Extractables & Leachables USA 2019 Agenda

The agenda for Extractables & Leachables USA 2019 is featured below.

The 2020 agenda will be released mid-January, 2020.

Workshop | Tuesday

Chemical Safety Qualification and Biocompatibility of Packaging Systems and Medical Devices “An Analytical Chemistry Perspective”

Coordinated and Presented By:

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

Paul Cummings, General Manager of Smithers Rapra Analytical Services

  1. Introduction

    • What is chemical safety qualification?
    • What is biocompatibility?
    • US regulatory perspective
  2. Chemical Safety Qualification

    • The PQRI recommendations and perspective
    • Extractables assessments (chemical characterization)
    • Leachables assessments
    • Preparing an individual chemical safety assessment
  3. Networking Break

  4. Biocompatibility

    • FDA CDER perspective (USP)
    • FDA CDRH perspective (ISO 10993)
    • Packaging systems (USP)
    • Medical devices (ISO 10993)
    • Combination products
  5. Summary

    • What does all this mean for pharmaceutical development?
    • Where is USP headed?
    • Where is ISO 10993 headed?
    • Where is FDA headed?

Day 1 | Wednesday

Registration & Welcome

  1. Registration & Exhibit Hall Open

  2. Welcome & Opening Remarks

    Paul Cummings | General Manager E&L of Smithers Rapra

Session I: The Evolving Regulatory Standards for Extractables and Leachables

In the opening session of this conference, we will explore recent and upcoming stringent regulatory requirements and how these changes can impact future evaluations of pharmaceutical, drug delivery systems and biomedical devices systems. We will discuss any gaps that exist in guidelines and potential future needs of the industry with key agency experts.

 

Moderator:   Paul Cummings, General Manager, Smithers Rapra Analytical Services

  1. (Tentative) 3D Printing of Pharmaceuticals: Considerations for the future of pharmaceutical manufacturing

    Aprecia Pharmaceuticals

    • Binder jet printing and options in dosage form performance made possible by 3D printing
    • Technical considerations when using 3D printing to produce pharmaceutical products
    • Distributed manufacturing with 3DP and direct delivery to patients
    • 3D printed products and comparisons to traditional formulation methods with respect to extractables and leachables
  2. <665> and <1665>: USP Monographs for the Selection and Qualification of Pharmaceutical and Biopharmaceutical Manufacturing Systems

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

    • Polymeric components of drug product manufacturing systems can add process related leachables (PERLs) to the manufacturing process stream.
    • PERLs could impact a quality attribute of the process stream, affect manufacturing process efficiency and impact drug product quality attributes such as stability and patient safety.
    • USP Chapter <665>, Polymeric Components and Systems Used in the Manufacturing of Pharmaceutical and Biopharmaceutical Drug Products addresses provides a risk-based approach for chemically characterizing polymeric materials and components used to manufacture pharmaceuticals/ biopharmaceuticals.
    • USP chapter <1665>, Characterization of Polymeric Components and Systems used to Manufacture Pharmaceutical and Biopharmaceutical Drug Products) communicates the key concepts behind <665> and addresses the applicability and the application of <665>.
    • This presentation discusses the continuing evolution and current status of <665> and <1665>
  3. ISO 10993-18; Practical Approaches to Chemical Characterization of Medical Devices

    Theodore Heise, PhD, RAC | Vice-President Regulatory and Clinical Services of MED Institute

    • An overview of the ISO 10993-18 approach to chemical characterization of medical devices, including context within the broader biological evaluation process
    • Discussion of changes in the standard currently underway
    • Expectations from regulators that are developing, and
    • An illustration of lessons learned from a brief case study
  4. Networking Break & Coffee - Poster Session in Exhibition Hall

    Attend the Poster Session in the exhibition hall to find out about cutting-edge techniques and enjoy interactive Q&A with the authors.

