development, Manufacturing and Deployment of Pharmaceutical Countermeasures for Unanticipated and Unmet Medical Needs
Potentially catastrophic biological threats exist which can place populations at considerable risk. These may represent either deliberate (e.g., counterfeiting, malicious intent, etc.) or unintentional (e.g., natural disaster, pandemic, etc.) events and necessitate extremely rapid assessment and review processes to deploy life-saving countermeasures with an acceptable and appropriately scaled benefit/risk ratio. Agencies such as the US FDA have developed cross-functional programs with pharma and non-pharma collaborators (e.g., DoD, DOE, EPA) and guidance (e.g., Emergency Use Authorization) to expedite development and deployment of drugs to treat life-threatening diseases and unanticipated, unmet medical needs.  However, the implementation of such efforts is not without significant technical challenges, such as development of rapid, robust and portable technologies for threat identification, simple and effective risk assessment processes for rapid development, storage, deployment and delivery of drug products and countermeasures, and ensuring supply chain integrity.  These processes are required to be agile and necessarily rely upon SUS and platform technologies (e.g., digital, rapid, reconfigurable manufacturing for small and moderate targeted therapeutic population needs).   Benefits and some technical and regulatory challenges with implementing accelerated development and deployment of countermeasures will be explored, and as well as the future direction of this rapidly evolving area.
Douglas Kiehl | Research Advisor, Eli Lilly and Company
Panel Discussion: COVID Lessons Learned

Panelists:

  • Diane Paskiet, Sr. Director Scientific Affairs, West Pharmaceutical Sciences
  • Lee Nagao, ELSIE
Panel: Future Direction of E&L
Adapting and Thriving in the Face of Change: Navigating     the Challenges of an Evolving Landscape and Preparing for the Future of E&L
Chair: Paul Cummings