High-performance thin-layer chromatography in combination with an acetylcholinesterase-inhibition bioassay with pre-oxidation of organothiophosphates to determine neurotoxic effects in storm, waste, and surface water.

Pesticides such as organothiophosphates (OTPs) are neurotoxically active and enter the aquatic environment. Bioassays, using acetylcholinesterase (AChE), a suitable substrate and reactant, can be applied for the photometric detection of AChE-inhibiton (AChE-I) effects. The oxidized forms of OTPs, so-called oxons, have higher inhibition potentials for AChE. Therefore, a higher sensitivity is achieved for application of oxidized samples to the AChE assay. In this study, the oxidation of malathion, parathion, and chlorpyrifos by n-bromosuccinimide (NBS) was investigated in an approach combining high-performance thin-layer chromatography (HPTLC) with an AChE-I assay. Two AChE application approaches, immersion and spraying, were compared regarding sensitivity, precision, and general feasibility of the OTP effect detection. The oxidation by NBS led to an activation of the OTPs and a strong increase in sensitivity similar to the oxons tested. The sensitivity and precision of the two application techniques were similar, although the spray method was slightly more sensitive to the oxidized OTPs. The 10% inhibition concentrations (IC10) for the spray approach were 0.26, 0.75, and 0.35 ng/spot for activated malathion, parathion, and chlorpyrifos, respectively. AChE-I effect recoveries in samples from a stormwater retention basin and receiving stream were between 69 and 92% for malathion, parathion, and chlorpyrifos. The overall workflow, including sample enrichment by solid-phase extraction, HPTLC, oxidation of OTPs, and AChE-I assay, was demonstrated to be suitable for the detection of AChE-I effects in native water samples. An effect of unknown origin was found in a sample from a stormwater retention basin.

High-performance thin-layer chromatography in combination with a yeast-based multi-effect bioassay to determine endocrine effects in environmental samples.

Effect-directed analysis (EDA) that combines effect-based methods (EBMs) with high-performance thin-layer chromatography (HPTLC) is a useful technique for spatial, temporal, and process-related effect evaluation and may provide a link between effect testing and responsible substance identification. In this study, a yeast multi endocrine-effect screen (YMEES) for the detection of endocrine effects is combined with HPTLC. Simultaneous detection of estrogenic, androgenic, and gestagenic effects on the HPTLC plate is achieved by mixing different genetically modified Arxula adeninivorans yeast strains, which contain either the human estrogen, androgen, or progesterone receptor. Depending on the yeast strain, different fluorescent proteins are formed when an appropriate substance binds to the specific hormone receptor. This allows to measure hormonal effects at different wavelengths. Two yeast cell application approaches, immersion and spraying, are compared. The sensitivity and reproducibility of the method are shown by dose-response investigations for reference compounds. The spraying approach indicated similar sensitivities and higher precisions for the tested hormones compared to immersion. The EC10s for estrone (E1), 17ß-estradiol (E2), 17α-ethinylestradiol (EE2), 5α-dihydrotestosterone (DHT), and progesterone (P4) were 95, 1.4, 10, 7.4, and 15 pg/spot, respectively. Recovery rates of E1, E2, EE2, DHT, and P4 between 88 and 120% show the usability of the general method in combination with sample enrichment by solid phase extraction (SPE). The simultaneous detection of estrogenic, androgenic, and gestagenic effects in wastewater and surface water samples demonstrates the successful application of the YMEES in such matrices. This promising method allows us to identify more than one endocrine effect on the same HPTLC plate, which saves time and material. The method could be used for comparison, evaluation, and monitoring of different river sites and wastewater treatment steps and should be tested in further studies.

Quality control of cytostatic drug preparations-comparison of workflow and performance of Raman/UV and high-performance liquid chromatography coupled with diode array detection (HPLC-DAD).

