Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening.

Plastic components are essential in the pharmaceutical industry, encompassing container closure systems, laboratory handling equipment, and single-use systems. As part of their material qualification process, studies on interactions between plastic contact materials and process solutions or drug products are conducted. The assessment of single-use systems includes their potential impact on patient safety, product quality, and process performance. This is particularly crucial in cell and gene therapy applications since interactions with the plastic contact material may result in an adverse effect on the isolated therapeutic human cells. We utilized the cell painting assay (CPA), a non-targeted method, for profiling the morphological characteristics of U2OS human osteosarcoma cells in contact with chemicals related to plastic contact materials. Specifically, we conducted a comprehensive analysis of 45 common plastic extractables, and two extracts from single-use systems. Results of the CPA are compared with a standard cytotoxicity assay, an osteogenesis differentiation assay, and in silico toxicity predictions. The findings of this feasibility study demonstrate that the device extracts and most of the tested compounds do not evoke any measurable biological changes on the cells (induction ≤ 5%) among the 579 cell features measured at concentrations ≤ 50 µM. CPA can serve as an important assay to reveal unique information not accessible through quantitative structure-activity relationship analysis and vice versa. The results highlight the need for a combination of in vitro and in silico methods in a comprehensive assessment of single-use equipment utilized in advanced therapy medicinal products manufacturing.

Impurity assessment, development and validation of an RP-HPLC method for the determination of eleven potential impurities of eltrombopag precursor.

Eltrombopag is an oral non-peptide thrombopoietin receptor (TPO-R) agonist indicated for the treatment of thrombocytopenia in patients with persistent or chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura, ITP) or chronic hepatitis C infection and the treatment of severe aplastic anemia. The purpose of this research was to assess the possible impurities that may carry over to eltrombopag from its precursor Eltro-1 (3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid) and to develop a specific analytical method for the determination of these impurities. Eltro-1 samples synthesized by two different synthesis routes were investigated during the evaluation and method development studies. Besides the expected process-related impurities (Eltro-1A - Eltro-1J), e.g., starting materials, intermediates, and/or compounds formed from their further reactions, an unknown impurity detected above 0.10% was identified by LC-MS, synthesized and fully characterized by NMR, MS and FTIR (Eltro-1K). Accordingly, an HPLC-RP method for the determination of eleven impurities (Eltro-1A - Eltro-1K) in Eltro-1 was developed and validated according to ICH Q2. The control limits for impurities in Eltro-1 were set at ≤ 0.15% for Eltro-1A - Eltro-1J and ≤ 1.0% for Eltro-1K based on fate, spike-purge and carryover studies and in accordance with the ICH M7 classification for impurities in drug substance. Eltro-1 and eleven impurities at the specification limit were separated from each other and the diluent peaks with sufficient resolution without interference. Separation was performed on a Waters XBridge C18 column (150 × 4.6 mm, 3.5 µm) at 40 °C with a 10 µL injection volume at a detection wavelength of 220 nm and 15 °C sample temperature. The gradient elution is performed at a flow rate of 1.0 mL/min for 40 min with mobile phase A (0.1% orthophosphoric acid in water) and B (acetonitrile) according to the following program: Time (min) / Acetonitrile (%): 0/0, 35/70, 36/0, 40/0. Test and standard solutions were prepared at a concentration of 1.0 mg/mL and 1.0 µg/mL, respectively, using a mixture of mobile phase A and acetonitrile (75/25) as diluent. This is the first specific, selective, sensitive, linear, precise, accurate, and robust HPLC method for the determination of Eltro-1A - Eltro-1K in Eltro-1, which showed no significant degradation under thermal stress, photostability (UV and VIS), and standard accelerated and long-term stability conditions.

How to Evaluate If Microorganisms Isolated From Sterile Drug Production Environments Monitoring Are Undesirable.

This study addresses the identification of undesirable microorganisms (MOs) recovered during the environmental monitoring in manufacture of sterile medicinal products. We developed a methodology evaluation based on a decision tree; then, such approach was applied to hypothetical scenarios of uncommon MOs isolation in sterile drugs production settings. The scenarios were formulated on the basis of our field experience, in terms of both MOs selection and types of sampling site. The MOs were chosen in order to include emerging pathogens and MOs responsible for drug recall, and several sampling sites were considered for their detection (air, surfaces, and personnel). The classification of the unusual MOs revealed that most of them were undesirable, because they represented the loss of environmental control or a potential impact on the quality of the product. In some cases, the uncommon MOs were not considered as undesirable. Therefore, our results demonstrated the importance of a methodology, also in terms of recovery rate of unusual MOs and of the threshold probability for the unacceptability (e.g., 1% or 5%). The proposed methodology allowed an easy and documented evaluation for the undesirable MOs isolated from the environment of the analyzed settings for sterile drugs production.

