Extractables & Leachables 2016のアジェンダ
2016年の学会では、FDA、NIBRT、AbbVie、Johnson & Johnsonなどの幹部による講演が予定されています。
Dr. Andrew Feilden | Chemistry Operations Director of Smithers Rapra
This is a lecture style introduction to extractables and leachables. This will be a useful introduction to the field of E&L and will enable new entrants to the field to get the most out of the following two day conference.
Glaxo Smith Klineでの製剤のリスク評価
Mike Hodgson | Extractable and Leachables Analytical Scientist of Glaxo Smith Kline
This is a fully interactive exercise that mimics a real life E&L project within a Pharmaceutical application. Participants will be tasked with selecting materials to be used in a fictitious device using supplier data and purchasing theoretical experimental data to support the team’s decision. Phase 2 & 3 of the exercise involve risk assessing a biopharmaceutical manufacturing process and the fictitious device; defining “Severity” and “Probability” terms, identifying, scoring and defining risks that warrant further understanding. Again, there will be opportunity for teams to purchase typical experimental packages from the facilitator to ensure this is as realistic and close to a real life project as possible. The final phase of the game involves regulatory questions, where teams will be tasked with responding to typical regulatory questions that are designed to test the robustness of their approach.
The intent of the exercise is to initiate discussion on key topic areas and risk assessment in general, with each phase designed such that key points are highlighted and addressed as part of a wider discussion.
Dr. Timothy Robison | Pharmacology and Toxicology Team Leader, CDER of FDA
米国薬局方のBiocompatibility General Chapters <87>、<88>、<1031>の改定作業についての報告
Dr. Daniel Norwood | Executive Partner of SCIO Analytical
- A summary of the overall goals and process of USP biocompatibility general chapter revision.
- A discussion of the current progress of biocompatibility general chapter revision.
- A discussion of the proper place of USP biocompatibility general chapters within the overall framework of other USP general chapters related to extractables and leachables.
非経口薬および点眼薬 (PODP) での抽出物と浸出物の閾値とベストプラクティス
Diane Paskiet | Director Scientific Affairs of West Pharmaceutical Sciences
The PODP Leachables and Extractables Working Group conducted multiple studies over several years and after evaluating a prolific body of data, the team has concluded that the Thresholds and Best Practices approaches developed for Orally and Inhaled Nasal Drug Products (OINDP) can be interpolated for Parenteral and Ophthalmic Drug Products. The PODP project incorporated components associated with container closure systems for small and large volume parenterals, prefilled syringes and ophthalmics . Factors specific to parenteral and ophthalmic dosage forms as well a variety of component materials were considered. Although commonalities exist between PODP and OINDP best practices , it was found that distinct approaches were needed in some cases, specifically , large volume parenterals, ophthalmics and biologics. In addition, thresholds were further investigated leading to a categorization approach for identified compounds that are non-genotoxic. This presentation will highlight the key outcomes associated with best practices for chemical characterization of container closure materials, safety thresholds for identification, indications for potential leachables and understanding issues of compatibility that can impact drug product quality
Dr. Gyorgy Vas | Research Fellow of Intertek
Anesthetic medical devices are very complex instrumentation, what are delivering anesthetic agents during surgeries. They are consists of multiple metal and polymeric parts, what needs to be tested for extractables and leachables. Since the volume of the inhaled agents is delivered with the life supporting oxygen, for a long surgery the exposure can be significant. There are very limited data were presented in the past how to evaluate such devices.
The e-cigarettes presenting the similar exposure route as the anesthetic devices. In the past few years the traditional tobacco products are getting less and less popular, however the “smokless” e-products are getting more and more popular. The e-cigarettes are generating aerosol, which carries the nicotine (and other chemicals such flavors, PEG 400), to the human pulmonary system. Those devices are containing multiple polymer parts, therefore the impurities of the polymers could potentially leach into the vapor and enters the lung directly.
To evaluate those devices and consumer products are very challenging for multiple reasons.
- The “extraction media” is gas with water or other chemicals in the vapor, therefore even to design an appropriate extraction study is not simple.
- The complexity of the vapor could cause interferences (flavors).
- Evaluate the actual leachable and validate analytical methods are requires non-routine extraction methods and as well detection capability down to ppb level.