The drugs used for treatment during chemotherapy are manufactured individually for each patient in specialised pharmacies. Thorough quality control to confirm the identity of the delivered active pharmaceutical ingredient and the final concentration of the prepared application solution is not standardized yet except for optical or gravimetric testing. However, solution stability problems, counterfeit drugs, and erroneous or deliberate underdosage may occur and negatively influence the quality of the product and could cause severe health risks for the patient. To take a step towards analytical quality control, an on-site analytical instrument using Raman and UV absorption spectroscopy was employed and the results were compared to high-performance liquid chromatography coupled to diode array detection. Within the scope of the technology evaluation, the uncertainty of measurement was determined for the analysis of the five frequently used cytostatic drugs 5-fluorouracil, cyclophosphamide, gemcitabine, irinotecan and paclitaxel. The Raman/UV technique (2.0-3.2% uncertainty of measurement; level of confidence: 95%) achieves a combined uncertainty of measurement comparable to HPLC-DAD (1.7-3.2% uncertainty of measurement; level of confidence: 95%) for the substances 5-fluorouracil, cyclophosphamide and gemcitabine. However, the uncertainty of measurement for the substances irinotecan and paclitaxel is three times higher when the Raman/UV technique is used. This is due to the fact that the Raman/UV technique analyses the undiluted sample; therefore, the sample has a higher viscosity and tendency to foam. Out of 136 patient-specific preparations analysed within this study, 96% had a deviation of less than 10% from the target content.

Effect-based evaluation of ozone treatment for removal of micropollutants and their transformation products in waste water.

The aim of this interdisciplinary research project in North Rhine-Westphalia (NRW), Germany, entitled "Elimination of pharmaceuticals and organic micropollutants from waste water" involved the conception of cost-effective and innovative waste-water cleaning methods. In this project in vitro assays, in vivo assays and chemical analyses were performed on three municipal waste-water treatment plants (WWTP). This publication focuses on the study of the in vitro bioassays. Cytotoxic, estrogenic, genotoxic and mutagenic effects of the original as well as enriched water samples were monitored before and after wastewater treatment steps using MTT and PAN I, ER Calux and A-YES, micronucleus and Comet assays as well as AMES test. In most cases, the measured effects were reduced after ozonation, but in general, the biological response depended upon the water composition of the WWTP, in particular on the formed by-products and concentration of micropollutants. In order to be able to assess the genotoxic and/or mutagenic potential of waste-water samples using bioassays like Ames test, Comet assay or micronucleus test an enrichment of the water sample via solid-phase extraction is recommended. This is in agreement with previous studies such as the "ToxBox"-Project of the Environmental Agency in Germany.

Comparison of Software Tools for Liquid Chromatography-High-Resolution Mass Spectrometry Data Processing in Nontarget Screening of Environmental Samples.

The field of high-resolution mass spectrometry has undergone a rapid progress in the last years due to instrumental improvements leading to a higher sensitivity and selectivity of instruments. A variety of qualitative screening approaches, summarized as nontarget screening, have been introduced and have successfully extended the environmental monitoring of organic micropollutants. Several automated data processing workflows have been developed to handle the immense amount of data that are recorded in short time frames by these methods. Most data processing workflows include similar steps, but underlying algorithms and implementation of different processing steps vary. In this study the consistency of data processing with different software tools was investigated. For this purpose, the same raw data files were processed with the software packages MZmine2, enviMass, Compound Discoverer, and XCMS online and resulting feature lists were compared. Results show a low coherence between different processing tools, as overlap of features between all four programs was around 10%, and for each software between 40% and 55% of features did not match with any other program. The implementation of replicate and blank filter was identified as one of the sources of observed divergences. However, there is a need for a better understanding and user instructions on the influence of different algorithms and settings on feature extraction and following filtering steps. In future studies it would be of interest to investigate how final data interpretation is influenced by different processing software. With this work we want to encourage more awareness on data processing as a crucial step in the workflow of nontarget screening.

Advanced photocatalytic oxidation processes for micropollutant elimination from municipal and industrial water.

The objective of this study was to develop and validate an innovative technology to ensure efficient elimination of different types of micropollutants and toxic compounds in waste water. The process is a tertiary treatment process, which can be easily integrated into municipal and industrial waste water treatment plants. It is based on oxidation by ozone and subsequent photocatalytic treatment. After development and validation of this system at laboratory scale, the solution was tested at pilot scale. The first part of this work was to develop a TiO2-based film on glass substrate, characterize its physico-chemical properties and optimize its composition at laboratory scale to be photoactive on the degradation of model water containing several pollutants. The model water consisted of a mixture of 22 major micropollutants including pesticides, plasticizers, brominated compounds, and pharmaceuticals. The best photocatalyst for the degradation of the selected micropollutants was a TiO2 coating doped with 2 wt% of Ag and where 10 wt% P25 was added. Then, in order to scale up the process, its deposition on steel substrates was tested with dip and spray coating at laboratory scale. Calcination parameters were optimized to limit steel corrosion while keeping similar photoactive properties regarding the degradation of the model polluted water. The optimized solution was deposited by spray coating in a pilot scale reactor in order to assess its efficiency in a pilot water treatment plant.

