Perspectives on designing extractables and leachables studies and conducting safety assessments for cell and gene therapies
  • General overview of cell and gene therapies (C&GT) – a growing area of research and therapeutic development with a number of C&GT products being approved, and many in clinical trials
  • Setting the stage regarding leachables:  these “new” modalities and their extraordinary progress presents interesting scientific, technical and regulatory challenges with respect to product manufacture and storage, including leachables risk assessment. 
  • Current thinking on leachables risk assessment as well as the existing regulatory landscape and gaps will be discussed, e.g.,
    • Qualification of materials and containers used in manufacturing and storage risk mitigation strategy in support of leachable assessments; process validation on performance and product quality requirements to support leachables risk management
    • Overview and assessment of currently available guidelines and publications relevant to E&L risk assessments that can be used to support C&GT products, including discussion of challenges in extractables testing strategies relevant to the specific manufacturing and storage conditions of C&GT products

Petra Booij | Senior Scientist, PDS-CMCA-SFC-Trace Analysis and E&L, GlaxoSmithKline
How to implement USP 665 requirements before 2026
  • Management of existing items, lifecycle and retrospective approach
  • Management of new items created between 2021 and 2026
  • Ensure full compliance for items after 2026
  • Quid of Chinese pharmacopea ?
Marine Lepoutre, GSME E&L, GSK Vaccines
Etienne Michel | Global Quality Expert, GSK Vaccines
Technology in the world of E&L: how far have we come and how far can we go?
The presentation will start with a recap of how technology has advanced the world of E&L so far, followed by thoughts on when technology becomes artificial intelligence and where the line is. It will then discuss how AI could be used in E&L and what benefits it could bring as well as what other impacts need to be considered. It will also consider how the use of AI could be regulated to enable it to be used in validated work environments.
Dr. Amy Johnson | Principal Scientist, Medical Device Testing, Smithers
Panel Discussion: Opportunities brought by advances in technology and collaboration
Moderator: Michael Creese, Operations Director of Chemistry Medical Device Testing, Smithers
Vincent Jeanguyot, Director Science & Technology - Extractables and Leachables, Novartis Pharma AG
Dr Amy Johnson, Principal Scientist, Medical Device Testing, Smithers
Armin Hauk, Principle Scientist, Sartorius Stedim Biotech GmbH
Jason Creasey,
Managing Director, Maven E&L 
Networking Break
Extractables and leachables from single-use systems and their assessment in advanced therapy medicinal product (ATMP) production
The differences between Advanced Therapy Medicinal Products (ATMP) and traditional biopharmaceutical products create new challenges for extractables and leachables (E&L) assessments. These issues are particularly important considering the increasing reliance on single-use systems (SUS). While SUS extractables data can serve as a basis for assessing ATMP applications, there are significant opportunities to improve assessment tools for exposure estimation and toxicological evaluation. In ATMP applications cells or viruses are the therapeutic product and a patient exposure estimation for leachables must consider both the liquid phase and the therapeutic biological material.
We tested forty-five commonly found extractbales and processing aids in a high-throughput screening cell-painting assay using a human cell line. Results showed that most compounds did not create a response in the > 550 cell features analyzed. Only three candidates were found to show an effect in this assay, including the antioxidant degradant bDtBPP, known to be detrimental to cell growth. Further, a concept is developed that allowes to model process equipment-related leachables (PERLs) exposure in an ATMP production environment.
In summary, cell-based products' exposure to PERLs is expected to fall far below critical effective concentrations. Nonetheless, avoiding materials of construction containing extractables with a known detrimental effect to cells is advisable.
Dr Armin Hauk | Principal Scientist, Sartorius Stedim Biotech GmbH
Case study: pressurized metered dose inhalers (pMDIs) reformulation: evaluation of the impact on the leachables profiles
HFA-152a and HFO-1234ze(E) are being investigated in order to reduce the Global Warming Potential of medical propellants and to replace current HFAs in pressurized metered dose inhalers (pMDIs). As these propellants have different physico-chemical properties, a reformulation of pMDIs will be needed as well as the selection of a new container closure system. Leachables assessment appears as a key point for this new generation of products. The case study described here looks at the leachable profile measured in canisters filled with three different propellants with or without the presence of ethanol and compared it to the extractable profiles of each material used in the metering valve. The leachables stability study ran for 6 months at 40°C and 75% RH and showed that notable differences in leachable levels were observed between the different configurations.
Pauline Faucard | Laboratory Study Leader , Aptar Pharma
Extractables and leachables in hospital pharmacy - A concept of quality control
  • Swiss hospital pharmacies compound and manufacture drug products in order to compensate for the lack of market availabilities e.g. drug shortages, clinical trial or neonatal/paediatric population with specific needs.
  • Ready-to-use or to-administer products are provided in prefilled plastic syringes, prefilled IV plastic bags and prefilled glass or plastic vials, which are stored long-term.
  • As part of a PhD project, an analytical quality screening system by LC-HRMS and a multi-functional database were set up for the identification and the semi-quantification of non-volatile leachable compounds in hospital pharmacy-prepared drug products.
  • Estimative toxicology and endocrine disrupting properties are also assessed.
  • A new E&L quality control concept in hospital pharmacy