Paraffin waxes in the North-Western Mediterranean Sea: A comprehensive assessment in the Pelagos Sanctuary, a Specially Protected Area of Mediterranean Importance.

Paraffin waxes are widely recognized as emerging marine pollutants, even their classification by the recent monitoring programs and the knowledge of their occurrence, and sources of contamination in marine ecosystems are poorly defined and reported. Wax presence and distribution have been evaluated in different environmental compartments in the Pelagos Sanctuary (Mediterranean Sea) floating on the sea surface and stranded on beaches, focussing on their characterization, accumulation areas and pollution inputs. More than 2500 yellow paraffin residues were detected and analysed in the study area showing a prevailing dimension smaller than 5 mm. The Genoa Canyon and the waters facing Gorgona Island resulted in the more polluted areas representing two distinct hotspots of wax accumulation potentially related to the high density of tanker vessels sailing to and from the harbour of Genova and Livorno. Higher concentrations of beached particles were found along the Tuscan coast (11 items/100 m) and on Pianosa Island (110 items/m2). This study gives valuable insights into paraffin wax pollution in the Pelagos Sanctuary, emphasizing the need for harmonized monitoring and detection methods to elucidate the potential impacts on marine organisms. Moreover, mitigating actions are crucial to prevent and curb the waxes pollution of marine ecosystems.

Evaluation of a Novel LC-MS/MS Based Analytical Method for the Risk Assessment of Nitrosamines in Pharmaceutical Products and Packaging Materials.

The detection of nitrosamine impurities, particularly small dialkyl types, which are frequently known to be potent mutagenic carcinogens, in some Sartan group active pharmaceutical ingredients (APIs) and finished drug products caused global regulatory organizations to have concerns. Accordingly, Registration Holders/Applicants, API manufacturers, and their raw material suppliers are required to check the presence of nitrosamines in their products and carry out risk assessments using the quality risk management principles specified in the ICH Q9 guide. In this context, a new LC-MS/MS method has been developed and validated for the simultaneous determination of NDMA, NDEA, NMBA, NDIPA, NEIPA, NDBA, and MeNP nitrosamine compounds in API and finished products as well as in primary packaging materials, one of the risk sources. This validated method was applied to check the nitrosamine content may occur from canister, blister, printed aluminum foil, nasal spray, and eye drop packaging materials as part of the Extractables & Leachables studies arising from interactions between the product and the primary packaging. For the determination and quality control of nitrosamines in sartan group pharmaceutical products and packaging materials, the developed LC-MS/MS analytical method offers highly reliable, fast, high accuracy, good sensitivity and simultaneous detection even at low concentrations.

Nutritional and Microbial Quality of teff Grain as Influenced by Economically Motivated Adulteration Along the Supply Chain.

Teff is a gluten-free cereal crop widely cultivated in Ethiopia and is a critical ingredient in making injera, a unique flatbread. However, there is a significant issue with adulteration of teff, impacting its safety and quality. This study evaluated economically-driven adulteration effects on teff grains' nutritional and microbial quality. A preliminary survey revealed that it is a common practice to adulterate teff grains with inexpensive and inedible materials throughout the supply chain in the study area. One hundred and thirty teff grain samples were collected from producers, collectors, whole-sellers, and retailers in the cities of Tulu bolo and Jimma to determine the types and extents of adulterants present and their effect on the nutritional and microbial quality of the grains. They were mixed separately to create composite samples representing different supply chain actors. Standard protocols were used to evaluate nutritional and microbial quality. The results showed significant differences among the supply chain actors regarding identified adulterants, nutritional content, and microbial quality. The study identified chaff, soil + sand, and dukkaa (a combination of nonedible substances separated from teff grains in milling houses and warehouses) as the significant adulterants, with mean ranges of 1.17-8.07%, 1.29-7.23%, and 8.93-37.13% respectively. The study also evaluated the proximate composition and microbial load of the teff samples collected from different supply chain actors. The ranges of values for moisture, protein, fat, ash, fiber, carbohydrate, and energy were 8.33-10.53%, 6.49-9.42%, 2.29-3.86%, 2.33-6.39%, 2.42-3.95%, 70.9-73.76%, and 333.52-361.9 kcal, respectively. The microbial load showed ranges of 6.92-7.98, 3.17-3.22, 1.78-2.04, 6.73-7.89, and 6.88-7.93 log CFU/g for Total Plate Count, Escherichia coli, Salmonella, mold, and yeast, respectively. The results showed an increase in teff adulteration from producers to Jimma retailers, indicating multiple-stage adulteration throughout the supply chain, posing a threat to product safety and quality. The study recommends good coordination among the bodies responsible for food safety, producers, and consumers to mitigate this issue effectively.

