Safety risk management for low molecular weight process-related impurities in monoclonal antibody therapeutics: Categorization, risk assessment, testing strategy, and process development with leveraging clearance potential.

Process-related impurities (PRIs) derived from manufacturing process should be minimized in final drug product. ICH Q3A provides a regulatory road map for PRIs but excludes biologic drugs like monoclonal antibodies (mAbs) that contain biological PRIs (e.g. host cell proteins and DNA) and low molecular weight (LMW) PRIs (e.g., fermentation media components and downstream chemical reagents). Risks from the former PRIs are typically addressed by routine tests to meet regulatory expectations, while a similar routine-testing strategy is unrealistic and unnecessary for LMW PRIs, and thus a risk-assessment-guided testing strategy is often utilized. In this report, we discuss a safety risk management strategy including categorization, risk assessment, testing strategy, and its integrations with other CMC development activities, as well as downstream clearance potentials. The clearance data from 28 mAbs successfully addressed safety concerns but did not fully reveal the process clearance potentials. Therefore, we carried out studies with 13 commonly seen LMW PRIs in a typical downstream process for mAbs. Generally, Protein A chromatography and cation exchange chromatography operating in bind-and-elute mode showed excellent clearances with greater than 1,000- and 100-fold clearance, respectively. The diafiltration step had better clearance (greater than 100-fold) for the positively and neutrally charged LMW PRIs than for the negatively charged or hydrophobic PRIs. We propose that a typical mAb downstream process provides an overall clearance of 5,000-fold. Additionally, the determined sieving coefficients will facilitate diafiltration process development. This report helps establish effective safety risk management and downstream process design with robust clearance for LMW PRIs.

Efficacy of water filters for dental chair units: assessment of the filtration action versus Coxsackievirus B5.

INTRODUCTION: The microbiological safety and control of the water used in dental practice has a critical importance for avoiding cross-linked infections in the dental office. The aim of this study was to establish coxsackie virus filtration of the water applied to a dental unit. METHODS: A specific water filter-system was used, to verify the viral load in the outgoing water. The statistical analysis was performedusing the Shapiro-Wilk and t-Student test. RESULTS: The outcome of the evaluation of the virologic tests shows an excellent capability of virus filtration that attested 99.9999% in the volume analyzed. A statistical difference was found in the bacterial water contamination parameter before and after filtration. (P = 0.000000). CONCLUSIONS: According to the tests, medical devices applied to a dental unit are able to filter viruses and therefore reduce risk of contamination in the dental office.

Assessment of Capacity to Capture DNA Aerosols by Clean Filters for Molecular Biology Experiments.

Experimental contamination by exogenous DNA is a major issue in molecular biological studies for data quality and its management. We herein assessed DNA aerosols for the risk of contamination and tested the capacity of clean air filters to trap and remove DNA aerosols. DNA aerosols were generated by atomizing a DNA solution and introduced into a laminar flow clean air unit. Capture and detection performed upstream and downstream of the clean air unit showed that a significant fraction (>99.96%) of introduced molecules was trapped and removed by the filter. Although DNA aerosols appear to be an avoidable source of exogenous contamination, a clearer understanding and careful experimental procedures are needed in order to perform contamination-free, high-quality molecular biology experiments.

Effectiveness of table top water pitcher filters to remove arsenic from drinking water.

Arsenic contamination of drinking water is a serious threat to the health of hundreds of millions of people worldwide. In the United States ~3 million individuals drink well water that contains arsenic levels above the Environmental Protection Agency (EPA) maximum contaminant level (MCL) of 10µg/L. Several technologies are available to remove arsenic from well water including anion exchange, adsorptive media and reverse osmosis. In addition, bottled water is an alternative to drinking well water contaminated with arsenic. However, there are several drawbacks associated with these approaches including relatively high cost and, in the case of bottled water, the generation of plastic waste. In this study, we tested the ability of five tabletop water pitcher filters to remove arsenic from drinking water. We report that only one tabletop water pitcher filter tested, ZeroWater®, reduced the arsenic concentration, both As3+ and As5+, from 1000µg/L to < 3µg/L, well below the MCL. Moreover, the amount of total dissolved solids or competing ions did not affect the ability of the ZeroWater® filter to remove arsenic below the MCL. Thus, the ZeroWater® pitcher filter is a cost effective and short-term solution to remove arsenic from drinking water and its use reduces plastic waste associated with bottled water.