William Bello | Analytical Pharmacist, Lausanne University Hospital
Networking Lunch
Leachables and biotech drug products: not only toxicity but also product quality-related concern
  • We are proposing a New Extractable & Leachable workflow for biotechnological products
  • Our aim is to Predict protein-leachable covalent interaction by using specific software
  • We are also proposing an integrated approach in order to confirm Covalent Interaction prediction with analytical activities

Daniele Zarini | Project Manager - BioPharma, Eurofins Biopharma Product Testing
Interference of leachables with biopharmaceuticals during manufacturing, storage and administration
The current trend within the biopharmaceutical industry is to apply single-use systems (SUS) for manufacturing of Biologics drug substance (DS) and drug product (DP). This is due to several advantages over stainless steel equipment. Due to the vast amount of SUS employed in a complex manufacturing process for Biologics, it is becoming key to apply risk-based EL assessments. The main focus of these EL assessments is patient safety. However, the quality of biologics DS and DP can potentially be altered by compounds that are present far below safety thresholds. Here, we show case studies were EL compounds in trace analytical amounts were detected in components used for manufacturing, storage and administration of biologics DS and DP.
Lukas Mogler | Group Leader Extractables and Leachables, Lonza DPS
Case studies to demonstrate the susceptibility of ophthalmic drug products to the leachable compounds originated from the plastic packaging containers
  • Drug products packaged in plastic containers can be susceptible to leachables/migrants, which are substances that leach or migrate out from the packaging material and can potentially contaminate the product
  • This phenomenon occurs due to various factors associated with the packaging material, storage conditions, and the drug product itself
  • The susceptibility of drug products packaged in plastic containers to leachables is a complex issue that requires careful consideration
  • Case studies play a crucial role in demonstrating the occurrence of leachables in drug products. These studies involve subjecting the packaged drug products to specific storage conditions, simulating real-world scenarios followed by testing utilizing advanced analytical techniques, such as gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS).

Ramarao Gollapalli | Associate Director, R&D, Akron
Networking break
ISO 18562 - Biocompatibility evaluation of breathing gas pathway medical devices
The assessment of patient safety from gas pathway medical devices includes testing for particulate matter, volatile organic compound emissions, and leachable substances in condensate. Whilst there are some similarities with the regulatory requirements for pharmaceutical products and other medical devices the testing requirements for these high-risk devices (as per ISO 18562) are unique. This presentation provides an overview of the testing requirements, the types of products which are included in the scope of the standard, a summary of the key differences in testing requirements and the associated challenges and will include some recent case studies.
Nick Morley | Principal Scientist, Element Materials Technology
Implantable medical devices: new frontiers in biomonitoring using ICP-MS
The advantages of chromatographic endpoint determination in exhaustive extractions of medical device E&L studies
  • Definition and regulatory framework for exhaustive extraction based on ISO 10993-18
  • Advantages of the chromatographic approach for exhaustive endpoint determination
  • Non-Volatile Residue determination vs chromatographic approach
  • ISO 10993-17 based toxicological evaluation using daily exposure vs. exhaustive extraction
  • Extraction time points (24 hours vs 72 hours

Tim Petermann | Principal Chemist, Obernburg Laboratory Services, NAMSA
Chair’s conference summary
Networking Drink Reception
Registration & Welcome Refreshments
Harmonization of read-across methodology for drug substance extractables and leachables (E&Ls)
  • The purpose was to develop a read-across methodology for extractables and leachables to derive health based exposure limits for compounds with limited toxicology data
  • The methodology was based on responses from pharmaceutical companies surveyed on current E&L practices and read-across approaches, as well read-across literature from other industries
  • Oral to parenteral bioavailability factors based on phys-chem properties were proposed for compounds lacking experimental and/or predicted bioavailability
Anders Burild, Novo Nordisk on behalf of the ELSIE Consortium
Anders Burild | Specialist, PhD Toxicology Development Projects, Novo Nordisk
Extractables and leachables (E&L) chemical classification and considerations for class-based thresholds
  • Distinct chemical clusters derived from a set of E&L covered 78% of the chemicals in the set
  • Methods for deriving class-based limits will be discussed
  • A case-study describing the derivation of a class-based limit for cyclosiloxanes will be presented

Candice Johnson, Ph.D. | Senior Research Scientist, Instem
Expanding the toxicologist’s toolbox: application of proposed new approaches in ISO 10993-17 (FDIS) to facilitate toxicological risk assessment of medical devices
Networking Break
Understanding and modelling the clearance behaviour of selected organic compounds and elements during ultrafiltration/diafiltration (UF/DF) from process streams
A key challenge for the biopharmaceutical industry is the demonstration that downstream purification stages effectively remove leachables from process streams, proving that they do not reach the drug product. The clearance behaviour of 20 common organic and 22 elemental leachables during representative ultrafiltration/diafiltration (UF/DF) processes for 3 monoclonal antibodies with differing pIs was investigated. 
Most organic compounds and inorganic species were efficiently removed. The most influential clearance factors were determined and mathematical models were developed to characterise and predict the behaviour of potential leachable substances beyond those included in this study. 

