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Dennis Jenke - One of the best experts on this subject based on the ideXlab platform.
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the implications of chromatographically screening medical products for organic Leachables down to the aet adjusted for response factor variation
Pda Journal of Pharmaceutical Science and Technology, 2020Co-Authors: Dennis Jenke, Ted HeiseAbstract:A drug product is chromatographically screened for organic Leachables, derived from the product′s packaging system, as Leachables might adversely impact the health of a patient to whom the drug product is administered. Similarly, medical device and packaging system extracts are chromatographically screened for organic extractables as probable Leachables. To be protective of patient health, the screening methods must produce recognizable responses for all potentially unsafe substances. To be efficient, the screening methods should provide a means of differentiating between responses linked to likely to be safe and potentially unsafe substances. The analytical evaluation threshold (AET) was established as a means of differentiating chromatographic peaks, based on concentration, that are unlikely to be unsafe (and thus do not need safety assessment) and that are possibly unsafe (and thus require safety assessment). Thus, the AET manages the competing objectives of protection and efficiency. Although the AET is based on concentration, it is applied based on response. As no chromatographic detection method applied to E&L screening produces a uniform response to all potential analytes (thus, the response strength differs across analytes), the objectives of protection or efficiency can be compromised by false negatives and positives. To ensure protection, at the expense of efficiency, the AET can be adjusted to address response variation. This manuscript addresses the practical issue that the protectiveness of the AET is affected both by response factor bias and variation and thus correction for only variation is incomplete and ineffective. The manuscript illustrates the proper adjustment of the AET for bias and variation.
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identifying and mitigating errors in screening for organic extractables and Leachables part 1 introduction to errors in chromatographic screening for organic extractables and Leachables and discussion of the errors of omission
Pda Journal of Pharmaceutical Science and Technology, 2020Co-Authors: Piet Christiaens, Jeanmarie Beusen, Philippe Verlinde, Jan Baeten, Dennis JenkeAbstract:Substances leached from materials used in pharmaceutical manufacturing systems, packages, and/or medical devices can be administered to a patient as part of a clinical therapy. These Leachables can have an undesirable effect on the effectiveness of the therapy and/or patient safety. Thus, relevant samples such as material extracts or drug products are chromatographically screened for foreign organic impurities, where screening is the analytical process of discovering, identifying, and quantifying these unspecified foreign impurities. Although screening methods for organic extractables and Leachables have achieved a high degree of technical and practical sophistication, they are not without issues with respect to their ability to accomplish the aforementioned three functions. In this first part of a series of three manuscripts, the process of screening is examined, limitations in screening are identified, and the concept of using an internally developed analytical database to identify, mitigate, or correct these errors is introduced. Furthermore, errors of omission are described, where an error of omission occurs when a screening method fails to produce a recognizable response to an analyte present in the test sample. The error may be that no response is produced (“falling through the cracks”) or that a produced response is not recognizable (“failing to see the tree for the forest”). In either case, proper use of a robust internal extractables/Leachables database can decrease the frequency with which errors of omission occur. Examples of omission errors, their causes, and their possible resolution are discussed.
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identifying and mitigating errors in screening for organic extractables and Leachables part 2 errors of inexact identification and inaccurate quantitation
Pda Journal of Pharmaceutical Science and Technology, 2020Co-Authors: Piet Christiaens, Jeanmarie Beusen, Philippe Verlinde, Jan Baeten, Dennis JenkeAbstract:Patients can be exposed to Leachables derived from pharmaceutical manufacturing systems, packages and /or medical devices during a clinical therapy. These Leachables can adversely decrease the therapy′s effectiveness and/or adversely impact patient safety. Thus, extracts or drug products are chromatographically screened to discover, identify and quantify organic extractables or Leachables. Although screening methods have achieved a high degree of technical and practical sophistication, they are not without issues in terms of accomplishing these three functions. In this Part 2 of our three-part series, errors of inexact identification and inaccurate quantitation are addressed. An error of inexact identification occurs when a screening method fails to produce an analyte response that can be used to secure the analyte′s identity. The error may be that the response contains insufficient information to interpret, in which case the analyte cannot be identified or that the interpretation of the response produces an incorrect identity. In either case, proper use of an internal extractables - Leachables data database can decrease the frequency of encountering unidentifiable analytes and increase the confidence that identities that are secured are correct. Cases of identification errors are provided, illustrating the use of multi-dimensional analysis to increase confidence in procured identities. An error of inaccurate quantitation occurs when an analyte′s concentration is estimated by correlating the responses of the analyte and an internal standard and arises due to response differences between analytes and internal standards. The use of a database containing relative response factors or relative response functions to secure more accurate analyte quantities is discussed and demonstrated.