Occurence and Prioritization of Pharmaceutical Active Compounds in Domestic/Municipal Wastewater Treatment Plants.

In this study, pharmaceutically active compounds (PhACs) were analyzed in the influent and effluent of a domestic wastewater treatment plant in Turkey and a municipal wastewater treatment plant in Germany and the toxicity of these wastewaters were estimated using a toxic unit (TU) approach. A total of 21 and 32 PhACs were detected in the domestic wastewater and the municipal wastewater, respectively. The TUs estimated for PhACs in municipal wastewater were higher than the TUs estimated for PhACs present in domestic wastewater. The levels of the anti-anxiety drug, oxazepam were estimated to be in the high risk category (HQ > 10) in both wastewaters. In bench-scale tests with ozonation, the removals of four PhACs in the municipal wastewater were investigated. At a dose of 2 mg/L ozone, 97%-98% of diclofenac and carbamazepine were removed. The lowest removal rate at 71% was observed for metoprolol.

Development of an analytical method to assess the occupational health risk of therapeutic monoclonal antibodies using LC-HRMS.

Monoclonal antibodies are a group of commonly used therapeutics, whose occupational health risk is still discussed controversially. The long-term low-dose exposure side effects are insufficiently evaluated; hence, discussions are often based on a theoretical level or extrapolating side effects from therapeutic dosages. While some research groups recommend applying the precautionary principle for monoclonal antibodies, others consider the exposure risk too low for measures taken towards occupational health and safety. However, both groups agree that airborne monoclonal antibodies have the biggest risk potential. Therefore, we developed a peptide-based analytical method for occupational exposure monitoring of airborne monoclonal antibodies. The method will allow collecting data about the occupational exposure to monoclonal antibodies. Thus, the mean daily intake for personnel in pharmacies and the pharmaceutical industry can be determined for the first time and will help to substantiate the risk assessment by relevant data. The introduced monitoring method includes air sampling, sample preparation and detection by liquid chromatography coupled with high-resolution mass spectrometry of individual monoclonal antibodies as well as sum parameter. For method development and validation, a chimeric (rituximab), humanised (trastuzumab) and a fully humanised (daratumumab) monoclonal antibody are used. A limit of detection between 1 µg per sample for daratumumab and 25 µg per sample for the collective peptide is achieved. Graphical abstract Demonstration of the analytical workflow, from the release of monoclonal antibodies to the detection as single substances as well as sum parameter.

Investigation of full-scale ozonation at a municipal wastewater treatment plant using a toxicity-based evaluation concept.

Effluents from municipal wastewater treatment plants (WWTPs) are known to be point sources of micropollutants for surface waters. The aim of this study was to examine a reconstructed full-scale ozonation equipped with a pump-injector system for ozone (O3) dosage and a fluidized moving-bed reactor as biological posttreatment at a municipal WWTP utilizing an effect-directed approach. This approach consists of chemical analysis in combination with toxicological tests for the assessment of treatment efficiency of the plant. Chemical analysis showed elimination rates > 80% for pharmaceuticals and industrial chemicals. Analysis of endocrine disruptors was limited due to substance concentrations below the limit of detection (LOD). Estrogenic activity was detected by the Arxula Adeninivorans yeast estrogen screen (A-YES) at low concentrations (pg to ng EEQ/l range). Estrogenic activity was reduced by more than 90% after ozonation. In contrast, androgenic activity (measured in the Adeninivorans yeast androgen screen, A-YAS) was still found after O3 treatment and after biological posttreatment, which is consistent with the data obtained by chemical analysis. Furthermore, no marked genotoxic or cytotoxic effects were observed after ozonation using the alkaline comet and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) assays, respectively. Results suggest that the applied specific O3 dose of 0.4 mgO3/mgDOC is a safe operation setup in terms of toxicologically relevant transformation products. In addition, no adverse effects on primary producers, as evidenced by algae growth inhibition tests, were detected. The monitored biofilm growth in the biological posttreatment exhibited a steady state after one month. Based on computational fluid dynamics (CFD) simulations and biomass, one might conclude that O3 did not apparently enter biological posttreatment to a great extent and that hydraulic retention time in the O3 reactor was sufficient. Our data demonstrate the effectiveness of a full-scale O3 treatment in combination with a fluidized moving-bed reactor as biological posttreatment for the reduction of a majority of micropollutants without the release of relevant toxic transformation products as assessed by a chemical and toxicity-based approach.