The complex formulation combined with the low level testing requirement are very challenging analytical task. Component identification, analytical method development and validation are not as simple as for the components present at a ppm level or above. Aspects of method development including different extraction techniques, and method validation will be discussed. Case studies will be presented for analytical evaluation of anesthetic devices and e-cigarettes.
Allen Kesselring | Chief Science Officer of E.K.G. Life Science Solutions
Electronic cigarettes are being review by the FDA as to the manner in which they should be classified and regulated. Currently, only such products which claim to be nicotine cessation devices are governed by CDRH oversight. As part of the decision process to regulate, there is the need to evaluate extractable profiles from the atomizers and containers holding vapor solutions. Due to the wide variety in product types, sizes and end-user intake, the development of a universal protocol for evaluation and risk assessment is a taxing undertaking. This presentation will review the type and extent of extractable testing that should be considered along with challenges in assessing risk and threshold levels.
Pete Watts | Director of Toxicology of bibra toxicology advice and consulting
Certain well-known toxicants have been detected at low concentrations in vapours emitted from e-cigarettes, including diacetyl, formaldehyde, diethylene glycol, acetone, isoprene and acetaldehyde. These are not intended e-cigarette additives but require health risk assessments. The revised Tobacco Products Directive (TPD22; 2014/40/EU) will require e-cigarette manufacturers to take responsibility for the quality and safety of their products under normal use conditions. PW could describe approaches for their human health hazard and risk assessment and the opportunities for establishing Tolerable Exposure limits for these emission products.
Dr. Cheryl Stults | Principal of C&M Technical Consulting
The qualification of materials for combination products involves assessing the suitability of a particular material for use in a container closure, delivery device or both. Typically physicochemical testing and biological activity evaluation are the main considerations. Recently extractables testing has been added to the suite of physicochemical tests in the USP. Leachables evaluation is commonly performed for liquid formulations. The type of information required to confirm suitability for use may be different for a container closure than for a device. When the container closure also functions as a delivery device in a combination product this may increase the complexity of the testing. This presentation will explore strategic approaches to integrate other information sources and develop a simplified E&L and biocompatibility test plan.
Mike Hodgson | Extractable and Leachables Analytical Scientist of Glaxo Smith Kline
Stephen Duckworth | Head of Global Segment - Medical and Pharmaceutical of Clariant
Plastics play a vital role in both protecting the drug and the patient. Increasingly substances such as pigments and functional additives are used to enhance the properties of the polymer to, for example, help easy identification by colors, or improve release properties of closures, or protect the polymer during gamma sterilization. There are in addition new challenges such as the need to reduce packaging costs, and protect new generations of drugs from light and oxygen.
Whilst new polymer technologies are available, regulations become tougher, and these polymer modifications introduce the potential risk of extractables and leachables. The FDA has stated that anything added to the polymer should be considered a ‘contaminant’, and that impact of changes in the supply chain could invalidate historical test data. Even mis-understanding of pharmacopeia , and lack of understanding where risk can arrive, can impact yet the most basic white plastic bottle.
This paper will summarize the main elements of risk, and show how by managing these elements, where there are opportunities to address ‘technical challenges’ and perhaps be more creative in packaging design.
Neil Steinmeyer | Principal Scientist of Pfizer
To ensure patient safety, a comprehensive extractable and leachable program for biologics has been developed and implemented at Pfizer. The holistic approach uses both risk-based evaluation and testing strategies to systematically assess potential risks associated with all process stream contact materials and container closure systems (CCS). Process equipment risk factors include the proximity to the bulk drug substance or drug product, the extraction capability of the process stream, the product contact surface area, duration of contact, temperature, and the inherent resistance of the material to extraction. Extractable studies for higher risk components and CCS are used to identify potential target leachables for further study. An analytical evaluation threshold (AET) for each extractable study is determined to help with the selection of relevant potential leachable target compounds. The AET determination includes a safety concern threshold (SCT) and project-specific maximum daily dosing information. The SCT’s are based on Product Quality Research Institute (PQRI) recommendations proposed for parenteral drug products and accepted for orally inhaled and nasal drug products. Leachable testing is used to monitor for potential target compounds and to screen for unexpected leachables. Analytical methods are validated for volatile, semi-volatile, non-volatile, and elemental target leachables. Leachable studies are performed at labeled storage conditions over the shelf life of the product.