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identification analysis and safety assessment of Leachables and extractables
Trends in Analytical Chemistry, 2017Co-Authors: Dennis JenkeAbstract:Abstract Pharmaceutical drug products (DP) can contain foreign impurities due to contact with manufacturing, storage, distribution and administration systems. These foreign impurities (Leachables) are leached from these systems by the drug product and can be linked to extractables measured in the systems during laboratory investigations. Assessing the impact of Leachables on the suitability of the DP requires that it be screened to discover, identify and quantify Leachables. Given the large number and great chemical diversity of potential Leachables, an analytical strategy involving multiple, orthogonal analytical methods is necessary to generate a complete Leachables profile. Once the profile has been delineated, the effect of Leachables on the DP's suitability can be established. The potential adverse effect of Leachables on patient safety can be established via chemical safety risk assessment, which involves comparing a DP user's (patient) exposure to individual Leachables with exposure thresholds which are toxicologically established for the individual Leachables.
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moving forward towards standardized analytical methods for extractables and Leachables profiling studies
Pda Journal of Pharmaceutical Science and Technology, 2015Co-Authors: Dennis JenkeAbstract:This commentary considers the standardization of analytical methods used in extractables and Leachables screening and proposes that method standardization is not the end goal but rather the necessary first step for enabling efficient, effective, robust, and consistent extractables and Leachables profiling. Standardized methods are the platform upon which a knowledge set and a knowledge management process can be built, and it is the combination of the methods, the set, and the process that facilitates extractables and Leachables profiling.
Nicole Scherer - One of the best experts on this subject based on the ideXlab platform.
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new studies on Leachables in commercial scale protein drug filling lines using stir bar sorptive extraction coupled with td gc ms and uplc qtof ms ms analytics
International Journal of Pharmaceutics, 2019Co-Authors: Nicole Scherer, Klaudia Marcsekova, Tobias Posset, Gerhard WinterAbstract:Abstract The increasing application of Single-Use Systems (SUSs) in pharmaceutical manufacturing lines poses a potential risk of polymer-related impurities leaching into the process stream and persisting through the manufacturing process. To minimize any potential toxicity and impairment to the product’s quality, safety thresholds are strictly regulated and enforced in particular for parenteral solutions. At present, impurities are estimated from extractable profiles, which are generated for each SUS with thermal or static extraction. In this study we employed target leachable-testing by taking samples directly from an industrial filling line probed during real-life processing of three parenteral drugs (n = 2) under actual process-conditions, to estimate the concentration of Leachables throughout drug-manufacturing. At five different points, samples were drawn to study the individual impact of SUSs on the leachable accumulation within the drug-filling process. The drug products were examined for Leachables using stir-bar-sorptive-extraction (SBSE) with polydimethylsiloxane (PDMS) and ethylene glycol (EG)-PDMS coated stir-bars. Subsequent extraction from the stir-bars and analysis of the substances was performed with TD-GC–MS and solvent-back-extraction (SBE)-UPLC/QTOF-MS/MS analytics. Our study revealed the following main results: 1) Leachables were found in extremely low concentrations, all below toxicological thresholds (highest leachable concentration in the final drug product 1 (DP1): 0.274 ppm
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evaluation of stir bar sorptive extraction coupled with thermal desorption gc ms for the detection of Leachables from polymer single use systems to drugs
