Guidance For Industry Research Articles

Cybersecurity Resiliency of Marine Renewable Energy Systems Part 2: Cybersecurity Best Practices and Risk Management

Abstract Marine renewable energy (MRE) is an emerging source of power for marine applications, marine devices, and coastal communities. This energy source relies on industrial control systems and IT to support operations and maintenance activities, which create a pathway for an adversary to gain unauthorized access to systems and data and disrupt operations. Incorporating cybersecurity risk prevention measures and mitigation capabilities from inception, development, operation, to decommissioning of the MRE system and components is paramount to the protection of energy generation and the security of network architecture and infrastructure. To improve the resilience of MRE systems as a predictable, affordable, and reliable source of energy, cybersecurity guidance was developed to enable operators to assess cybersecurity risks and implement security measures commensurate with the risk. This publication is the second of a two-part series, with Part 1 addressing a framework to determine cybersecurity risk by assessing the vulnerability of an MRE system to potential cyber threats and the consequences a cyberattack would have on the end user. This Part 2 publication describes an approach to select appropriate cybersecurity best practices commensurate with the MRE system's cybersecurity risk. The guidance includes 86 cybersecurity best practices, which are associated with 36 cybersecurity domains and grouped into nine categories. The best practices follow the core functions of the National Institute of Science and Technology Cybersecurity Framework (e.g., identify, detect, protect, respond, and and recover) and insights from both maritime and energy industry guidance documents to identify security measures effective in protecting information and operational technology assets prevalent in MRE systems.

Enhanced Accuracy of Airborne Volcanic Ash Detection Using the GEOKOMPSAT-2A Satellite.

In this study, a technique facilitating the enhanced detection of airborne volcanic ash (VA) has been developed, which is based on the use of visible (VIS), near-infrared (NIR), and infrared (IR) bands by meteorological satellite systems. Channels with NIR and IR bands centered at ~3.8, 7.3, 8.7, 10.5, and 12.3 μm are utilized, which enhances the accuracy of VA detection. The technique is based on two-band brightness temperature differences (BTDs), two-band brightness temperature ratios (BTRs), and background image BTDs. The physical effects of the observed BTDs and BTRs, which can be used to distinguish VA from meteorological clouds based on absorption differences, depend on the channel and time of day. The Advanced Meteorological Imager onboard the GEOKOMPSAT-2A (GK-2A) satellite has several advantages, including the day- and nighttime detection of land and ocean. Based on the GK-2A data on several volcanic eruptions, multispectral data are more sensitive to volcanic clouds than ice and water clouds, ensuring the detection of VA. They can also be used as an input to provide detailed information about volcanoes, such as the height of the VA layer and VA mass. The GK-2A was optimized, and an improved ash algorithm was established by focusing on the volcanic eruptions that occurred in 2020. In particular, the 3.8 μm band was utilized, the threshold was changed by division between day and night, and efforts were made to reduce the effects of clouds and the discontinuity between land and ocean. The GK-2A imagery was used to study volcanic clouds related to the eruptions of Taal, Philippines, on 12 January and Nishinoshima, Japan, from 30 July–2 August to demonstrate the applicability of this product during volcanic events. The improved VA product of GK-2A provides vital information, helping forecasters to locate VA as well as guidance for the aviation industry in preventing dangerous and expensive interactions between aircrafts and VA.

Active Pharmaceutical Ingredients (API) Regulations in India, USA & Europe: A Comparative Study

ICH Q7 i.e., Good Manufacturing Practice guide for Active Pharmaceutical Ingredients was the late outcome of ICH. The ICH Q7 Guideline is originally based on a PIC/S draft guideline on API and was adopted by PIC/S in 2001, then integrated as part II of the PIC/S GMP Guide in 2007.Q7 is a firm list of what makes an operating Pharmaceutical Quality System. Active Pharmaceutical ingredient is the crucial part of any drug product that can directly influence the safety and efficacy of the medicinal product which may endanger the life of the patient. For this, we have assessed the knowledge on regulatory guidelines adopted by three different counties and to observe API has an appropriate manufacturing process that country should follow the stringent rules under the country’s respective regulatory barrier. We therefore looked onto the Main component of drug product i.e., ‘API’ taking into consideration the regulatory requirements associated with it in 3 different countries and the quality control parameters associated with same. This study is the Elucidation of Regulatory Requirements of GMP i.e., the part of Quality Assurance for API in different countries and guidance for drug industry whose intention is to harmonize actions or processes within a specific discipline. During this study we strictly followed three different regulatory guidelines followed by USA (USFDA), INDIA (SCHEDULE M), EUROPE (EUROPEAN UNION VOL 4). It is imperative to manufacture API abiding by the standard guidelines for subsequent processing and formulation of high-quality raw material.