Dr Aidan Sexton, Senior Principal Scientist in Material Sciences at Biotherapeutics Development & Supply (BTDS), Janssen
Noemí Dorival-García | PhD, Senior Research Scientist, NIBRT (National Institute for Bioprocessing Research and Training)
Leachables analysis from a closed connected single-use mAb purification process – data for what we all assume
  • A closed connected single-use monoclonal antibody purification process was performed in-house at Cytiva
  • Leachable screening using LC-MS, GC-MS and HS-GC-MS was performed on samples taken from different process steps and final storage
  • The data was used to monitor leachable sinks and to compare results from available extractable data

Alfred Haglind | Senior Scientist, Cytiva
3D Print it – Test it – Fix it: Introducing parylene coating as effective barrier for extractables migration
  • Extractables qualification of polymers for 3D printing of SU components
  • Analytical identification and cytotoxicity evaluation of a new extractables detrimental to cell-growth
  • Material coating introducing an effective barrier for E&L migration

Dr. Ina Pahl | Senior Scientist, Sartorius Stedim Biotech
Networking lunch
Modelling the diffusion of extractables from processing materials: use cases and future possibilities
Inspired by the work of Armin Hauk and David Saylor and based on Piringer, a Python-based diffusion model has been developed. The practical uses of that diffusion model are demonstrated based on various real-life examples in the context of E&L assessments including i) interpolation of extractables amounts based on analytical data (e.g. BPOG study) to obtain a more realistic patient exposure and ii) the calculation of extractables in filled containers after inline filtration. The analytical data and the geometry of the material are considered, and diffusion is calculated. If unknown, the diffusion coefficient D, the partition coefficient Kpl and the maximum concentration of the extractable in the liquid phase cmax are fitted. The model delivers results of acceptable accuracy, and it makes additional extractable studies redundant.
Nicole Heider | Junior Material Qualification Scientist, Octapharma
Determination of non-volatility of extractables and quantitation of non-volatile compounds utilizing liquid chromatography with charged aerosol detector
  • Accurate Determination of Non-Volatile extractable peaks using LC/Charged Aerosol Detector.
  • Differentiating non-volatile peaks from volatile and semi-volatile peaks for the confident identification and accurate quantitation during the LC analysis of non-volatile peaks.
  • Ways to reduce the response factors variation of non-volatile extractables with different chemical structures
  • Simple and economical operation with Sub nanogram sensitivity and non-dependency on presence of chromophores

Mohinish Sahai | Group Leader, Laboratory Services, GMP, PPD, part of Thermo Fisher Scientific
Degradation products of polysorbate: How to distinguish between polysorbate degradants and extractables and leachables?
  • Identification of compounds which can originate from Polysorbate and/or its degradation or packaging and single use materials.
  • Use of screening assays to better understand and predict polysorbate degradation.
  • Strategies to identify the source of potential extractables and leachables in matrices containing polysorbate

Steven Watt | Business Development Manager, , A&M STABTEST Labor für Analytik und Stabilitätsprüfung GmbH
Selecting the right surrogate standards for semi-quantitative concentration determinations of extractables in GC/MS: what the Nelson database can learn us
  • Quantitifcation challenges for non-targeted analysis (NTA): how to generate accurate concentrations estimates for extractables with unknown response characteristics
  • What trends can be drawn from the Nelson Labs GC/MS database ?
  • Translation of the uncertainty factor concept to protectiveness of the quantitation approach
  • Which compound properties can be used for achieving « protective concentrations » ?

Dr. Jan Baeten | Sr. Scientist – Technical Advisor, Nelson Labs
Panel Discussion - Standardisations: Drivers, opportunities, and challenges to overcome
Jason Creasey, Managing Director, Maven E&L    
Michael Creese, Operations Director of Chemistry Medical Device Testing, Smithers
Nick Morley, Principal Scientist, Element
Piet Christiaens, Scientific Director, Nelson Labs
Dr. Kimberly Ehman, Ph.D. Director of Regulatory Toxicology & Consulting, WuXi AppTec
Jason Creasey | Managing Director & Principal Consultant, Maven E&L Ltd.
Chair's closing remarks and end of conference

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