Extractables & Leachables 2018 Agenda

See below for the program for E&L USA 2018

The agenda for Extractables & Leachables US 2018 has been confirmed, and the 2018 program will feature a pre-conference workshop, 2 full days of presentations from industry experts such as FDA, Triad Scientific Solutions, Leo Pharma, Med Institute,  plus 3 panel discussions and more.

Workshop: May 7th

Designing an Extractables/Leachables Program for Regulatory Submission

Co-Authors:

  • Dr. Andrew Feilden, Chemistry Operations Director, Smithers Rapra
  • Dr. Daniel Norwood, Executive Partner, SCIO Analytical, LLC
  • Paul Cummings, General Manager E&L, Smithers Rapra
  1. Introduction

    Introduction

    • Types of regulatory submissions
    • Risk-based approach based on drug product dosage form
  2. Regulatory requirements for high-risk dosage forms

    • Inhalation
    • Parenterals and injectables
    • Ophthalmics
    • Transdermals
  3. Regulatory requirements for lower-risk dosage forms

    • Oral liquids
    • Topicals
    • Solid orals
  4. Coffee Break

  5. Designing an experimental program based on dosage form

    • Extractables study design
    • Leachables study design
    • Simulation studies (when are they appropriate?)
  6. Preparing the submission

     

    • Drug product registration application (NDA and ANDA)
    • Change control
    • Manufacturing process
  7. Summary and Conclusions

Day One: May 8th

Registration & Welcome

  1. Registration & Exhibit Hall Open

  2. Welcome & Opening Remarks

Session I: The Evolving Compendial and Regulatory Landscape

  1. Use of Thresholds for the Safety Qualification of Leachables in Parenteral Drug Products from a Regulatory Perspective

    Dr. Timothy Robison | Pharmacology and Toxicology Team Leader, CDER of FDA

    • Extending thresholds from OINDP to Parenteral Drug Products
    • Do Cramer classifications and thresholds apply to the safety qualification of leachables
    • Use of thresholds from the ICH M7 Guidances based upon short-term or long-term use
    • Considerations or potential irritation or sensitization toward the application of thresholds
    • Thresholds for other routes of administration
    • Use of simulation studies in the process of identification of leachables
  2. Compendial: USP Strategy for Pharmaceutical Materials

    Dr. Dennis Jenke | Chief Executive Scientist of Triad Scientific Solutions

    Pharmaceutical applications of polymers including packaging, medical devices and manufacturing equipment. Consistent with its mission to insure the safety and quality of pharmaceuticals, the United States Pharmacopeia has historically included monographs for plastic, glass and elastomeric materials intended for pharmaceutical packaging (but indiscriminately used in other applications).  In general, these monographs share a common emphasis in terms of addressing extracted substances, as it through the action of the extracted substances that the quality and safety of pharmaceutical products are impacted by packaging, devices and manufacturing equipment.

    As the scientific understanding of extractables and leachables has evolved, especially in the area of supporting analytical chemistry, a point was reached where the existing USP chapters no longer met the high standard of good science and a systematic effort was undertaken by the USP to re-invent relevant monographs involving glass, plastic and elastomeric materials, and considering both chemical and biological characterization.  Additionally, the drafting of  new monographs on new materials (e.g., metallic materials) and new applications (manufacturing equipment, medical devices) have been, are being, or will be drafted.

    The purpose of this presentation is to provide an overview of the USP efforts in this area, focusing on the harmonized methodology that the USP has used to revise its whole approach to the topic of the safety and applicability of materials used in pharmaceutical applications.      

  3. Panel: Bridging the Gap and Leveling the Playing Field

    Panelists: NovoNordisk, Aspen Research, Triad Scientific Solutions

    • How do we identify good science and get it in the Hands of the People who can use it?
    • What “good Science” do we wish we had?

    Chair: Paul Cummings, General Manager E&L, Smithers Rapra

    Panelists:

    Carsten Worsoe, Principal Scientist E&L, NovoNordisk

    Dr. Roger Pearson, President Analytical Services, Aspen Research Corporation

    Dr. Dennis Jenke, Chief Executive Scientist, Triad Scientific Solutions

  4. Networking Break and Coffee

Session II: Addressing Analytical Challenges in Extraction and Leaching Studies

The regulatory bodies are constantly testing and analyzing the interactions between all the components in the manufacturing pharmaceutical industry, this session will be dedicated to explore the methods and evaluation process to develop safer products.  