Xuejun Jay Liu | Senior Scientist of Johnson & Johnson
Johnson & Johnson Medical Devices segment produces a broad range of innovative products used primarily by health care professionals. In the area of surgery, the segment offers leading surgical technologies and solutions including sutures, meshes, staplers, energy devices, trocars, and hemostats. These diverse product lines involve wide ranges of materials and processes. Various analytical techniques and critical in-house expertise are required to evaluate extractables/leachables to support new product development and product life cycle management.
Packaging materials for permanently implantable medical devices include various components, such as folders, trays, lids, and labels, which are made from a wide range of materials (foil, polymeric materials, coated paper, etc.). The packaging materials are also exposed to different sterilization processes including high dose gamma irradiation. Extractables/leachables of medical device packaging materials are important factors to consider as they could impact efficacy and safety of the final devices.
The major analytical challenges for profiling the extractables from medical device packaging materials are how to identify and quantitate the extractable compounds in the extracts. Two case studies related to chemical evaluation of the aqueous extractables from suture packaging materials will be presented. The first example is an unprinted paper label. It is used on the outside and/or inside of various suture product packages. The second example is about a low density polyethylene (LDPE) foam that is used for “parking” suture needles. The packaging components were extracted using deuterated water (D2O) for ease of analysis by NMR directly. The complete analytical characterization of the extractable profiles using various analytical techniques including NMR, MS, and IR will be discussed.
Christopher Houston | Director of Analytical Chemistry of iuvo bioscience
- Looking at important and hot topics for the E&L community
- Summary of conference day 1 and looking forward to conference day 2
Dr. Piet Christiaens | Scientific Director of Toxikon
It is commonly known that halogenated rubber oligomers are a group of compounds which are often observed, both as extractables, in controlled extraction studies, as well as – in certain cases - as leachables in some drug products.
Although there is an ongoing debate upon the toxicity of this group of compounds, it is a fact that these compounds are alkylating agents with a high reactivity for certain functional groups. These interactions have been widely observed – forming adducts with components of the drug products (API, Peptides, proteins, excipients).
A second observation is that, when performing a controlled extraction study on rubbers with more aggressive solvents (like IPA, Hexane), a potentially longer list of UNKNOWNS is generated, both in GC/MS and LC/MS, of which the origin is not always very clear.
The question now arises: knowing and understanding the high reactivity of these halogenated rubber oligomers, would it be possible that a group of these reported unknowns could be linked to reaction products of the oligomers with other rubber ingredients, such as curing agents, activators, accelerators…
Toxikon is currently running an R&D programme to systematically allow the halo rubber oligomers – which are available at Toxikon – react with other rubber ingredients under the typical conditions of rubber curing. Initial results of this R&D programme will be shared with the audience.
Roger Pearson | President of Analytical Services of Aspen Research Corporation
Infusion devices for intended use with multiple drugs carried by multiple delivery solvents pose an interesting analytical problem as regards potential leachable compounds and elements. In many cases a device is dedicated to a single drug and delivery solvent. In those cases it is usually possible to find the set of analytical conditions that allow the drug product to be interrogated for leachables after the appropriate extractables assessments have been performed. This presentation will describe the steps taken to perform the initial extractables assessments and the following work that was done using the drug carrier simulants and finally the full drug package in the leachables study.
Aspen Research Corporation is a premier contract research organization that provides analytical services and materials R&D. Our ISO 17025 accreditation and GLP program enable the company to be at the forefront of extractable and leachable studies, food contact notification studies, method development and pre-clinical support studies. Aspen partners with food packaging, biotech, pharmaceutical and medical device industries to deliver the support that is needed for product development and regulatory submission.
Jonathan Bones | Principal Investigator of National Institute for Bioprocessing Research and Training (NIBRT)
Samuel Kikandi | Senior Scientist of Sanofi Pasteur
An E&L qualification case study of new label on plastic PFS. The presentation will encompass of the following studies: 1) Extractable studies of ink, label and adhesive; 2) Simulated In-use leachable study with labeled plastic PFS; 3) Leachable migration study from label into the plastic syringe.