Session II: Quality Standards and Risk Assessments

Key success factors for effective product stewardship and manufacturing licensing is the ability to formulate healthy supplier partnerships, establish consistent supply chain standards and quality agreements. Other important influencers are adhering to good manufacturing practices and meeting agency requirements and guidelines to mitigate regulatory risks and/or safety concerns associated with packaging or device material early in the drug development process.

 

Moderator: Nick Morley, Principal Scientist, Hall Analytical Laboratories

  1. Regulatory Uncertainty in E&L: Potential Impact

    Stephen Warren | Scientist of AstraZeneca

    We talk about E&L, but what does it mean to an individual or organization? How do we go about doing a risk assessment, conducting an extraction study, or evaluating and controlling to the appropriate level? What is it that you follow or what relevant guideline do you reach out to?

    What this presentation tries to make clear is that in the context of E&L there is no such thing as a single relevant guideline. We don’t have a formal international standard. What we have is a series of regional guidances, standards, recommendations, and publications. There is no hierarchy regarding the various documents. They are potentially divergent and even conflictory, making it difficult to follow a consistent process.

    Do you define your approach by taking all the best parts from the various documents and condense them to come up with your internal strategy? Is this the best way to go about it? The problem is that most of us go through such an exercise, but what happens in terms of the submission if my interpretation is different from yours? What if the regulatory reviewer or CMC inspector has their own perspective? How does anyone make sense out of it when even the experts in the area struggle to come to grips with how it all fits together.

    What are the consequences? The disconnect can result in different filing requirements across regions, protracted reviews and approvals of marketing applications, and request for additional studies without clear scientific foundation. From a regulatory stand point it must be difficult to establish a position, because even if you are well versed on the subject matter, it is not as simple as referring to a few documents.  The uncertainties lend weight to the adoption of a global position…the need for an ICH guideline.

  2. Background information on FDA Guidance leading to IPAC-RS Guidelines and Initiatives

    Barbara A Falco | Consultant/Owner of Barbara Falco Pharma Consult LLC

    Application of risk management tools to Supply Chain and OINDP specifically:

    • Selection of suppliers of raw materials and components
    • Risk mitigation strategies for suppliers
    • Raw material selection
    • Component selection
    • Risk mitigation strategies for materials and components
    • Development and Management of Quality Agreements
  3. Light at the End of the Tunnel: The Evolving Consensus On Risk Assessments With Supplier Extractables Data

    James Hathcock | Senior Director, Regulatory and Validation of Pall Biotech, USA

    With stronger alignment between the proposed USP <665> standard and the Biophorum Extractables user requirement, there is now light at the end of the tunnel driving consensus expectations for supplier datasets. Herein examples of the 2019 USP <665> low, medium, and high-risk datasets as well as those using the Biophorum Extractables protocol are shared, now including multiple types of components. Specifically, components where there is strong consistency in the USP and BPOG high pH profiles, as well as materials where there tended to be significantly more degradation products at higher pH conditions are considered. Standardized tools and risk assessment examples for multi-component single-use systems using component data, as well as approaches using process-specific model solvent are reviewed. Additional updates of ongoing work within the supplier and end user community to address frequent questions; standardized spreadsheet reporting templates; and share data are reviewed. The goal of these activities is to drive alignment among suppliers, integrators, end-users and regulators to accelerate realization of the benefits of single use technologies. 

  4. Ready-To-Use Calibrants for Extractables & Leachables Testing Methods

    Markus Obkircher, PhD | Head of Reference Materials Research & Development of Millipore Sigma