  1. What do Petroleomics, Jet Fuel and Pharmaceuticals have in common?

    Doug Kiehl | Research Advisor, Team Leader Spectroscopy and E&L, Bio product Research & Development of Eli Lilly Company

    Characterization complex mixture of E&L and other Pharmaceutically relevant compounds using high Resolution2-D and 3-D Mass.

    The detection, identification and profiling of impurities, degradation products and related substances in drug products and associated materials is essential to the establishment of safety and purity of pharmaceutical products.  Extractables and leachables (E&L) represent impurities that may be present in drug products as a consequence of direct or indirect product contact with container/closure systems, manufacturing system components, drug delivery devices, and primary, secondary and tertiary packaging components and systems.  E&L are of concern with regard to patient safety and product quality, and thus it is necessary to comprehensively characterize and profile these compounds.  E&L samples can represent highly complex mixtures of diverse organic molecules and thus present significant analytical challenges.  This presentation discusses the application of techniques often used for characterizing petroleum and fuels, such as 2-D/3-D mass mapping, mass difference correlation and visualization of high resolution LC-MS datasets to simplify interpretation of such complex mixtures.  Some case studies illustrating analytical challenges will also be examined.

  2. Evaluation of Relative Response Factors for Multiple Common Extractable Chemicals

    Gyorgy Vas, Ph.D. | Business Technical Scientific Liaison of Intertek

    It is a common practice in extractable testing that semi-quantitation is performed using one or more surrogate Internal Standards along with an uncertainty factor to compensate for differences in response factors for compounds of different chemical classes. This approach has provided fairly good quantitative estimates for GC-MS based testing. The idea of using a conservative uncertainty factor for common extractable components was published by PQRI more than a decade ago, is a commonly used practice, and has been accepted by regulatory agencies.  However, the idea behind this approach is that a database should be developed with a wide range of components and that the database should be validated prior to being used.

    While the use of an uncertainty factor has been commonly used for over a decade, few technical issues have not been discussed. The presentation will focus on evaluating the response factors for over a 100 commonly present extractables from different chemical classes (hydrocarbons, siloxanes, PNA’s, antioxidants, halogenated components). Data will be presented to show how the response factors change due to different sample introduction techniques or different instrumentation used for the testing.

    While it is highly practical to use the PQRI response factor concept in the daily laboratory routine, it is important to understand the limitations and the applicability of such.

    Co-Authors: Louis Fleck, Howard Carpenter, Jin Tang Huang

  3. Extractables/Leachables Identification Process - LOD and LOQs

    Dr. Daniel Norwood | Executive Partner of SCIO Analytical & Senior Consultant at Smithers Rapra

    • Summary of the evolution and acceptance of identification criteria and data elements for organic extractables and leachables.
    • Examples of identifications using these identification criteria and data elements.
    • Summary of an overall identification process for organic extractables/leachables.

    The structure elucidation process (i.e., the identification process) for organic extractables and leachables is very similar to the process for any other trace analyze in a complex matrix.  Since the late 1960s, the field of trace organic analysis has been driven by developments in mass spectrometry (particularly GC/MS and LC/MS) and identification processes for trace organic analyses have thus been centered on mass spectrometry.  Recently, the USP has included identification criteria and data elements for organic extractables and leachables within its general guidance chapters.  This presentation will discuss the overall identification process for organic extractables and leachables, present and discuss the accepted identification criteria and data elements, and present case study examples.

  4. E&L Challenges on topical drug products

    Rasmus Worm Mortensen | Senior R&D Scientist Analytical Support of Leo Pharma

    • How Extractables are a challenge
    • How simulate studies can bridge the gap between E&L for this products
  5. Lunch Break

Session III: Focus on Medical Devices

The requirements for testing medical devices and evaluation of E&L analyzing toxicity of the leachables and the potential impact on the drug product need considered. The possible routes of entry in a patient system are highly important in short and long term exposure with the chemicals.    