An authentic assessment method for cordyceps sinensis.

Cordyceps Sinensis, renowned for its diverse pharmacological properties and the rarity of its natural species, faces significant challenges due to rampant adulteration by counterfeit products. Consequently, there is a crucial need to reliably identify Cordyceps species to ensure their quality and efficacy. While current analytical techniques predominantly rely on LC-MS, there remains a notable deficiency and substantial demand for the development of a unified, reproducible, and fast method suitable for commercial applications. In this study, we employed a cost-effective and straightforward approach utilizing headspace GC-MS to authenticate Cordyceps sinensis. This method enables the comprehensive analysis of the chemical profile, facilitating the identification of quality and authenticity in Cordyceps samples. Through a comparative analysis of the chemical profiles of seven authentic Cordyceps samples with seven other Cordyceps samples, we propose a Quality Assessment System for Authentic Cordyceps, encompassing the following criteria: 1) the presence of 29 compounds commonly found in authentic Cordyceps within the chemical profile, and 2) the area ratio of 3-methylbutanal to 2-methylbutanal falling within the range of 2.09-3.01. This method exhibits considerable promise as a standardized, reproducible, and expeditious technique for the quality assessment and authentication of Cordyceps.

The operational and financial impact of adding anaerobic screening of platelets.

BACKGROUND AND OBJECTIVES: We evaluated the operational and safety impact of implementing anaerobic culture screening of apheresis and pooled platelets at the American Red Cross on the already established use of the aerobic culture screening of each donation performed no sooner than 24 h following collection. MATERIALS AND METHODS: Platelets were screened for bacterial contamination with the BACT/ALERT 3D® (bioMérieux, Durham, NC) microbial detection testing system. The addition of anaerobic culture to the already existing aerobic culture resulted in sampling an additional 8-10 mL from each donation. RESULTS: Implementation of anaerobic testing resulted in an approximate 3.5-fold increased rate of False Positive BACT/ALERT alarms. There was a modest increase in the rate of True Positive alarms of 1.4-fold with increased detection of Klebsiella and Propionibacterium species, including Cutibacterium acnes. In addition, there was an approximate 3.5-fold increase rate of False Positives and a 13.5-fold increase rate of Indeterminates, the majority (~57%) were due to Cutibacterium acnes. The combined costs and lost revenue associated with adding anaerobic screening increased by ~$1,000,000/year due to testing cost and product discards. CONCLUSION: The addition of anaerobic culture to aerobic culture to the original donation (without the introduction of sampling delay) resulted in a significant increase in the rate of alerts. The 40% increased rate of True Positive alarms may have modestly improved platelet safety. However, there was a disproportionate increase in the rate of False Positive and Indeterminate bacterial culture alarms, which added substantial cost and overall loss of platelet products.

A critical application of different methods for the vulnerability assessment of shallow aquifers in Zhengzhou City.

Groundwater vulnerability can partially reflect the possibility of groundwater contamination, which is crucial for ensuring human health and a good ecological environment. The current study seeks to assess the groundwater vulnerability of Zhengzhou City by adopting an amended version of the traditional DRASTIC model, i.e., the DRASTICL model, which incorporates land use type indicators. More specifically, the AHP-DRASTICL, entropy-DRASTICL, and AE-DRASTICL models were established by optimizing weights using the analytic hierarchy process (AHP) and entropy weight method. The evaluation results for these five models were divided into five levels: very low, low, medium, high, and very high. Using Spearman's rank correlation coefficient, the nitrate concentration was used to verify the groundwater vulnerability assessment results. The AE-DRASTICL model was found to perform the best, with a Spearman correlation coefficient of 0.78. However, the AHP and entropy weight method effectively improved the accuracy of vulnerability assessment results, making it more suitable for the study area. This study provides important insights to inform the design of strategies to protect groundwater in Zhengzhou.