    MilliporeSigma’s R&D teams developed two ready-to-use certified reference material mixtures suitable for use as calibrants in LC-MS or GC-MS methods. The components of those two mixes consist of the most relevant organic chemicals for multiple market segments. All substances were individually characterized, and their contents determined by quantitative nuclear magnetic resonance (qNMR) spectroscopy according to ISO/IEC 17025 accreditation. In the qNMR measurements a value for the mass fractions was obtained and direct traceability to the SI unit was achieved using acknowledged NIST primary reference materials. Subsequently, these characterized batches were used as raw materials to prepare the final solutions by gravimetrically dissolving and diluting them in an appropriate solvent according the ISO 17034 accreditation workflow. The resulting bulk solutions were collected in ampules and the process controlled through homogeneity testing by LC-MS or GC-MS, respectively. The final ampules were further investigated thoroughly to guarantee stability of the product during transportation and throughout the whole shelf-life at storage temperature. The concentration of each individual component is stated in the certificate including their respective expanded uncertainties U (k=2) according to ISO Guide 35. Uncertainties from measurement, homogeneity as well as stability contribute to those expanded overall uncertainties as indication of the precision of the stated concentrations.

    With these two ready-to-use standard calibration sets; manufacturers, suppliers and testing labs are provided with a very reliable, high-quality product suitable for their individual method. Not only will laboratories save time, since there is no need for a preparation of in-house working solutions; they will also benefit from the use of certified reference materials prepared under double accreditation, and the clear documentation according to ISO norms and guides ensures correct results and facilitates audits.

  5. Networking Lunch

Session III: Biocompatibility Testing and Evaluation

A medical device or material that comes in contact with the human body is expected to perform without adverse effects. In this session, we will explore different considerations and concerns related to the medical device or combination product design, material components and manufacturing processes for testing as it relates to potential risks of medical devices, challenges associated with personalized 3D printed devices and considerations in safety evaluations for medical devices through chemical characterization studies.

 

Moderators:

Dr. Dennis Jenke, Chief Executive Scientist, Triad Scientific Solutions
Dr. Cheryl Stults, Principal, C&M Technical Consulting LLC

  1. The 2016 CDRH Biocompatibility Guidance and ISO 10993-1:2018

    Jennifer L. Goode | Biocompatibility Program Advisor, Office of Device Evaluation of FDA, Center for Devices and Radiologic Health (CDRH)

     Attendees will learn how the newest revision of ISO 10993-1:2018 “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” compares to the 2016 CDRH Biocompatibility Guidance on the use of ISO 10993-1.

    This presentation will include:

    • Overview of the 2016 CDRH Biocompatibility Guidance.
    • Key changes to ISO 10993-1:2018 from prior versions of the standard.
    • When/how biocompatibility is considered.
    • Important risk-based considerations.
    • Endpoint assessments for CDRH submissions.
    • How chemistry information is used in biocompatibility evaluations.
  2. The Biocompatibility Evaluation Dilemma for Combination Products

    Dr. Cheryl Stults | Principal of C&M Technical Consulting

    More Details Coming Soon!

  3. Extractable and Leachable Chemistry Testing for Personalized 3D Printed Medical Device Biocompatibility

    Dr. Matthew Jorgensen | Senior Extractables and Leachables Expert of Nelson Laboratories

     Personalized devices produced using additive manufacturing present a special challenge from the perspective of biocompatibility, especially when the material is a polymer and Extractables and Leachables chemistry testing is involved. This presentation will provide an overview of a testing strategy to conduct extractable and/or leachable testing in support of 3D printed devices. The discussion focuses on specifics related to sample preparation, extraction, appropriate analytical techniques, and toxicological risk assessment. As the standards and expectations of medical device chemistry testing have been rapidly evolving, an overview of these changes will be discussed with attention to new requirements and potential gaps in current approaches. Special attention will be given to a case study of a 3D printed medical device that was recently tested for biocompatibility.