  1. Extractables & Leachables Testing of Medical Devices; View From ISO 10993-18

    Theodore Heise, Ph.D., RAC | Vice-President Regulatory and Clinical Services of MED Institute

    • Understand the ISO standard for E&L evaluation of medical devices
    • Learn circumstances in which E&L testing may not be necessary
    • Get advance information on upcoming changes to the ISO standard
  2. Considerations in Safety Evaluations for Medical Devices through Chemical Characterization

    John Iannone | Former Director of Extractables/Leachables & Impurities at AMRI Currently Principal Consultant of iCG Solutions

    This presentation will highlight the benefits and limitations that must be addressed during Chemical Characterization studies that aim to provide data for Toxicological Risk Assessment and overall determination of Biocompatibility of a Medical Device. This presentation will discuss challenges when:

    • Determining which chemical compounds will become available to the patient
    • Depicting the amount of a chemical leachate that will be exposed to the patient
    • Utilizing orthogonal assays to increase the confidence in determining safety/biocompatibility. 
  3. Chemical Characterization of Extractables /Leachables Analysis for Medical Devices

    Keaton Nahan, Ph.D. | ORISE Fellow at Center for Devices and Radiological Health of FDA

    Chemical Characterization (described in ISO 10993-18) refers to identification and quantification of chemicals present in a medical device. Our objective was to identify challenges in chemical characterization of medical devices to determine leachable and extractable through extraction studies and chemical analysis. Exaggerated extractions of PVC, silicone, and EPDM (typical device materials) were performed using isopropyl alcohol, hexane, and water. Extractables were identified using proprietary databases and semi-quantification was performed. Using GC-MS, nearly 250 extractables were tentatively identified between all the materials. Preliminary results included pyrene, heneicosane, Irganox 1076, and siloxanes, which are typical monomeric, oligomeric components, or additives in these polymers. Challenges observed in this study included false positives, missing compounds in the database, and loss of analytes during sample preparation. Our work has demonstrated that extraction conditions, analytical methods, and data analysis substantially impact the outcome. Future work aims to address these gaps and contribute improvements to chemical characterization consensus standards.

  4. Networking Break

  5. Biocompatibility Evaluation of Breathing Gas Pathways in Healthcare Applications - A New ISO Standard

    Charles Ducker, Ph.D. | Principal Chemist/Group Leader of Eurofins Medical Device Testing

    The purpose of this talk is to present an overview of the new ISO 18562 standard and its application to the safety evaluation of breathing gas pathways of medical devices.  ISO 10993, which covers biological evaluation of medical devices, does not sufficiently address the biological evaluation of the gas pathways of medical devices. ISO 18562 addresses the risk of potentially hazardous substances being conveyed to the patient by the gas stream in three ways:

    • Emission of particulate matter into the gas stream;
    • Emission of volatile organic compounds into the gas stream
    • Substances leached by liquid water condensing into gas pathways of medical devices. In this presentation, we will discuss what this new standard entails and the methods used to meet the testing needs outlined in ISO 18562.
  6. E&L Study of a Pre-Filled Syringe IV Drug Formulated in a Complex Matrix

    Jianfeng Hong | Sr. Research Scientist, Chemistry Lab Manager of Fresenius Kabi USA LLC

    • The experimental designs of an extractable study and a leachable/simulation study, including the selections of extraction solvents and conditions will be presented.
    • The challenges of and the solutions to testing organic and inorganic extractable/leachable compounds using a wide variety of analytical techniques (GC/MS, UPLC/MS and ICP/MS) will be presented.
    • The selections of target leachables, validation of the analytical method for testing target leachables will be presented.
    • The testing results of target leachable in the pharmaceutical formulation during long term stability storage and conclusion will be presented. 
  7. Toxicological evaluation of materials in combination products and purposeful study design

    Doris Zane, PhD, DABT | Sr. Director, Preclinical Development of Intarcia Therapeutics, Inc.

    Coming soon!

  8. Closing Remarks

  9. Opening Reception

Day Two: May 9th

Registration & Welcome

  1. Exhibit Hall Open and Breakfast

  2. Opening Remarks

Session IV: Global Update for Extractables & Leachables

Session dedicated to bring an update on what it’s happening is the world regulatory panorama and expectations. Most of products developed now days have multiple components that come from all around the world. How research, development, manufacturing and regulations in a global market impact the industry.  