Journal of Pharmaceutical and Biomedical Analysis, 2018Co-Authors: Nicole Scherer, Klaudia Marcsekova, Tobias Posset, Gerhard WinterAbstract:Abstract Stir-bar Sorptive Extraction (SBSE) in combination with thermal desorption and gas chromatography-mass spectrometry (TD-GC–MS) is widely accepted as the gold–standard analysis method for trace amounts of organic substances, including Leachables in aqueous matrices. Meanwhile, as far as pharmaceutical quality control in protein-based parenteral drugs is concerned, the use of SBSE analysis remains unexplored. Previous studies reported a strong influence of the matrix on the method’s recovery. The scope of the present work was to fill in the unexplored territory in a threefold manner 1) by quantifying the effects that various matrices commonly found in pharmaceutical processing have on the recovery, 2) by comparing between different coating materials for stir bar (namely between polydimethylsiloxane (PDMS) material and ethylene-glycol (EG)-PDMS), and 3) by proposing a preparation step for stir-bar to mitigate inhibitory effects. The current study shows no inhibition of SBSE by protein matrices (p > 0.15). Further the influence of various drug matrices on the recovery of Leachables with a log Ko/w ≥ 3.6 is negligible (−3.9 to 3.8%). In contrast, the inhibition effect caused by an alkaline media led to a recovery decrease of −42.9%. For Leachables with a log Ko/w 0.992). On average, the conventional PDMS coating resulted in a 28-fold higher signal-to-noise ratio compared to EG-PDMS. Furthermore, a broader range of Leachables was detectable with the PDSM coating. Preceding stir-bar preparation consisting of a simple soaking step improved the enrichment by 14%, effectively lowering the limit of detection.
Gerhard Winter - One of the best experts on this subject based on the ideXlab platform.
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new studies on Leachables in commercial scale protein drug filling lines using stir bar sorptive extraction coupled with td gc ms and uplc qtof ms ms analytics
International Journal of Pharmaceutics, 2019Co-Authors: Nicole Scherer, Klaudia Marcsekova, Tobias Posset, Gerhard WinterAbstract:Abstract The increasing application of Single-Use Systems (SUSs) in pharmaceutical manufacturing lines poses a potential risk of polymer-related impurities leaching into the process stream and persisting through the manufacturing process. To minimize any potential toxicity and impairment to the product’s quality, safety thresholds are strictly regulated and enforced in particular for parenteral solutions. At present, impurities are estimated from extractable profiles, which are generated for each SUS with thermal or static extraction. In this study we employed target leachable-testing by taking samples directly from an industrial filling line probed during real-life processing of three parenteral drugs (n = 2) under actual process-conditions, to estimate the concentration of Leachables throughout drug-manufacturing. At five different points, samples were drawn to study the individual impact of SUSs on the leachable accumulation within the drug-filling process. The drug products were examined for Leachables using stir-bar-sorptive-extraction (SBSE) with polydimethylsiloxane (PDMS) and ethylene glycol (EG)-PDMS coated stir-bars. Subsequent extraction from the stir-bars and analysis of the substances was performed with TD-GC–MS and solvent-back-extraction (SBE)-UPLC/QTOF-MS/MS analytics. Our study revealed the following main results: 1) Leachables were found in extremely low concentrations, all below toxicological thresholds (highest leachable concentration in the final drug product 1 (DP1): 0.274 ppm
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evaluation of stir bar sorptive extraction coupled with thermal desorption gc ms for the detection of Leachables from polymer single use systems to drugs
Journal of Pharmaceutical and Biomedical Analysis, 2018Co-Authors: Nicole Scherer, Klaudia Marcsekova, Tobias Posset, Gerhard WinterAbstract:Abstract Stir-bar Sorptive Extraction (SBSE) in combination with thermal desorption and gas chromatography-mass spectrometry (TD-GC–MS) is widely accepted as the gold–standard analysis method for trace amounts of organic substances, including Leachables in aqueous matrices. Meanwhile, as far as pharmaceutical quality control in protein-based parenteral drugs is concerned, the use of SBSE analysis remains unexplored. Previous studies reported a strong influence of the matrix on the method’s recovery. The scope of the present work was to fill in the unexplored territory in a threefold manner 1) by quantifying the effects that various matrices commonly found in pharmaceutical processing have on the recovery, 2) by comparing between different coating materials for stir bar (namely between polydimethylsiloxane (PDMS) material and ethylene-glycol (EG)-PDMS), and 3) by proposing a preparation step for stir-bar to mitigate inhibitory effects. The current study shows no inhibition of SBSE by protein matrices (p > 0.15). Further the influence of various drug matrices on the recovery of Leachables with a log Ko/w ≥ 3.6 is negligible (−3.9 to 3.8%). In contrast, the inhibition effect caused by an alkaline media led to a recovery decrease of −42.9%. For Leachables with a log Ko/w 0.992). On average, the conventional PDMS coating resulted in a 28-fold higher signal-to-noise ratio compared to EG-PDMS. Furthermore, a broader range of Leachables was detectable with the PDSM coating. Preceding stir-bar preparation consisting of a simple soaking step improved the enrichment by 14%, effectively lowering the limit of detection.