Poster presenters will be stationed in the poster exhibition space during this break to answer any questions that you may have
See the full line up of posters: poster-sessions.shtml
Greg Erexson | Principal Occupational and Environmental Toxicologist of AbbVie
Dai Shen | Manufacturing Process and Productivity Improvement Lead of Shire
A lifecycle approach to risk management related to Leachables and Extractables in facilities and processes with significant investment in single use technology requires (1) determination of the cumulative risk using “right-sized” risk based approach, (2) ability to store, aggregate, and analyze large amount of single use component as well as extractable data, and (3) ability to continuously verify E/L control upon addition of new parts and/or vendor change notification. This case study will demonstrate how the BPOG methodology AND the capability of a validated analytics and database platform (Dell Statistica) were leveraged to create the infrastructure for such a lifecycle approach. A risk based approach, aligned with BPOG methodology was utilized in conjunction with the streamlined analytics workflow for powerful, rules-based analytics of Statistica to create an E/L study plan. Subsequently, leveraging BPOG extractable protocol enabled rapid development of Extractable study design as well as simplified the contract lab selection process. The validated repository as well as the streamlined auto aggregation, transformation, and deployment features of Statistica in turnwas critical to enabling feasibility of continuous verification.
Dr. Dennis Jenke | Baxter Distinguished Scientist of Baxter Healthcare
Doug Ball | Research Fellow in Drug Safety Evaluation of Pfizer
David Weil, Application Scientist, Agilent Technologies
As drug product formulations continue to move from small molecule (API’s) to Biologics, the complexity and the impact of potential extractable and leachable compounds on stability and safety continues to increase. Being able to detect E/L in these complex mixtures can be a challenge due to the presence of oligomeric solubilizing agents and heterogeneity of higher molecular weight biologics.
Extractable and leachable analysis routinely use GC/MS and LC/MS with various ionization methods (EI, APCI ESI, APCI, DESI, ASAP, etc.). For GCMS analysis many standard methods exist, with identification using commercially available EI libraries (NIST, Wiley). For LCMS analysis several challenges exist: 1) finding the best stationary phase and separation method (C3, C8, C18) (effect of buffers); 2) the complex nature of mass spectral data with series of multiply charged species and adducts, 3) variation in ionization efficiency (response factor) dependent on compound class sample preparation and type of ionization source and 4) Identification limited by lack of commercial MS and MS/MS database. To study the effect of many of these challenges, a complex mixture (> 200) commercially available additives, chemically induced degradation products and surfactants were analyzed using multiple ionization methods chromatographic conditions and concentration levels to determine the optimum conditions by sample classification. To enhance identification, a custom accurate mass MS/MS mass spectral database was developed using these experimental results as a function of collision energy in addition to precursor ion selection (adducts).
To test the automated analytical data mining workflow, exaggerated extractions were obtained from various components of a pMDI device. The diverse nature of an extractable leachable experiment in many cases requires the use of both GC/MS and LC/MS analysis methods. Herein we compare the experimental results obtained from both separations method in addition to various ionization methods (APPI, APCI, ESI) and polarity to determine the optimum conditions for determining various class of compounds being extracted from the model and real pharmaceutical construct components. In addition, statistical analysis software tools can also be used to determine the presence of low-level degradation components as a function of polymer class.
Kyle D'Silva | Pharma & Biopharma Vertical Marketing Manager of Thermo Fisher Scientific
E&L impurities span a range of chemical species; from volatile small molecules to polymer additives and even metals. These unknowns require an arsenal of analytical techniques to meet regulatory guidelines. Thermo Fisher Scientific are unique in offering comprehensive workflows for identification and quantification of extractable and leachable impurities.
Baiba Cabovska | Senior Applications Chemist of Waters
Extractable and leachable components, which are potentially harmful to human health, are of great concern to manufacturing industries, particularly manufacturers of food contact materials, pharmaceutical packaging and devices as well as cosmetics packaging. Globally, much legislation exists to try to mitigate exposure to these components, which results in a significant demand for rapid, accurate, and reliable analytical methodologies. One such method is targeted screening using LC-MS techniques. Typically, in identification of compounds, retention time, accurate mass, and fragmentation ion information is used. However, if different chromatographic methods are used, the retention times will vary. If the compound is present at trace levels, the fragments might be absent. In this work, we demonstrate how the inclusion of collisional cross section (CCS) values, acquired using ion mobility-mass spectrometry, can provide increased confidence in compound identification.
Collisional cross section is a key physicochemical property of compounds. The CCS depends on an ion’s size, shape and charge. For example, in the case of two ions with the same m/z but different shapes, the less compact, straight-chain species will have a longer drift time than the smaller, more compact species.