Characterization and toxicity of hospital wastewaters in Turkey.

The aim of the study was to present first preliminary characterization of Turkish hospital wastewaters, their environmental risk, and a method for toxicity assessment. The hospital wastewater samples were collected from two of the largest medical faculty hospitals and a training and research hospital in Istanbul, Turkey. The samples from the selected hospitals were taken as grab samples on March 2014. Overall, 55 substances including pharmaceuticals and their metabolites, pesticides, and corrosion inhibitors were analyzed in all hospital wastewaters. Analysis of toxicity and the antibiotic resistance bacteria were investigated in addition to the chemical analysis in the wastewater of one hospital. Hazard quotients (HQs) and toxic units (TUs) were calculated as basis of the environmental risk assessment. Fourteen pharmaceuticals in hospital wastewater (HWW) were classified as "high risk" with HQ > 10. HQHWW values higher than 100 were determined for five antibiotics and one analgesic, namely, ofloxacin, clarithromycin, ciprofloxacin, sulfapyridine, trimethoprim, and diclofenac. Ofloxacin with an HQHWW of 9090 was observed to be the most hazardous compound. HQ and TU values of the wastewater treatment plant (WWTP) effluent dropped significantly due to dilution in the sewer. Further elimination by biological degradation or adsorption was observed only in some cases. However, the decreased HQWWTPeffluent values do not the change environmental load significantly. Therefore, advanced treatment processes should be applied to remove the persistent compounds. In combination with the results on antibiotic resistance, we would prefer on-site treatment of hospital wastewater. Toxicological assessment was performed using cytotoxic and mutagenic screening tests. The results of the Ames assay showed that the native hospital wastewaters had strongly mutagenic activity with a ≤10-fold increase relative to negative controls. The mutagenic potentials of the samples were generally concentration and metabolic activation dependent. Multiple antibiotic resistances were demonstrated with the tested isolates to ciprofloxacin, trimethoprim, and ceftazidime. This study demonstrates that the hospital wastewaters in Istanbul exhibit strong environmental and toxicological risks, as well as high multiple drug resistance to commonly used antibiotics.

Micro-liquid chromatography mass spectrometry for the analysis of antineoplastic drugs from wipe samples.

A fast quantification method for the determination of 11 antineoplastic drugs from wipe samples was developed using micro-scale liquid chromatography in combination with tandem mass spectrometry. The extraction efficiency from the wipes has been investigated using different extraction solvents. The results indicate that a mixture of 70/30 water/isopropanol (v/v) acidified with 0.1 % formic acid is suitable to desorb the antineoplastic drugs with sufficient recovery between 80 and 120 %. Compared to conventional liquid chromatography, the total analysis time can be reduced to 2.25 min using a 50 × 0.3 mm column at a flow rate of 25 µL min-1. Ion source parameters as well as the injection volume were optimized to ensure the highest sensitivity. The results of method validation showed an instrumental limit of quantification between 0.0068 and 0.0488 ng mL-1 using an injection volume of 4.25 µL estimated by the signal to noise ratio. Moreover, the retention time repeatability was determined with a maximum relative standard deviation of 0.4 %. Graphical abstract Micro-LC-MS/MS separation of 11 antineoplastic drugs from wipe samples.

Online and splitless NanoLC × CapillaryLC with quadrupole/time-of-flight mass spectrometric detection for comprehensive screening analysis of complex samples.