Qiaozhen Guo - One of the best experts on this subject based on the ideXlab platform.
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detection and identification of Leachables in vaccine from plastic packaging materials using uplc qtof ms with self built polymer additives library
Analytical Chemistry, 2016Co-Authors: Yun Zhang, Shuqi Sun, Xuebin Xing, Zhenxia Du, Qiaozhen Guo, Wenlian YuAbstract:The direct contact of plastic parts with the medical products raises the possibility that plastic-related contaminants (Leachables) may be present in the finished medical product. The leachable components from plastic materials may impact the safety and efficacy of the final medical product, so identification and determination of the Leachables are essential for the safety assessment of medical products. A method to identify main Leachables-polymer additives in medical products was developed by ultraperformance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF MS) and a self-built library. The library contains 174 additives and the information on their names, formulas, structures, retention times, fragments, classifications, origin, and corresponding MSE and MSMS spectra. The reliability of the construction process of the library was guaranteed by the system stability and suitability test. Identification parameters of library application, such as mass error, retention times, fra...
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detection and identification of Leachables in vaccine from plastic packaging materials using uplc qtof ms with self built polymer additives library
Analytical Chemistry, 2016Co-Authors: Yun Zhang, Shuqi Sun, Xuebin Xing, Qiaozhen GuoAbstract:The direct contact of plastic parts with the medical products raises the possibility that plastic-related contaminants (Leachables) may be present in the finished medical product. The leachable components from plastic materials may impact the safety and efficacy of the final medical product, so identification and determination of the Leachables are essential for the safety assessment of medical products. A method to identify main Leachables-polymer additives in medical products was developed by ultraperformance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF MS) and a self-built library. The library contains 174 additives and the information on their names, formulas, structures, retention times, fragments, classifications, origin, and corresponding MS(E) and MSMS spectra. The reliability of the construction process of the library was guaranteed by the system stability and suitability test. Identification parameters of library application, such as mass error, retention times, fragments, and isotope pattern, were evaluated. Leachables in real vaccine and the intermediates were identified using automatic library searching. In vaccine, the peak m/z 239.0887 that could not be assigned by the library was identified as dimethyl 2-hydroxy-1,3-cyclohexanedicarboxylate using a series of elucidation tools. As a result, the concentrations of Leachables in vaccine and the intermediates ranged from 0.85 to 21.91 μg/L.
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Detection and Identification of Leachables in Vaccine from Plastic Packaging Materials Using UPLC-QTOF MS with Self-Built Polymer Additives Library
2016Co-Authors: Yun Zhang, Shuqi Sun, Xuebin Xing, Qiaozhen GuoAbstract:The direct contact of plastic parts with the medical products raises the possibility that plastic-related contaminants (Leachables) may be present in the finished medical product. The leachable components from plastic materials may impact the safety and efficacy of the final medical product, so identification and determination of the Leachables are essential for the safety assessment of medical products. A method to identify main Leachables-polymer additives in medical products was developed by ultraperformance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF MS) and a self-built library. The library contains 174 additives and the information on their names, formulas, structures, retention times, fragments, classifications, origin, and corresponding MSE and MSMS spectra. The reliability of the construction process of the library was guaranteed by the system stability and suitability test. Identification parameters of library application, such as mass error, retention times, fragments, and isotope pattern, were evaluated. Leachables in real vaccine and the intermediates were identified using automatic library searching. In vaccine, the peak m/z 239.0887 that could not be assigned by the library was identified as dimethyl 2-hydroxy-1,3-cyclohexanedicarboxylate using a series of elucidation tools. As a result, the concentrations of Leachables in vaccine and the intermediates ranged from 0.85 to 21.91 μg/L
Lee M Nagao - One of the best experts on this subject based on the ideXlab platform.