Throughput Optimization of Continuous Biopharmaceutical Manufacturing Facilities.

In order to operate profitably under different product demand scenarios, biopharmaceutical companies must design their facilities with mass output flexibility in mind. Traditional biologics manufacturing technologies pose operational challenges in this regard due to their high costs and slow equipment turnaround times, restricting the types of products and mass quantities that can be processed. Modern plant design, however, has facilitated the development of lean and efficient bioprocessing facilities through footprint reduction and adoption of disposable and continuous manufacturing technologies. These development efforts have proven to be crucial in seeking to drastically reduce the high costs typically associated with the manufacturing of recombinant proteins. In this work, mathematical modeling is used to optimize annual production schedules for a single-product commercial facility operating with a continuous upstream and discrete batch downstream platform. Utilizing cell culture duration and volumetric productivity as process variables in the model, and annual plant throughput as the optimization objective, 3-D surface plots are created to understand the effect of process and facility design on expected mass output. The model shows that once a plant has been fully debottlenecked it is capable of processing well over a metric ton of product per year. Moreover, the analysis helped to uncover a major limiting constraint on plant performance, the stability of the neutralized viral inactivated pool, which may indicate that this should be a focus of attention during future process development efforts.LAY ABSTRACT: Biopharmaceutical process modeling can be used to design and optimize manufacturing facilities and help companies achieve a predetermined set of goals. One way to perform optimization is by making the most efficient use of process equipment in order to minimize the expenditure of capital, labor and plant resources. To that end, this paper introduces a novel mathematical algorithm used to determine the most optimal equipment scheduling configuration that maximizes the mass output for a facility producing a single product. The paper also illustrates how different scheduling arrangements can have a profound impact on the availability of plant resources, and identifies limiting constraints on the plant design. In addition, simulation data is presented using visualization techniques that aid in the interpretation of the scientific concepts discussed.

Flattening filter-free accelerators: a report from the AAPM Therapy Emerging Technology Assessment Work Group.

This report describes the current state of flattening filter-free (FFF) radiotherapy beams implemented on conventional linear accelerators, and is aimed primarily at practicing medical physicists. The Therapy Emerging Technology Assessment Work Group of the American Association of Physicists in Medicine (AAPM) formed a writing group to assess FFF technology. The published literature on FFF technology was reviewed, along with technical specifications provided by vendors. Based on this information, supplemented by the clinical experience of the group members, consensus guidelines and recommendations for implementation of FFF technology were developed. Areas in need of further investigation were identified. Removing the flattening filter increases beam intensity, especially near the central axis. Increased intensity reduces treatment time, especially for high-dose stereotactic radiotherapy/radiosurgery (SRT/SRS). Furthermore, removing the flattening filter reduces out-of-field dose and improves beam modeling accuracy. FFF beams are advantageous for small field (e.g., SRS) treatments and are appropriate for intensity-modulated radiotherapy (IMRT). For conventional 3D radiotherapy of large targets, FFF beams may be disadvantageous compared to flattened beams because of the heterogeneity of FFF beam across the target (unless modulation is employed). For any application, the nonflat beam characteristics and substantially higher dose rates require consideration during the commissioning and quality assurance processes relative to flattened beams, and the appropriate clinical use of the technology needs to be identified. Consideration also needs to be given to these unique characteristics when undertaking facility planning. Several areas still warrant further research and development. Recommendations pertinent to FFF technology, including acceptance testing, commissioning, quality assurance, radiation safety, and facility planning, are presented. Examples of clinical applications are provided. Several of the areas in which future research and development are needed are also indicated.

Assessment of wastewater treatment plant design for small communities: environmental and economic aspects.

The preliminary design and economic assessment of small wastewater treatment plants (less than 2000 population equivalent) are issues of particular interest since wastewaters from most of these agglomerations are not covered yet. This work aims to assess nine different technologies set-up for the secondary treatment in such type of facilities embracing both economic and environmental parameters. The main novelty of this work is the combination of an innovative environmental decision support system (EDSS) with a pioneer approach based on the inclusion of the environmental benefits derived from wastewater treatment. The integration of methodologies based on cost-benefit analysis tools with the vast amount of knowledge from treatment technologies contained in the EDSS was applied in nine scenarios comprising different wastewater characteristics and reuse options. Hence, a useful economic feasibility indicator is obtained for each technology including internal and external costs and, for the first time, benefits associated with the environmental damage avoided. This new methodology proved to be crucial for supporting the decision process, contributing to improve the sustainability of new treatment facilities and allows the selection of the most feasible technologies of a wide set of possibilities.