A novel multidimensional separation system based on online comprehensive two-dimensional liquid chromatography and hybrid high-resolution mass spectrometry has been developed for the qualitative screening analysis and characterization of complex samples. The core of the system is a consistently miniaturized two-dimensional liquid chromatography that makes the rapid second dimension compatible with mass spectrometry without the need for any flow split. Elevated temperature, ultrahigh pressure, and a superficially porous sub-3-µm stationary phase provide a fast second dimension separation and a sufficient sampling frequency without a first dimension flow stop. A highly loadable porous graphitic carbon stationary phase is employed in the first dimension to implement large volume injections that help countervailing dilution caused by the sampling process between the two dimensions. Exemplarily, separations of a 99-component standard mixture and a complex wastewater sample were used to demonstrate the performance of the dual-gradient system. In the second dimension, 30 s gradients at a cycle time of 1 min were employed. One multidimensional separation took 80-90 min (~120 min including extended hold and re-equilibration in the first dimension). This approach represents a cost-efficient alternative to online LC × LC strategies working with conventionally sized columns in the rapid second dimension, as solvent consumption is drastically decreased and analytes still are detectable at environmentally relevant concentrations.

Application and assessment of a regular environmental monitoring of the antineoplastic drug contamination level in pharmacies - the MEWIP project.

A large-scale study was carried out in order to determine the contamination level of antineoplastic drugs in pharmacies and to investigate the suitability and effects of wipe sample monitoring at regular intervals. A specific study design was developed. The 130 participating pharmacies were divided into a study and a control group, carrying out five and two wipe sampling cycles, respectively. The work practice was analyzed using questionnaires to identify factors that influence the contamination level. From 1269 wipe samples, 774 (61%) were contaminated with at least one of the analyzed cytotoxic drugs: cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, methotrexate, and paclitaxel. A significant decrease of the contamination with cyclophosphamide and 5-fluorouracil was observed in the study group. The Monitoring-Effect Study of Wipe Sampling in Pharmacies method has proven to be a reliable and affordable tool for contamination control. Based on the 90th percentile of the contamination values, a substance-independent performance-based guidance value of 0.1ng cm(-2) has been derived.

Pollutant load and ecotoxicological effects of sediment from stormwater retention basins to receiving surface water on Lumbriculus variegatus.

The overflow of stormwater retention basins during intense and prolonged precipitation events may result in the direct input of particulate pollutants and remobilization of already sedimented particle-bound pollutants to receiving freshwater bodies. Particle-bound pollutants may cause adverse effects on aquatic biota, particularly sediment dwellers. Therefore, we investigated the sediment pollution load of a stream connected to the outfalls of two stormwater basins to determine the impact of the basins' discharges on the metal and organic pollutant content of the sediment. Also, the possible adverse effects of the pollutant load on benthic dwellers were evaluated in sediment toxicity tests with Lumbriculus variegatus and the effects on its growth, reproduction and the biomarkers catalase, acetylcholinesterase and metallothionein were analyzed. The results showed that the retention basins contained the highest load of pollutants. The pollutant load in the stream did not show a clear pollution pattern from the inlets. However, metal enrichment ratios revealed contamination with Cu, Pb and Zn with Pb and Zn above threshold effect concentrations in all sites. Ecotoxicity results showed that the retention basin samples were the most toxic compared to sediment from the stream. Exposure experiments with the stream sediment did not show considerable effects on reproduction, catalase activity and metallothionein concentration. However, modest inhibitions of growth and activity of acetylcholinesterase were detected. Based on the observed results, it cannot be concluded that overflows of the retention basin are responsible for the pollutant contents downstream of their inlet. Other sources that were not considered in this study, such as diffuse input, historic pollution and point sources further upstream as well as along the stream, are likely the major contributors of pollutant load in the sediment of the studied transects of the stream. Additionally, the observed results in the stormwater basin sediment further highlight their importance in retaining particle-bound pollutants and preventing ecotoxicological effects from receiving surface water bodies.

Quality Control of Personalized Drug Products - Identity and Quantity of Monoclonal Antibodies as Active Pharmaceutical Ingredient.

Deliberate underdosing occurred in personalized preparations of drugs such as monoclonal antibodies as the active pharmaceutical ingredient in the past. To ensure the required quality standard and to prevent future fraud attempts at an early stage, a HPLC-DAD-HRMS method was established. Thereby, identity and quantity of the active ingredients bevacizumab, rituximab and trastuzumab were determined. The analysis of ten samples from seven pharmacies fulfilled the quality criteria and were therefore not objectionable.

In-use stability of ready-to-administer daratumumab subcutaneous injection solution in plastic syringes.