  1. Extractables & Leachables Testing in Brazil: Status, Challenges and Opportunities

    GLAUCIA KARIME BRAGA, Ph.D. | Quality Assurance Auditor of Public-Private Partnership at FURP of Fundacao para o Remedio Popular

    Extractables and Leachables (E&L) studies for final packaging systems have recently been mandated by the Brazilian Regulatory Agency ANVISA for both parenterals and inhalation medicines. While the mandate has been put in place for marketing authorization in Brazil, there is an absence of any national guidance on how to  conduct E&L studies, what data needs to be produced to support an application and awareness of the potential patient safety and drug quality impact of the final packaging system on the finished drug product.  With Brazil being the 8th largest pharmaceutical market in the world and a push by ANVISA to address this current gap, industry understanding and knowledge and expertise is expected to grow exponentially over the next decade. Dr. Braga’s presentation will provide an overview of the Brazilian landscape regarding E&L testing,  current regulatory mandate, gaps in current regulations, such as the absence of any national guidance. She will also discuss challenges that the pharmaceutical industry and analytical labs are facing on designing and executing E&L studies, along with potential opportunities in Brazil.

  2. Pharmaceutical Materials Quality Regulation in China: An Overview

    Lee M. Nagao, Ph.D. | Senior Director, Science, Regulation & Policy of Drinker Biddle & Reath LLP

    Coming soon!

  3. Panel Q&A

    Panelists Include: FURP, Drinker Biddle & Reath LLP

    Panelists include:

    • FURP
    • Drinker, Biddle & Reath LLP
  4. Networking Break

Session V: Focus on Packaging, Containers and Single Use Systems in E&L

The pharmaceutical and medical device products have to be under high level of testing to avoid the contamination risk that chemicals could represent for patients. This block will explore different angles of the challenge dealing with packaging, containers and single use systems in E&L.

  1. Analytical Challenges on Extractables Studies of Plastic Single-Use Bioprocess Bags

    Dr. Dujuan Lu | Technical Client Manager/Global Lead - Life Science of SGS

    Single-use bioprocess bags are used for the preparation, storage and transport of biopharmaceutical solutions, intermediates and final bulk products.  Most of the bioprocess bags are made of plastics and those plastics additives and degradants may easily leach out into the drug products. As part of safety risk assessment, it is very important to identify and quantify those extractables and leachables as they may pose safety risks to patients and/or change the efficacy of the medical products.

    An extractable study was performed on plastic bioprocess bags by using different solvent systems (recommended by USP and BPOG proposals), such as acidified water, alkaline water, and organic/aqueous solvent mixtures to bracket and mimic pH values, ionic strength and hydrophobicity of common process fluids. During this study, there was one unexpected finding that the vapor of the volatile organic solvents in the plastic bags could migrate into the solvents in other bags. Modified experiments were then applied to investigate the root cause and effectively eliminated the problem. In addition, the diversified extractable profiles were compared and discussed for different extraction solvents. The results also demonstrate that High Resolution Accurate Mass (HRAM) and MS/MS data facilitate confident compound identification and unknown compound structure elucidation.

  2. Is it safe? How do we answer this simple question? Appropriate Procedures

    Nick Morley | Principal Scientist of Hall Analytical

    In a product's lifecycle material changes happen all the time, particularly with single use manufacturing components. Clients/Project teams often have one simple question for E&L subject matter experts - Is it safe?

    This question can often have a complex answer. Various types of information may be available to help us answer this question e.g. physiochemical compliance, food compliance, biocompatibility statements or extractable studies. What do these studies/compliance statements actually tell us? This presentation will discuss some of the different E&L and pharmacopeial studies available; exploring how the information gathered can be interpreted to answer this simple question.

  3. Challenges faces by the end users during the qualification of Single Use System

    Ben Jeyaretnam, Ph.D., MBA | Deputy Director, Unit Leader, E&L Analytical Lead of SANOFI

    Recently the pharmaceutical industry has been increasingly using single use systems (SUS).  Before a SUS could be used in the manufacturing process, it needs to be qualified for use by a pre-determined process.  This presentation will discuss a variety of challenges that the end use faces during the qualification process.  Complexity of SUS, varying quality of vendor data, component change management, changing regulatory expectations, E&L study execution, analytical challenges, and the potential impact of unexpected E&L study results will be presented.  