Assessment of Kalman filter bias-adjustment technique to improve the simulation of ground-level ozone over Spain.

The CALIOPE air quality modelling system has been used to diagnose ground level O(3) concentration for the year 2004, over the Iberian Peninsula. We investigate the improvement in the simulation of daily O(3) maximum by the use of a post-processing such as the Kalman filter bias-adjustment technique. The Kalman filter bias-adjustment technique is a recursive algorithm to optimally estimate bias-adjustment terms from previous measurements and model results. The bias-adjustment technique improved the simulation of daily O(3) maximum for the entire year and the all the stations considered over the whole domain. The corrected simulation presents improvements in statistical indicators such as correlation, root mean square error, mean bias, and gross error. After the post-processing the exceedances of O(3) concentration limits, as established by the European Directive 2008/50/CE, are better reproduced and the uncertainty of the modelling system, as established by the European Directive 2008/50/CE, is reduced from 20% to 7.5%. Such uncertainty in the model results is under the established EU limit of the 50%. Significant improvements in the O(3) timing and amplitude of the daily cycle are also observed after the post-processing. The systematic improvements in the O(3) maximum simulations suggest that the Kalman filter post-processing method is a suitable technique to reproduce accurate estimate of ground-level O(3) concentration. With this study we evince that the adjusted O(3) concentrations obtained after the post-process of the results from the CALIOPE system are a reliable means for real near time O(3) forecasts.

Multicriteria decision-aid method to evaluate the performance of stormwater infiltration systems over the time.

Nowadays, stormwater infiltration systems are frequently used because of their ability to reduce flows and volumes in downstream sewers, decrease overflows in surface waters and make it possible to recharge groundwater. Moreover, they come in various forms with different uses. Despite these advantages the long term sustainability of these systems is questionable and their real performances have to be assessed taking into account various and sometimes conflicting aspects. To address this problem a decision support system is proposed. It is based on a multicriteria method built to help managers to evaluate the performance of an existing infiltration system at different stages of its lifespan and identify whether it performs correctly or not, according to environmental, socio-economic, technical and sanitary aspects. The paper presents successively: the performance indicators and the way they were built, the multicriteria method to identify if the system works properly and a case study.

[Risk management of soybean-related asthma: monitoring and surveillance]. / Gestión del riesgo de asma por haba de soja: monitorización y vigilancia.

OBJECTIVES: Allergen emissions during soybean unloading operations in the Barcelona harbor have caused asthma epidemics. The present article aimed to describe the surveillance and control measures carried out by the public health services. METHODS: Data were extracted from control systems from 1999 to 2009, with description of the surveillance schemes for allergen emissions, environmental concentrations (with defined reference levels) and for health. RESULTS: Of 95 studies of plant emission, four were above the reference levels, and filters were found to be the most likely cause. Mean environmental concentrations were low but were above the reference levels on 13 days; these levels were related to adverse meteorological conditions and incidents in the plants. No health effects were detected in the panel of patients nor epidemic asthma days. CONCLUSIONS: The system detects incidents and has shown its usefulness in protecting public health.

Fouling indices for low pressure hollow fiber membrane performance assessment.

This study evaluated the use of fouling indices to describe low pressure membrane fouling. One critical aspect of this study was the use of a bench-scale hollow fiber membrane system that imitated full-scale operation (constant flux with automatic hydraulic backwash and chemical cleaning). Fouling indices were based on a resistance-in-series model. Two different hollow fiber membrane types (membrane A and B) were tested with water from two water utilities (A and B) and three other natural sources (oligotrophic, algal bloom impacted, and wastewater impaired). The bench-scale testing included use of the same membrane as utilized at Utility B. Most fouling was reversible by hydraulic backwash and chemical cleaning. Specific flux and fouling indices for the bench-scale system were higher than those determined from full-scale data but fouling index ratios were comparable, suggesting a similar fouling nature. At similar organic loading, fouling was specific to water source and membrane type, i.e., no generalization on the impact of water source was possible. Full-scale data were compared with bench-scale data to validate the use of fouling indices. Fouling indices based on a resistance-in-series are useful tools to describe membrane performance data for both raw and pretreated water, for different water sources, and different membrane types.