  4. The Results of the Interlaboratory Investigation of ISO 10993 Extraction Conditions

    Anita Y. Sawyer | Independent Biocompatability Expert of ISO/TC I94 Extraction Task Force Leader

    • Investigation of the suitability of ISO 10993-12 extraction conditions for the identification of potential hazards/ toxic chemicals in medical devices
    • Evaluation of the extent to which various 10993-12 extraction conditions affect the amount of extractables/ leachables from a medical device
    • Analysis and comparison of analytical chemical extraction data from test laboratories
  5. Networking Break & Coffee

  6. Designing Chemical Characterization Studies to Meet Upcoming Changes to ISO 10993 and the Medical Device Regulation (MDR)

    Sandi Schaible | Senior Director, Analytical Chemistry and Regulatory Toxicology of WuXi AppTec, USA

    Chemical characterization of final finished medical devices and combination products must be planned and conducted to provide meaningful data for a toxicological risk assessment. If the information is insufficient, additional chemical characterization will be required. Important considerations in designing these studies include the appropriate analytical evaluation threshold (AET). High-end sensitive chromatography tools such as UPLC-MS (TOF) have been commercialized. Although these systems are capable of providing accurate mass information and even information about possible chemical formula, the absence of commercially available chemical libraries can still lead to studies with numerous unknowns. Chemical characterization studies with unknowns above the AET are problematic for the toxicologists and often yield an unfavorable risk assessment. Which leads to the question: What do you do with peaks that cannot be identified?

  7. Analysing Chemicals Released From Respiratory Medical Devices According to ISO 10993-1

    Dr. Nikhil Sahotra | Materials Emission Market Specialist of Markes International, UK

    Updated regulation highlights the need for measuring chemicals released from materials in the air/gas stream and the need to safeguard against it. The regulation refers to ‘biocompatibility evaluation of breathing gas pathways in healthcare applications’ and is detailed in ISO 10993-1 (2018). Importantly, the standard cites a further standard, ISO 18562, which has recently been recognised by the FDA (US Food and Drug Administration). ISO 18562-3 describes how medical devices or components should be evaluated. As wide range of medical devices are affected, this has deeper implications for businesses in the industry and their supply chains. For instance, medical device manufacturers in the US and beyond whose products contain breathing gas pathways need to follow ISO 18562. There are three tests associated with breathing gas pathways of medical devices listed in ISO 18562: extractables and leachables, particulate matter and volatile organic compounds (VOCs). The talk will focus on best practice in collecting and sampling volatile organic compounds from respiratory medical devices.

    • ISO 10993-1 (2018) & ISO 18562
    • Chemical released in breathing gas pathway
    • Sampling from respiratory medical devices
    • Analysis of volatile chemical
    • Increasing sensitivity of E&L analysis 
    • Thermal desorption (TD)
    • Gas Chromatography (GC)
  8. Panel: Key Considerations for Guidance Development & Existing Gaps in Biocompatibility Testing

    Topics to be discussed during this 45-minute panel include but are not limited to questions surrounding:

    • How should E&L for medical device & component biocompatibility be different by design than for what is the standard for pharmaceutical containers?
    • Do the limitations to medical device E&L for biocompatibility mean that this data is less predictive or valuable than animal studies? How can we feel comfortable using this data to assess patient safety?
    • “Exhaustive extraction” is part of medical device studies that has been built into biocompatibility standards, including ISO 10993-18. Considering that medical devices do not commonly have a follow-up leachables study, does performing exhaustive extractions make sense?
    • Biocompatibility evaluation has become all about risk; these ideas are replete in the new ISO 10993-1 and FDA guidance on biocompatibility; what does it mean to use a “risk based approach” in our chemistry testing and how can we embed that into the guidance we develop?
    • Evaluation of wide ranging and novel materials, like those used in additive manufacturing often produce unknown results, when even the most robust databases are used. What are the best practices in these situations?           

    Confirmed Panelists Include:

    Dr. Matthew R. Jorgensen, PhD, Senior Extractables and Leachables Expert, Nelson Labs

    Anita Y. Sawyer, Independent Biocompatibility Expert and ISO/TC I94 Extraction Task Force Leader

    Doris Zane, Ph.D.,  Executive Director, Nonclinical Development, Intarcia Therapeutics, Inc.