An update on formaldehyde adulteration in food: sources, detection, mechanisms, and risk assessment.

Formaldehyde is added illegally to food to extend its shelf life due to its antiseptic and preservation properties. Several research has been conducted to examine the consequences of adulteration with formaldehyde in food items. These findings suggest that adding formaldehyde to food is considered harmful as it accumulates in the body with long-term consumption. In this review includes study findings on food adulteration with formaldehyde and their assessment of food safety based on the analytical method applied to various geographical regions, food matrix types, and their sources in food items. Additionally, this review sought to assess the risk of formaldehyde-tainted food and the understanding of its development in food and its impacts on food safety in light of the widespread formaldehyde adulteration. Finally, the study would be useful as a manual for implementing adequate and successful risk assessment to increase food safety.

Immunogenicity risk assessment of synthetic peptide drugs and their impurities.

Peptide drugs play an important part in medicine owing to their many therapeutic applications. Of the 80 peptide drugs approved for use in humans, at least five are now off-patent and are consequently being developed as generic alternatives to the originator products. To accelerate access to generic products, the FDA has proposed new regulatory pathways that do not require direct comparisons of generics to originators in clinical trials. The 'Abbreviated New Drug Application' (ANDA) pathway recommends that sponsors provide information on any new impurities in the generic drug, compared with the originator product, because the impurities can have potential to elicit unwanted immune responses owing to the introduction of T-cell epitopes. This review describes how peptide drug impurities can elicit unexpected immunogenicity and describes a framework for performing immunogenicity risk assessment of all types of bioactive peptide products. Although this report primarily focuses on generic peptides and their impurities, the approach might also be of interest for developers of novel peptide drugs who are preparing their products for an initial regulatory review.

Controlling cleaning agent residues in pharmaceutical manufacturing: A harmonized scientific strategy.

This paper proposes a scientifically justified and harmonized strategy to control cleaning agent ingredients' (CAIs) residues in pharmaceutical manufacturing. Firstly, we demonstrate that worst-case cleaning validation calculations on CAI residues with representative GMP standard cleaning limits (SCLs) are enough to control CAI residues of low concern to safe levels. Secondly, a new harmonized strategy for the toxicological assessment of CAI residues is presented and validated. The results establish a framework applicable to cleaning agent mixtures based on hazard and exposure considerations. This framework is primarily based on the hierarchy of a single CAI's critical effect, where the lowest resulting limit may become the driver of the cleaning validation process. The six critical effect groups are: (1) CAIs of low concern based on safe exposure reasoning; (2) CAIs of low concern based on the mode of action reasoning; (3) CAIs with local concentration-dependent critical effects; (4) CAIs with dose-dependent systemic critical effects for which a route-specific PDE should be calculated; (5) poorly characterized CAIs with unknown critical effect for which a default value of 100 µg/day is proposed; (6) poorly characterized CAIs which should be avoided because of potential mutagenicity and/or potency.

Development, stability-indicating assessment, and evaluation of influential method conditions using a full factorial design for the determination of Nintedanib esylate-related impurities.

The design of an appropriate analytical method for assessing the quality of pharmaceuticals requires a deep understanding of science, and risk evaluation approaches are appreciated. The current study discusses how a related substance method was developed for Nintedanib esylate. The best possible separation between the critical peak pairs was achieved using an X-Select charged surface hybrid Phenyl Hexyl (150 × 4.6) mm, 3.5 µm column. A mixture of water, acetonitrile, and methanol in mobile phase-A (70:20:10) and mobile phase-B (20:70:10), with 0.1% trifluoroacetic acid and 0.05% formic acid in both eluents. The set flow rate, wavelength, and injection volumes were 1.0 ml/min, 285 nm, and 5 µl, respectively, with gradient elution. The method conditions were validated as per regulatory requirements and United States Pharmacopeia general chapter < 1225 >. The correlation coefficient for all impurities from the linearity experiment was found to be > 0.999. The % relative standard deviation from the precision experiments ranged from 0.4 to 3.6. The mean %recovery from the accuracy study ranged from 92.5 to 106.5. Demonstrated the power of the stability-indicating method through degradation studies; the active drug component is more vulnerable to oxidation than other conditions. Final method conditions were further evaluated using a full-factorial design. The robust method conditions were identified using the graphical optimization from the design space.