OBJECTIVE: In multiple myeloma patients, daratumumab is preferably injected subcutaneously. The summary of product characteristics of daratumumab subcutaneous injection solution specifies physicochemical stability for the prepared syringe for 24 hours at 2-8°C protected from light, and another 12 hours at room temperature (15-25°C) in ambient light conditions. The aim of this study was to determine the in-use stability of ready-to-administer daratumumab subcutaneous injection solution in different types of syringe and different conditions over a 28-day period. METHODS: Daratumumab subcutaneous (DARZALEX 1800 mg) injection solution was withdrawn into disposable three-piece Luer-Lock syringes (20 mL, 50 mL), capped, and stored light protected at 2-8°C or at room temperature (22±2°C) over a maximum period of 28 days. Samples were taken immediately after preparation (day 0) and after 2, 7, 14, 21, and 28 days. Physicochemical stability was determined by ion-exchange high-performance liquid chromatography (IE-HPLC) and size-exclusion high-performance liquid chromatography (SE-HPLC) with ultraviolet detection, pH measurement and visual inspection for particles or colour changes. RESULTS: In the IE-HPLC assay, peak areas and peak-to-peak area ratios remained unchanged over the whole study period, and showed no additional peaks of degraded daratumumab charge variants. In the SE-HPLC assay, neither a formation of aggregates nor of fragments was detected. Daratumumab monomer concentrations exceeded 95% of the initially measured concentrations over the entire test period. pH values remained constant. Test solutions remained clear, and no colour changes or visible particles were detected. All results were independent of storage conditions. CONCLUSION: Daratumumab subcutaneous injection solution proved to be physicochemically stable in capped three-piece plastic syringes for at least 28 days when stored light protected at 2-8°C or at room temperature (22±2°C). For microbiological reasons aseptic preparation and refrigerated storage are recommended. In-use stability of ready-to-administer daratumumab subcutaneous syringes prepared under appropriate aseptic conditions is given for 28 days.

Influence of water matrix on the degradation of organic micropollutants by ozone based processes: A review on oxidant scavenging mechanism.

The prevalence of organic micropollutants (OMPs) in aquatic environment has expedited scientific and regulatory efforts to retrofit existing wastewater treatment plants (WWTPs). The current strategy involves WWTPs upgrading with post-ozonation i.e., ozone (O3) and/or peroxone process (O3 +H2O2). Still, ozone-based degradation of OMPs faces several challenges. For example, the degradation mechanism and kinetics of OMPs could largely be affected by water matrix compounds which include inorganic ions and natural organic matter (NOM). pH also plays a decisive role in determining the reactivity of the oxidants (O3, H2O2, andHO•), stability and speciation of matrix constituents and OMPs and thus susceptibility of OMPs to the reactions with oxidants. There have been reviews discussing the impact of matrix components on the degradation of OMPs by advanced oxidation processes (AOPs). Nevertheless, a review focusing on scavenging mechanisms, formation of secondary oxidants and their scavenging effects with a particular focus on ozonation and peroxone process is lacking. Therefore, in order to broaden the knowledge on this subject, the database 'Web of Science' was searched for the studies related to the 'matrix effect on the degradation of organic micropollutants by ozone based processes' over the time period of 2004-2021. The relevant literature was thoroughly reviewed and following conclusions were made: i) chloride has inhibitory effects if it exits at higher concentrations or as free chlorine i.e. HOCl/ClO-. ii) The inhibitory effects of chloride, bromide, HOBr/OBr- and HOCl/ClO- are dominant in neutral and alkaline conditions and may result in the formation of secondary oxidants (e.g., chlorine atoms or free bromine), which in turn contribute to pollutant degradation or form undesired oxidation by-products such as BrO3-, ClO3- and halogenated organic products. ii) NOM may induce inhibitory or synergetic effects depending on the type, chemical properties and concentration of NOM. Therefore, more efforts are required to understand the importance of pH variation as well as the effects of water matrix on the reactivity of oxidants and subsequent degradation of OMPs.

Flexible Digitization of Highly Individualized Workflows Demonstrated Through the Quality Control of Patient-Specific Cytostatic Application Bags: Digitization from the Perspective of Small and Medium-Sized Laboratories.