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assessing safety of extractables from materials and Leachables in pharmaceuticals and biologics current challenges and approaches
Regulatory Toxicology and Pharmacology, 2016Co-Authors: Thomas H Broschard, Lee M Nagao, Cheryl L M Stults, Susanne Glowienke, Uma S Bruen, Andrew Teasdale, Laurie Iciek, Greg Erexson, Elizabeth A Martin, Douglas J. BallAbstract:Abstract Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential Leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and Leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of Leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or Leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or “guidelines.”
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inhalation drug products for safety thresholds and best practices recommendations perspectives on the pqri extractables and Leachables
2016Co-Authors: Daniel L. Norwood, Lee M Nagao, Cheryl L M StultsAbstract:In 2006, the Product Quality Research Institute’s (PQRI) Leachables and Extractables Working Group released a comprehensive and detailed recommendation document related to Leachables and extractables for inhalation drug products. The document includes best pharmaceutical development practice recommendations regarding container closure/delivery system component composition and selection, controlled extraction studies, drug product Leachables studies, and routine extractables testing for component release. Also included in the document are two safety-based thresholds for Leachables in inhalation drug products, the qualification threshold (QT) and the safety concern threshold (SCT), the first such safety-based thresholds for Leachables in any drug product type. A process was described for converting the SCT into an analytically useful threshold for Leachables/extractables characterization, the analytical evaluation threshold (AET), with consideration of individual drug product dosing parameters and container closure system component characteristics. This commentary presents the history and evolution of this recommendation document starting from the propellant changeover (chlorofluorocarbons to hydrofluorocarbons) in metered dose inhaler drug products, which helped prompt interest in inhalation drug product Leachables, through the work process of the PQRI group. The overall positive acceptance of the PQRI recommendations is discussed, along with a brief summary of regulatory initiatives influenced by the recommendations. Also presented and discussed are certain key issues and questions that have arisen since the recommendation document was released. The extension and application of best practice recommendations to other high risk drug product types (e.g., large and small volume parenterals, ophthalmics), led by the PQRI Parenteral and Ophthalmic Drug Product Working Group, is introduced and considered.
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a risk based approach to management of Leachables utilizing statistical analysis of extractables
Aaps Pharmscitech, 2015Co-Authors: Cheryl L M Stults, Jaromir Mikl, Oliver Whelehan, Bradley D Morrical, William Duffield, Lee M NagaoAbstract:To incorporate quality by design concepts into the management of Leachables, an emphasis is often put on understanding the extractable profile for the materials of construction for manufacturing disposables, container-closure, or delivery systems. Component manufacturing processes may also impact the extractable profile. An approach was developed to (1) identify critical components that may be sources of Leachables, (2) enable an understanding of manufacturing process factors that affect extractable profiles, (3) determine if quantitative models can be developed that predict the effect of those key factors, and (4) evaluate the practical impact of the key factors on the product. A risk evaluation for an inhalation product identified injection molding as a key process. Designed experiments were performed to evaluate the impact of molding process parameters on the extractable profile from an ABS inhaler component. Statistical analysis of the resulting GC chromatographic profiles identified processing factors that were correlated with peak levels in the extractable profiles. The combination of statistically significant molding process parameters was different for different types of extractable compounds. ANOVA models were used to obtain optimal process settings and predict extractable levels for a selected number of compounds. The proposed paradigm may be applied to evaluate the impact of material composition and processing parameters on extractable profiles and utilized to manage product Leachables early in the development process and throughout the product lifecycle.