Generic Drug Shortage in Japan: GMP Noncompliance and Associated Quality Issues.

Government campaigns to replace off-patent brand pharmaceuticals with low cost generic products in national health insurance systems have apparently increased their production in the last two decades in Japan. The contamination of a batch of generic itraconazole tablets with the sleep inducer rilmazafone caused significant adverse events and related accidents in 2020, amidst increasing use of the generic products in healthcare. Investigations revealed many Good Manufacturing Practice (GMP) violations and other evidence of poor quality management in the manufacturing/marketing authorization holder (MAH). Urgent inspection of other MAHs found multiple cases of GMP noncompliance that resulted in temporary administrative suspension. Various quality issues, including nonconformity in stability monitoring, in these generic MAHs resulted in prolonged suspension of product shipments and shortages in medical institutions. These problems highlighted long-standing issues in quality management by MAHs and inspections by authorities, which had been neglected during rapid production expansion. This review introduces these manufacturing control and management problems and their countermeasures, and discusses the impact of habitual inadequate development processes that disregard the quality-by-design (QbD) perspective as the root cause of the issues.

Human norovirus contamination challenge in fresh produce: a global prevalence and meta-analytic assessment.

AIMS: Among fresh produce (FP)-associated foodborne infections, human noroviruses (HNoV) are the leading causative agent. The present study aimed to assess the prevalence of HNoV in FP. METHODS AND RESULTS: FP-associated HNoV records mined from 5 repositories until 25/05/2022 according to PRISMA standards were appraised, fitted to a generalized linear mixed-effects model and subgroup analysed by sample type, genogroup, and geographical location. Further, heterogeneity was assessed in the model coupled with a leave-one-out-cross-validation. The overall prevalence of HNoV in FP was 9.3% (95% confidence interval [CI] 3.7-21.7. HNoV prevalence was higher in fruits (9.8%[3.7-23.5]) than vegetables (9.4%[3.1-25.3]). Regarding geographical distribution, FP-associated HNoV prevalence varied from Africa (25.8%, 5.7-66.7), Asia (23.2%[4.6-65.0]), Europe (5.6%[0.7-33.9]), North America (12.4%[1.8-52.7]) to South America (7.5%[0.0-100.0]). HNoV GI overall prevalence in FP was 5.3% (2.5-11.1) and varied by sample type (fruits: 4.9%[1.7-13.2]; vegetables: 5.8%[1.6-18.8]). While the occurrence of GII in FP was 1.7% (0.7-3.9) and varied by sample type (fruits: 2.5%[1.0-6.5]; vegetables: 0.9%[0.2-4.9]), GIGII (detection of both GI and GII) was 0.3% (0.1-1.0) with 0.4% (0.1-2.2) and 0.2% (0.0-1.5) in fruits and vegetables, respectively. In all cases, the test for sample/regional prevalence differences were not significantly different with the exception of GII regional prevalence differences (p = 0.03). CONCLUSIONS: This study suggests that FP represents a critical vehicle for HNoV dissemination, a global and a high risk for public health.

A critical review on the assessment of the quality and authenticity of Tequila by different analytical techniques: Recent advances and perspectives.

Currently, the authenticity and traceability of Tequila are determined in an inspection process carried out by the Tequila Regulatory Council. However, in recent years, the authorities have seized illegal alcoholic products that are marketed as Tequila without being so, making it necessary to strengthen the current methods of detecting counterfeiting and/or adulteration. Therefore, it is important to establish a review of the current analytical techniques that have been proposed to solve this problem. In this review, emphasis is placed on the analysis of the analytical techniques that have been used to consolidate a profile of authenticity and quality in Tequila, thus highlighting new auxiliary analytical techniques to the current verification process, establishing future validation opportunities in terms of international quality control. The use of isotopic ratios stands out as the most robust technique because it establishes the type of sugar source used and the maturation time of the manufacturing process.

Exploring three-dimensional space of extractables and leachables in volatility, hydrophobicity, and molecular weight and assessment of roles of gas and liquid chromatographic methods in their comprehensive analysis.