Disposables in downstream processing.

Disposable equipment has been used for many years in the downstream processing industry, but mainly for filtration and buffer/media storage. Over the last decade, there has been increasing interest in the use of disposable concepts for chromatography, replacing steel and glass fixed systems with disposable plastic modules that can be discarded once exhausted, fouled or contaminated. These modules save on cleaning and validation costs, and their reduce footprints reduce buffer consumption, water for injection, labor and facility space, contributing to an overall reduction in expenditure that lowers the cost of goods. This chapter examines the practical and economic benefits of disposable modules in downstream processing.

Optimization of airborne endotoxin exposure assessment: effects of filter type, transport conditions, extraction solutions, and storage of samples and extracts.

Endotoxin exposure occurs in homes and occupational environments and is known to cause adverse health effects. In order to compare results from different studies and establish standards, airborne endotoxin exposures should be assessed using standardized methods. Although the European Committee for Standardization (CEN) developed guidelines for endotoxin exposure assessment, these leave room for individual interpretation. The influence of methods of sampling, extraction, and analysis has never been investigated in a full experimental design. Thus, we sought to fully elucidate the importance of all facets of endotoxin assessment. Inhalable dust samples collected simultaneously were used to investigate the effects on and interactions with airborne endotoxin concentration in two working environments of filter type (glass fiber or Teflon), transport conditions (with/without desiccant), sample storage (-20 or 4 degrees C), extraction solution (pyrogen-free water [PFW] or PFW plus 0.05% Tween 20), extract storage (-20 or 4 degrees C), and assay solution (PFW or PFW plus 0.05% Tween 20). Four hundred samples were collected and randomly distributed over the 20 combinations of treatments. There were no differences found for transport conditions and storage temperature of extracts. Also, no interactions between study variables existed. Sampling on glass-fiber filters, storage of samples in the freezer, and extraction in PFW plus 0.05% Tween 20 resulted in 1.3-, 1.1-, and 2.1-fold-higher estimated endotoxin concentrations, respectively. Use of PFW plus 0.05% Tween 20 in the assay solution had an additive effect. Thus, this study investigated gaps in the CEN protocol and provides data with which to fully specify a protocol for standardization of endotoxin exposure assessment.

Estimates of associated outdoor particulate matter health risk and costs reductions from alternative building, ventilation and filtration scenarios.

Although many studies have reported calculations of outdoor particulate matter (PM) associated externalities using ambient data, there is little information on the role buildings, their ventilation and filtration play. This study provides the framework to evaluate the health risk and cost reduction of building, ventilation and filtration strategies from outdoor PM pollution on a nationwide level and applied it to a case study in Singapore. Combining Indoor Air Quality (IAQ) and time weighted exposure models, with established concentration-response functions and monetary valuation methods, mortality and morbidity effects of outdoor PM on the population of Singapore under different building, ventilation and filtration strategies were estimated. Different interventions were made to compare the effects from the current building conditions. The findings demonstrate that building protection effect reduced approximately half the attributable health cases amounting to US$17.7 billion due to PM pollution when compared to levels computed using outdoor data alone. For residential buildings, nationwide adoption of natural ventilation from current state is associated with 28% higher cases of mortality and 13 to 38% higher cases for different morbidities, amounting to US$6.7 billion. The incurred cost is negligible compared to energy costs of air-conditioning. However, nationwide adoption of closed residence and air-conditioning are associated with outcomes including fewer mortality (10 and 6% respectively), fewer morbidities (8 and 4% respectively) and economic savings of US$1.5 and 0.9 billion respectively. The related savings were about a factor of 9 the energy cost for air-conditioning. Nationwide adoption of mechanical ventilation and filtration from current natural ventilation in schools is associated with fewer asthma hospital admissions and exacerbations; although the economic impact is not substantial. Enhanced workplace filtration reduces the mortality and morbidity cases by 14 and 13% respectively amounting to savings of up to US$2.4 billion. The huge costs savings are comparable to the average worker salary and insignificant to energy, installation and rental cost. Despite uncertainty about accurate benefits, this study shows that health and economic gain via different building, ventilation and filtration designs in minimizing ingress of outdoor PM applied to a nationwide scale can be very large. Importantly, the results suggest that PM associated externalities and legislative efforts should not only focus on ambient PM reduction policies but also include building-informed decisions.