In order to ensure a high level of product quality and safety, regular quality controls are mandatory, especially in the pharmaceutical industry. These quality controls are strictly regulated and require a high level of documentation. With the goal of complete traceability, these regulations are constantly being tightened, while a majority of laboratories are working still completely paper-based. This leads to an ever-increasing workload that keeps laboratory staff away from value-adding analytical work. In order to realize complete traceability, a reduction in documentation errors and at the same time a reduction of the individual workload, the digitization of complete workflows seems to be a promising solution.Due to the ongoing shortage of IT specialists and the resulting high implementation costs, many laboratories are understandably hesitant. In this chapter an alternative is presented on how to approach the digitization of complete workflows without the need for IT specialists. The example of quality control analysis of cytotoxic drug solutions was chosen to demonstrate the challenges of such a digitization project. In this way, we contribute to a comprehensive understanding of the tools already available, which can also help other laboratories in their digitization efforts. At the end compliance with GMP and EN ISO/IEC 17025 (2017) regulations was reached.

Development and validation of a method for airborne monoclonal antibodies to quantify workplace exposure.

Modern therapy strategies are based on patient-specific treatment where the drug and dose are optimally adapted to the patient's needs. In recent drugs, monoclonal antibodies (mAbs) are increasingly used as active ingredients. Their patient-specific formulations are not part of the pharmaceutical industry's manufacturing process but are prepared from concentrates by pharmaceutical personnel. During the manufacturing process, however, active pharmaceutical ingredients are released in trace amounts or, in the case of accidents and spills, also in high concentrations. Regardless of the source of entry, mAbs can become airborne, be inhaled, and cause undesirable side-effects such as sensitization. To assess the risk for pharmaceutical personnel, a personal air sampling method was developed and validated for bevacizumab, cetuximab, daratumumab, omalizumab, rituximab and trastuzumab. The method is based on the combination of high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The analytical method achieves a limit of detection of 0.30-8.8 ng mL-1, recoveries of 83-96 % (intra-day assay) and 75-89 % (inter-day assay), with no detectable carry-over. A polycarbonate filter proved suitable for sampling airborne monoclonal antibodies, as it achieved 80-104 % recovery across all mAbs. It also showed concentration-independent desorption efficiency. The sampling duration can be up to 480 min without negatively affecting the recovery. MAbs are stable on the polycarbonate filter at 5 °C for 3 days (recovery: 94 % ± 5 %) and at - 20 °C for 14 days (recovery: 97 % ± 4 %). Our method demonstrated that there is a potential for release when handling monoclonal antibodies. However, this can be reduced below the limit of detection by using pressure equalization systems (spikes).

Microplastic sampling from wastewater treatment plant effluents: Best-practices and synergies between thermoanalytical and spectroscopic analysis.

Wastewater treatment plants (WWTPs) may represent point sources for microplastic discharge into the environment. Quantification of microplastic in effluents of WWTPs has been targeted by several studies although standardized methods are missing to enable a comparability of results. This study discusses theoretical and practical perspectives on best practices for microplastic sampling campaigns of WWTPs. One focus of the study was the potential for synergies between thermoanalytical and spectroscopic analysis to gain more representative sampling using the complementary information provided by the different analytical techniques. Samples were obtained before and after sand filtration from two WWTPs in Germany using cascade filtration with size classes of 5,000 - 100 µm, 100 - 50 µm, and 50 - 10 µm. For spectroscopic methods samples were treated by a Fenton process to remove natural organic matter, whereas TED-GC-MS required only sample extraction from the filter cascade. µFTIR spectroscopy was used for the 100 µm and 50 µm basket filters and µRaman spectroscopy was applied to analyze particles on the smallest basket filter (10 µm). TED-GC-MS was used for all size classes as it is size independent. All techniques showed a similar trend, where PE was consistently the most prominent polymer in WWTP effluents. Based on this insight, PE was chosen as surrogate polymer to investigate whether it can describe the total polymer removal efficiency of tertiary sand filters. The results revealed no significant difference (ANOVA) between retention efficiencies of tertiary sand filtration obtained using only PE and by analyzing all possible polymers with µFTIR and µRaman spectroscopy. Findings from this study provide valuable insights on advantages and limitations of cascade filtration, the benefit of complementary analyses, a suitable design for future experimental approaches, and recommendations for future investigations.