    Jennifer L. Goode, Biocompatibility Program Advisor, Office of Device Evaluation, FDA,  Center for Devices and Radiologic Health (CDRH)

  9. Closing Remarks

  10. Evening Networking Reception

Day 2 | Thursday

Registration & Welcome

  1. Registration Desk and Exhibit Hall Open

  2. Welcome & Opening Remarks

Session IV: Study Designs for Extractable and Leachable Assessments

Novel applications and product designs are driving the need for new requirements for assessment and selection. In this session, we will discuss various considerations for determining the framework of toxicological risk assessments, the critical importance of safety evaluation, extraction conditions, emerging testing considerations for consumer products in other areas, and deficiencies and solutions for toxicological submissions.

 

Moderator: 

Dr. Daniel Norwood, Executive Partner, SCIO Analytical and Senior Consultant at Smithers Rapra

  1. How to Write a Toxicological Risk Assessment to Support Extractables and/or Leachables Profiles: A Step-by-Step Procedure

    Greg Erexson, PhD | Senior Principal Research Scientist of AbbVie

    Chemical substances leaching from container closure systems into drug products during the manufacturing process and storage may potentially adversely impact the safety or efficacy of a drug product and thus, patient health. Therefore, a comprehensive safety evaluation of extractable and/or leachable substances is of extreme importance. Data from extraction studies (profiles) are either used for safety evaluation (comparable to leachables) or provide the basis for the design of a leachable study. The safety evaluation process of leachable substances consists of two major components: (1) calculation of the maximum daily exposure (MDE) value or dose of the substance to patients based on calculated worst-case exposure scenarios, (2) the evaluation of the safety profile of an identified substance by derivation of a substance-specific limit dose (e.g., PDE or permitted daily exposure). In general, the safety profile of leachable substances should be based on substance-specific toxicity data, which might be available from different sources, e.g., subscription toxicity databases, open literature and publically-available databases (e.g., ChemID Plus) and how to deal with unknowns.

  2. Extractable and Leachable evaluation for complex pharmaceutical formulations (organic emulsions, and polymer based formulations). Testing of manufacturing surfaces through packaging. How to deal outside the "normal range” of the USP standard?

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

    Evaluation of manufacturing systems and the product related packaging is a complex analytical task. To execute the testing, USP standards must be followed when they are available, however even when standards are available they may not be appropriate to follow, since the formulation complexity is not addressed in the standard. The intention behind any standard is to cover 85-90% of the applications, and therefore a small percentage of the applications can fall outside the “normal range”. USP <665> provides an excellent framework for evaluation of polymer based manufacturing systems, for the majority of the systems, however it has some gaps for highly complex organic based formulations. This presentation will focus on presenting a case study related to a highly organic (80% organics) based process flow evaluation for Extractables and Leachables. A step by step approach will be presented for the evaluation, including various extraction and detection techniques. For proper evaluation state or the art sample preparation and HRAM based GC-MS and LC-MS detection systems were used.

  3. Future Directions of E/L Analysis from Automated Sample Preparation to Enhanced Compound Identification

    Dr. David Weil | Senior Application Scientist of Agilent Technologies

    Sample preparation remains a great bottleneck for many laboratories doing complex mixture analysis. A variety of automation products exists and are well suited to many sample preparations tasks including liquid/liquid extraction (LLE), filtration, dilution and diluent adjustment. Solid phase extraction (SPE), whether used as an offline or online process is a common tool to improve productivity for cases where liquid/liquid extraction is not applicable. In the environmental and food testing labs, online SPE and large volume injection techniques routinely used automate the sample cleanup and concentration prior to detection using LC/MS Systems. Preliminary data indicated that the same automation methods can be useful in the detection of low-level extractable and leachable compounds from reuse aqueous based pharmaceutical manufacturing products and container closer systems.