Measurement of the detective quantum efficiency in digital detectors consistent with the IEC 62220-1 standard: practical considerations regarding the choice of filter material.

As part of a larger evaluation we attempted to measure the detective quantum efficiency (DQE) of an amorphous silicon flat-panel detector using the method described in the International Electrotechnical Commission standard 62220-1 published in October 2003. To achieve the radiographic beam conditions specified in the standard, we purchased scientific-grade ultrahigh purity aluminum (99.999% purity, type-11999 alloy) filters in thicknesses ranging from 0.1 through 10.0 mm from a well-known, specialty metals supplier. Qualitative evaluation of flat field images acquired at 71 kV (RQA5 beam quality) with 21 mm of ultrahigh purity aluminum filtration demonstrated a low frequency mottle that was reproducible and was not observed when the measurement was repeated at 74 kV (RQA5 beam quality) with 21 mm of lower-purity aluminum (99.0% purity, type-1100 alloy) filtration. This finding was ultimately attributed to the larger grain size (approximately 1-2 mm) of high purity aluminum metal, which is a well-known characteristic, particularly in thicknesses greater than 1 mm. The impact of this low frequency mottle is to significantly overestimate the noise power spectrum (NPS) at spatial frequencies < or = 0.2 mm(-1), which in turn would cause an underestimation of the DQE in this range. A subsequent evaluation of ultrahigh purity aluminum, purchased from a second source, suggests, that reduced grain size can be achieved by the process of annealing. Images acquired with this sample demonstrated vertical striated nonuniformities that are attributed to the manufacturing method and which do not appear to appreciably impact the NPS at spatial frequencies > or = 0.5 mm(-1), but do result in an asymmetry in the x- and y-NPS at spatial frequencies < or = 0.2 mm(-1). Our observations of markedly visible nonuniformities in images acquired with high purity aluminum filtration suggest that the uniformity of filter materials should be carefully evaluated and taken into consideration when measuring the DQE.

Validation of sterilizing grade filtration.

Validation consideration of sterilizing grade filters, namely 0.2 micron, changed when FDA voiced concerns about the validity of Bacterial Challenge tests performed in the past. Such validation exercises are nowadays considered to be filter qualification. Filter validation requires more thorough analysis, especially Bacterial Challenge testing with the actual drug product under process conditions. To do so, viability testing is a necessity to determine the Bacterial Challenge test methodology. Additionally to these two compulsory tests, other evaluations like extractable, adsorption and chemical compatibility tests should be considered. PDA Technical Report # 26, Sterilizing Filtration of Liquids, describes all parameters and aspects required for the comprehensive validation of filters. The report is a most helpful tool for validation of liquid filters used in the biopharmaceutical industry. It sets the cornerstones of validation requirements and other filtration considerations.

Assessment of methods for detection of infectious Cryptosporidium oocysts and Giardia cysts in reclaimed effluents.

This study evaluates the occurrence of Cryptosporidium oocysts and Giardia cysts in reclaimed effluents if method 1623 with the Envirochek capsule filters (standard and high-volume [HV] filters) and a modified version of the Information Collection Rule method (ICR) with the polypropylene yarn-wound cartridge filter are used. The recovery efficiency of the analytical methods was evaluated with samples of reagent, tap, and reclaimed water by using flow cytometer-sorted spike suspensions. (Oo)cyst recovery efficiency determined filter performance and method reproducibility in the water matrix tested. Method 1623 with the Envirochek HV capsule filter generated significantly higher recovery rates than did the standard Envirochek filter and the modified ICR method. Notwithstanding, large variations in recovery rates (>80%) occurred with samples of reclaimed water, and none of the water quality parameters analyzed in the reclaimed effluents could explain such variability. The highest concentrations of indigenous oocysts were detected by method 1623 with the HV filter, which provided a sufficient number of oocysts for further confirmation of infectious potential. Confirmation of species and potential infectivity for all positive protozoan samples was made by using a nested PCR restriction fragment polymorphism assay and the focus detection method most-probable-number assay, respectively. The methodology and results described in the present investigation provide useful information for the establishment of pathogen numeric standards for reclaimed effluents used for unrestricted irrigation.