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perspectives on the pqri extractables and Leachables safety thresholds and best practices recommendations for inhalation drug products
Pda Journal of Pharmaceutical Science and Technology, 2013Co-Authors: Daniel L. Norwood, Lee M Nagao, Cheryl L M StultsAbstract:In 2006, the Product Quality Research Institute9s (PQRI) Leachables and Extractables Working Group released a comprehensive and detailed recommendation document related to Leachables and extractables for inhalation drug products. The document includes best pharmaceutical development practice recommendations regarding container closure/delivery system component composition and selection, controlled extraction studies, drug product Leachables studies, and routine extractables testing for component release. Also included in the document are two safety-based thresholds for Leachables in inhalation drug products, the qualification threshold (QT) and the safety concern threshold (SCT), the first such safety-based thresholds for Leachables in any drug product type. A process was described for converting the SCT into an analytically useful threshold for Leachables/extractables characterization, the analytical evaluation threshold (AET), with consideration of individual drug product dosing parameters and container closure system component characteristics. This commentary presents the history and evolution of this recommendation document starting from the propellant changeover (chlorofluorocarbons to hydrofluorocarbons) in metered dose inhaler drug products, which helped prompt interest in inhalation drug product Leachables, through the work process of the PQRI group. The overall positive acceptance of the PQRI recommendations is discussed, along with a brief summary of regulatory initiatives influenced by the recommendations. Also presented and discussed are certain key issues and questions that have arisen since the recommendation document was released. The extension and application of best practice recommendations to other high risk drug product types (e.g., large and small volume parenterals, ophthalmics), led by the PQRI Parenteral and Ophthalmic Drug Product Working Group, is introduced and considered. LAY ABSTRACT: The recommendation document released by the Product Quality Research Institute9s (PQRI) Leachables and Extractables Working Group in 2006 includes the first safety-based thresholds for Leachables in any drug product type, along with comprehensive best practice recommendations for inhalation drug product pharmaceutical development related to extractables and Leachables. The best practice recommendations encompass a number of important functional areas, including container closure/delivery system component composition and selection, controlled extraction studies, drug product Leachables studies, and routine extractables testing for component release. This commentary presents the history and evolution of this recommendation document starting from the propellant changeover (chlorofluorocarbons to hydrofluorocarbons) in metered dose inhaler drug products, which helped prompt interest in inhalation drug product Leachables, through the work process of the PQRI group. The overall positive acceptance of the PQRI recommendations is discussed, along with a brief summary of regulatory initiatives influenced by the recommendations. Also presented and discussed are certain key issues and questions that have arisen since the recommendation document was released. The extension and application of best practice recommendations to other drug product types (e.g., large- and small-volume parenterals, ophthalmics), led by the PQRI Parenteral and Ophthalmic Drug Product Working Group, is introduced and considered.
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development of safety qualification thresholds and their use in orally inhaled and nasal drug product evaluation
Toxicological Sciences, 2007Co-Authors: Douglas J. Ball, Daniel L. Norwood, James Blanchard, David Jacobsonkram, Roger O Mcclellan, Timothy Mcgovern, Wmark Vogel, Ron Wolff, Lee M NagaoAbstract:Safety thresholds for chemical impurities and Leachables in consumer products such as foods and drugs have helped to ensure public health while establishing scientifically sound limits for identification and risk assessment of these compounds. The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group, a collaboration of chemists and toxicologists from the U.S. Food and Drug Administration (FDA), industry, and academia, has developed safety thresholds for Leachables and extractables in orally inhaled and nasal drug products (OINDP), for application in United States pharmaceutical submissions. The PQRI safety concern threshold (SCT) is 0.15 μg/day, and the qualification threshold is 5 μg/day. OINDP are important in the treatment of lung diseases such as asthma and chronic bronchitis, as well as systemic diseases such as diabetes. Analysis of extractables and minimization of Leachables in OINDP are vital to ensuring the quality and safety of the final product. It is expected that the thresholds developed by the PQRI Leachables and Extractables Working Group will be used by both industry and regulators to ensure and assess such quality and safety in OINDP applications. In this article, we describe the importance of the PQRI safety thresholds in the OINDP pharmaceutical development process; the background and context of safety thresholds for consumer products; how these safety thresholds were developed using well-established, robust databases and quantitative risk assessment approaches; and how these thresholds can be applied in a pharmaceutical safety qualification process, including FDA regulatory perspectives on the use of safety thresholds for OINDP.