  4. Networking Break & Coffee

  5. Determining Relevant Low-Level Chemical Exposures for Safety Assessments of Consumer Products

    Kady Krivos, Ph.D. | Senior Scientist, Corporate Functions-Trace Analytical Capability of Procter & Gamble

    Evaluation of ingredient safety in consumer products requires understanding of consumer use (habits/practices) and how that translates to exposure. This is particularly challenging for complex articles with direct and/or indirect contact with consumers.  In this research, the direct contact of disposable diapers to an infant drove the development of a novel method based on in-use scenarios to determine the potential for low-level exposures.  Exposure to substances in a diaper can occur from direct transfer or potentially from migration of substances out of a diaper (“rewet”), which will only occur when the diaper is wet.  Historically, only targeted analysis of potential substances of concern have been addressed in the literature.  To fully evaluate the leachable substances from a diaper, a rewet sampling method was developed using the frequency and volume of urine output, average weights and diaper sizes, duration of wear, and frequency of changing events.  The rewet method involves wetting the diaper and pressing an appropriate skin mimic against the diaper to understand what could transfer.  The sampling method had to mimic dermal exposure, contribute no chemical background to the experiment, be compatible with the analytical instrumentation, and be able to detect very low levels of substances.  The analytical method (UHPLC-UV-CAD-HRMS) was then developed for the comprehensive profiling and identification of trace levels of chemicals extracted off the skin mimic. Validated analytical methods and consumer relevant in-lab exposure models facilitated the safety assessments of both diapers and their components. These experiments allowed a realistic assessment of potential exposure, which is an appropriate basis for the safety assessment (versus, for example, a harsh non-physiological extraction of the whole diaper). Several areas of conservatism are still built into this approach, offering opportunities for further refinement.

  6. Nonclinical Review of Extractable Leachable Studies: Practical Advice from an FDA Reviewer

    R. Daniel Mellon, PhD | Pharmacology Toxicology Supervisor of FDA, Center for Drug Evaluation and Research (CDER)

    Study design, extraction conditions, common deficiencies in submissions, and practical advice for regulatory submissions.

  7. Networking Lucnch

Session V: Case Studies and Analytical Challenges and Solutions

Case studies and strategies for medical device, pharmaceutical, and testing experts. Join us as we exchange information and views on real-world strategies, uses, and common pitfalls for products and services. In addition, we will explore best practices on the path to application approval in the pursuit of the health and safety of consumers.

 

Moderator: 

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

  1. Extractable Profiles of Printing Ink Used for Absorbable and Permanent Implantable Medical Devices Packaging

    Jing Kong, PhD | Senior Scientist, Analytical Characterization R&D of Ethicon (Johnson & Johnson Medical Devices)

    Packaging materials used for medical devices including foil, polymeric materials, coated paper, printing ink, adhesives, etc. inside sterile barrier systems may have direct or indirect contact with the patients, therefore should be carefully evaluated to ensure the safety and efficacy of the medical devices. In this presentation, a chemical evaluation focusing on printing inks, a component regularly used for packaging of medical devices will be discussed to illustrate an analytical testing approach and critical technical expertise required to support new product development and product life cycle management. 

    Specifically, 29 new printing inks, in three ink formulations following gamma or ethylene oxide sterilization were evaluated in compliance with ASTM standard F2475-11: Standard Guide for Biocompatibility Evaluation of Medical Device Packaging Materials. ASTM F2475-11 points out that specific attention should be paid to the potential for indirect contact components such as inks, varnish and adhesive to volatilize and migrate through the primary barrier into the product. In this study, the volatile organic compounds (VOCs) of the ink samples were characterized by Dynamic Headspace Gas Chromatography with Mass Spectrometry (DHS-GC-MS). Dynamic headspace has its unique advantages when analyzing the presence of VOCs in solid samples compared with static headspace. With adsorbent trap and cryogenic focusing, dynamic headspace is more sensitive than static headspace in detection of trace levels of impurities, contaminants, or hazardous compounds.