The three-dimensional (3D) global space of organic extractables and leachables (E&L) in volatility, hydrophobicity, and molecular weight (MW), covering the pharmaceutical container-closure system, biopharmaceutical single use equipment, and tissue-contacting medical devices, has been quantitatively explored by an extensive collection of E&L compounds from the publicly available sources. The total number of compounds collected is 776, including name, CAS number, MW, and boiling point (BP). The hydrophobicity of these compounds in logPo/w are computed by Abraham solvation parameter model, using compounds' descriptors generated by an online computational program "RMG: Solvation Tools". A "global" 3D space is built to represent the physicochemical property limits of E&L quantitatively, envisioned to cover a variety of materials extracted by different solvents. This 3D space also represents the scope and capability requirements of general-purpose chromatography-based methods to profile unknown material samples, if a limited number of analytical methods are used in a routine laboratory analysis. It is concluded from the study that the 3D space corresponding to MW of 1000 Da are: BP up to 857 °C and hydrophobicity in logPo/w between - 2.3-19. Additionally, the roles of temperature programmed GC (TPGC) and reversed-phase liquid chromatographic (RPLC) methods are quantitively and critically examined in the comprehensive analysis of the 3D space, particularly for RPLC methods in retention and resolution requirements, and it is also concluded that the current concept of analytical E&L testing strategies based on volatility needs to be challenged. Finally, this study proposes a semi-empirical method in correlation and prediction of the retention time of TPGC using Abraham solvation parameter model.

Assessment of Undeclared Synthetic Drugs in Dietary Supplements in an Analytical View: A Comprehensive Review.

Dietary supplements have gained widespread attention globally as they are supposed to be healthier than synthetic pharmaceutical compounds with fewer side effects. Unlike common prescription drugs, dietary supplements are readily available to the general public. However, over the past few years, all kinds of legal and illegal drugs, have been detected in dietary supplements without labeling to defraud consumers, resulting in serious public health consequences. Due to the increasing number of drug frauds in dietary supplements, their consumption will undoubtedly risk consumers. Therefore; the importance of high-tech analytical methods in their assessment for controlling food quality seems undeniable. The current review examines the analytical techniques that focus on adulterating health products with undeclared pharmaceuticals, including registered and banned drugs. The present study referred to a survey from 2004 to 2021 based on articles in the Scopus database.

Analytical Method Development for 19 Alkyl Halides as Potential Genotoxic Impurities by Analytical Quality by Design.

Major issues in the pharmaceutical industry involve efficient risk management and control strategies of potential genotoxic impurities (PGIs). As a result, the development of an appropriate method to control these impurities is required. An optimally sensitive and simultaneous analytical method using gas chromatography with a mass spectrometry detector (GC-MS) was developed for 19 alkyl halides determined to be PGIs. These 19 alkyl halides were selected from 144 alkyl halides through an in silico study utilizing quantitative structure-activity relationship (Q-SAR) approaches via expert knowledge rule-based software and statistical-based software. The analytical quality by design (QbD) approach was adopted for the development of a sensitive and robust analytical method for PGIs. A limited number of literature studies have reviewed the analytical QbD approach in the PGI method development using GC-MS as the analytical instrument. A GC equipped with a single quadrupole mass spectrometry detector (MSD) and VF-624 ms capillary column was used. The developed method was validated in terms of specificity, the limit of detection, quantitation, linearity, accuracy, and precision, according to the ICH Q2 guideline.

Framework for sensitization assessment of extractables and leachables in pharmaceuticals.

During the toxicological assessment of extractables and leachables in drug products, localized hazards such as irritation or sensitization may be identified. Typically, because of the low concentration at which leachables occur in pharmaceuticals, irritation is of minimal concern; therefore, this manuscript focuses on sensitization potential. The primary objective of performing a leachable sensitization assessment is protection against Type IV induction of sensitization, rather than prevention of an elicitation response, as it is not possible to account for the immunological state of every individual. Sensitizers have a wide range of potencies and those which induce sensitization upon exposure at a low concentration (i.e. strong, or extreme sensitizers) pose the highest risk to patients and should be the focus of the risk assessment. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium has reviewed the status of dermal, respiratory, and systemic risk assessment in cosmetic and pharmaceutical industries, and proposes a framework to evaluate the safety of known or potential dermal sensitizers in pharmaceuticals. Due to the lack of specific regulatory guidance on this topic, the science-driven risk-based approach proposed by ELSIE encourages consistency in the toxicological assessment of extractables and leachables to maintain high product quality and ensure patient safety.