  4. Successes and Ongoing Challenges with Implementation of Single Use Extractables Datasets – A Suppliers Perspective

    James Hathcock | Senior Director, Regulatory and Validation Consulting of Pall Corporation

    Establishing consistent, high caliber expectations for component extractables data has been a major industry focus intended to streamline and accelerate the adoption of single use components.  In this overview we will share lessons learned in execution of more than 17 studies using the BPOG protocol as well as limited studies using the USP <665> draft protocol.  In addition, we review current challenges and potential solutions associated with compiling extractables datasets from multiple suppliers to perform comprehensive risk assessments on single use processes, as well as approaches to risk assess low to medium risk components for which detailed extractables studies are not available.  The aim of this review of experiences to date is to drive further industry alignment among suppliers, end users and regulators that accelerates the adoption of single use technologies and serve the public good.  

  5. Introduction: Current State BPOG and USP 665

    Dr. Dennis Jenke | Chief Executive Scientist of Triad Scientific Solutions

    Coming soon!

  6. Panel BPOG vs USP Discussion

    Panelists Include: SANOFI, Pall Corporation, VR Analytical

    Chair: Dr. Dennis Jenke, Chief Executive Scientist, Triad Scientific Solutions

    Panelists:

    Ben Jeyaretnam, Ph.D., MBA, Deputy Director, Unit Leader, E&L Analytical Lead, SANOFI

    James Hathcock, PhD | Sr. Director, Regulatory and Validation Consulting | Pall Corporation

    Raymond Colton, Founder and President, VR Analytical

  7. Lunch Break

Session VI: Trends and Outlook for Extractables and Leachables

 We’ll dedicated the session to the understanding of E&L regulations evaluating which kind of testing is required  in interpreting results that are crucial in the future stages of a drug development. 

  1. Emerging Trends in Regulatory Expectations for Extractables and Leachables

    Paul Cummings | General Manager E&L of Smithers Rapra

    Coming soon!

  2. Exploring Mass Transport Modeling as a Critical Tool for Risk-Based E&L Study Designs

    Thomas Egert | Analytical Development of Boehringer Ingelheim Pharmaceuticals

    • Understanding Physicochemical Factors as Impacting Leaching
    • Deploying Partition Coefficients along the Analytical Work stream
    • How to Calculate the Extraction Strength of Simulating Solvent Mixtures
    • Mass Transport Modeling in the Context of QbD-Paradigms
  3. Panel Discussion

    Panelists Include: Smithers Rapra, Boheinger Ingelheim Pharma and Bibra

    Panelists include:

    Paul Cummings, General Manager E&L, Smithers Rapra

    Thomas Egert, Research Scientist Pharmaceutical Contact Materials, Boehringer Ingelheim Pharma GmbH & Co KG

    Dan Norwood, SCIO

    Gryogy Vas, Intertek

  4. Networking Break

Session VII: Trends in Extractables & Leachables

After two days of analyzing and reviewing many aspects in the industry that affect pharmaceuticals and medical devices we want to dedicate the time to explore on future trends and where the research is pointing to. 

  1. Back to Basics- Method development for extractables

    Kenneth D. Berthelette | Scientist II, Consumables Separations Group of Waters Corporation

    Plastic additives are used during manufacturing to establish appropriate mechanical and chemical properties. However, these additives can leach into the final consumer product. The analysis of extractable and leachable compounds from plastic is required in numerous fields, including both the pharmaceutical and food safety industry. Developing a robust analytical method can streamline the extractable and leachable testing required by regulating bodies. Additionally, achieving chromatographic separation allows for better characterization of the plastic material.

    The principles and benefits of analytical method development for an extracted low density polyethylene sample are shown and a final LCMS method using a UPLC system and a tandem quadrupole mass spectrometer was developed. A full factorial method development strategy was employed using various mobile phases and column chemistries in order to achieve a separation with minimal coalitions. Finally, the developed method was transferred to a UHPLC system with a single quadrupole mass detector for routine quality control testing.

  2. Impact of Selected Elements on the Accelerated Stability of Human Lysozyme

    Erica J. Tullo, Ph.D. | Technology Manager, E&L of WestPharma

    • The effects of aluminum, calcium, zinc, silicon, and magnesium on the stability of Human Lysozyme and a monoclonal antibody are studied at elevated temperature stress.  The samples are exposed to varying levels (10, 100, 1000, 10000, and 100000 ppb) of said elements at an elevated temperature. 
    • Resultant samples are evaluated by several analytical and biophysical assays as a function of concentration and stress condition to determine impact on protein stability Study strategies and results to date will be presented.
    • Additionally, computational studies are performed to support the experimental findings.   
  3. Closing Remarks