    Technical challenges encountered in this study will be highlighted, special considerations regarding extraction conditions, unknown identification, and semi-quantitation of VOCs will be discussed.

  2. Extractables and Leachables Evaluations: Support of mAb development Programs

    Katiria Flores, Ph.D. | Development Scientist I, Pharmaceutical Development of Alexion Pharmaceuticals, Inc.

    Extractables and Leachables program (E&L) evaluate safety of the future drug product (DP) from toxicological prospective of any potential leachable from all contact surfaces during its entire  manufacturing, handling, shipment and long term storage history. Biotherapeutics manufacturer is responsible to prove that the DP container closure systems, process equipment and packaging are toxicologically safe. Simulated extraction studies are currently an emerging approach, that are designed to be representative, albeit harsher than the real time conditions of the DP exposure to a studied system. The present study investigated how simulation extraction studies with single organic co-solvent can be used and applicable to various drug programs with different aqueous formulations. These studies evaluate an existing profile of extractable components, obtained via controlled extraction studies, to identify potential Leachables, such as antioxidants, plasticizers, dyes and metals. It is critical that E&L studies are designed specifically for each DP, dose regimen and the container closure materials so that the risks associated with leachable impurities can be assessed.

  3. Networking Break & Coffee

  4. Biopharmaceuticals: Combined In-Silico and Experimental Model (Marker Compound and Insulin) to Monitor the Potential Impact on Quality and Safety of Biopharmaceuticals

    Dr. Piet Christiaens | Scientific Director of Nelson Labs NV

    Piet Christiaens

    The presentation will address 2 ways of predicting if any of the chemical compounds, found in the  extraction profile of container/closure component, could lead to a chemical interaction if any of those extractables would become a leachable: (1) an in-silico reactivity approach and (2) a chemical reactivity test to actually screen for residual chemical reactivity. A recent scientific article (Kim Li et al., PDA J. Pharm. Sci. and Tech. 2015, 69, 590) outlined which types of organic reactions could occur between often encountered leachables and some functional groups in a therapeutic protein. Typical chemical reactions are Schiff Base Formation, Michael Addition, SN1, SN2, alkylating agents, acylating agents... Nelson Labs NV submitted all 5000 compounds in their extractables screener database to an in-silico reactivity evaluation. An evaluation of the potential reactivity of the universe of extractable compounds will be presented. In addition, a chemical reaction model, based on both (1) a Marker Compound (containing the main functional groups that are also present in a protein) and (2) Insulin was developed to actually verify chemical reactivity of a number of the compounds, specified above, with the Marker Compound/Insulin, this through covalent binding. This allowed us to compare the observed reactivity (Marker Compounds; Insulin) with the predicted in-silico reactivity for a predefined number of chemical entities. From this, a reactivity model could be developed to screen extracts of a controlled extraction study (CES).

  5. A Study On Migration Kinetics of Organic Compounds From a Bromobutyl Rubber Stopper

    Co-Presented by Dr. Benton Cartledge and Dr. Xiaochun Yu of the extractable and leachables group at PPD Laboratories

    A study was performed to measure the migration kinetics of multiple organic compounds from bromobutyl rubber stoppers at various timepoints and temperatures.  Three rubber stoppers were extracted in 1:1 IPA/Water at 5, 25, 40, 50, and 60 °C over the course of 4, 8, and 16 hours and 1, 2, 4, 6, 8, 10, 15, 20, 30, 60, 90, and 180 days.  All testing was performed in duplicate.  Target organic compounds were first identified by UHPLC/UV/MS and GC/MS.  HPLC was utilized to analyze for BHT while GC-FID was used to measure various bromobutyl rubber oligomers including C21­H40 and C13H24.  The concentration of each target compound (µg/stopper) 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, the data were evaluated with the Arrhenius equation per ASTM F1980-16 and a Q10 value was calculated.

  6. Closing Remarks & Farewell