Logging the Lambeth Group Upper Shelly Beds for the Thames Tideway Tunnel in London, UK: More than just “dark grey clay with shells”

Despite recent advances in the procedures for logging rotary borehole core, the Lambeth Group Upper Shelly Beds are often inadequately characterised during ground investigations for underground construction. With no recognised industry guidance, there has been a lack of clarity and detail in many logging records, other than a generic description of “dark grey clay with many shells and (local) hard bands.” Improvements in describing these deposits have been hindered by the relatively limited extent of their subcrop and rarity of surface exposure, allied to a lack of precedent intersection during underground construction excavation.Geological logging during construction of the Thames Tideway Tunnel has revealed a laterally continuous sequence of strata within the Upper Shelly Beds through central London. This ranges in lithology from strongly indurated shell ‘coquinas’, mudstones and limestones to organic-rich laminated clays, silts and fine sands. Abrupt changes in lithology and fossil fauna are displayed across sharp contacts between beds, indicative of rapid fluctuations in sea level (and so potentially of climate change) during the period of deposition.Notwithstanding their comparatively limited thickness of between 1.4 and 1.6 m within the area of investigation, the Upper Shelly Beds represent significant challenges for underground construction, most notably a reduction in the rate of excavation through the stronger layers of material. Early identification of the sequence has enabled modification and improvement to the on-site construction cycle and provided valuable assurance for the existing engineering design.This paper is intended to provide guidance for recognising the sequence of strata within the Upper Shelly Beds during future ground investigations in central London, with similar benefits for early recognition of the stronger layers during engineering design.

A quantitative LC–MS/MS method for the determination of tissue brincidofovir and cidofovir diphosphate in a MuPyV‐infected mouse model

Brincidofovir (BCV) is an investigational lipid conjugate of the nucleotide analog cidofovir (CDV), which is being developed as a medical countermeasure for the treatment of smallpox. BCV is active against double-stranded DNA viruses including BK and JC viruses. Here, we validated procedures for quantifying BCV and its pharmacologically active moiety cidofovir diphosphate (CDV-PP) in mouse kidney, brain and spleen tissue homogenates. Following homogenization, BCV and CDV-PP were extracted from the tissues by protein precipitation with their stable, isotopically labeled internal standards, BCV-d6 and 13 C3 15 N2 -CDV-PP. Then, samples were analyzed for BCV by reverse-phase chromatography on a Waters Xterra MS C18 (50 × 2.1 mm, 3.5 μm particle size) column while CDV-PP was analyzed on a Thermo BioBasic AX (50 × 2.1 mm, 5 μm particle size) column using anion exchange chromatography. Detection was achieved by electrospray ionization in positive ion mode on an AB Sciex API-5000 triple quadrupole mass spectrometer. The calibration curves were linear over a range of 1.00-1,000 ng/ml homogenate and 0.050-50.0 ng/ml homogenate for BCV and CDV-PP, respectively. These methods were validated according to US Food and Drug Administration guidance for industry and may be used to characterize the tissue pharmacology of both analytes to advance its preclinical development.

Dissolution Testing of Nicotine Release from OTDN Pouches: Product Characterization and Product-to-Product Comparison

In recent years, oral tobacco-derived nicotine (OTDN) pouches have emerged as a new oral tobacco product category. They are available in a variety of flavors and do not contain cut or ground tobacco leaf. The on!® nicotine pouches fall within this category of OTDN products and are currently marketed in seven (7) flavors with five (5) different nicotine levels. Evaluation of the nicotine release from these products is valuable for product assessment and product-to-product comparisons. In this work, we characterized the in vitro release profiles of nicotine from the 35 varieties of on!® nicotine pouches using a fit-for-purpose dissolution method, employing the U.S. Pharmacopeia flow-through cell dissolution apparatus 4 (USP-4). The nicotine release profiles were compared using the FDA’s Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms. The cumulative release profiles of nicotine show a dose dependent response for all nicotine levels. The on!® nicotine pouches exhibit equivalent percent nicotine release rates for each flavor variant across all nicotine levels. Furthermore, the nicotine release profiles from on!® nicotine pouches were compared to a variety of other commercially available OTDN pouches and traditional pouched smokeless tobacco products. The percent nicotine release rates were found to be dependent on the product characteristics, showing similarities and differences in the nicotine release profiles between the on!® nicotine pouches and other compared products.

AN ASSET VALUE EVALUATION FOR DOCKING FINANCE LEASE PROBLEMS IN THE PEER-TO-PEER PLATFORM

The convenience and rapidity of financial leasing modes in the peer-to-peer (P2P) platform enable small and medium-sized enterprises (SMEs) to solve financing problems. The core of risk management in the P2P platform is to improve the quality of the docking assets. Therefore, the purpose of this paper is to establish a financial leasing value model of debt cession with an optimal economic pattern and an analysis of the risk assessment to improve the management of the asset value docking quality of both parties. For the transaction price of the leased assets in a P2P platform, this paper establishes multi-periodic, continuous, and variable models of the leased assets value evaluation, taking rent, lease term, and interest as independent variables. The paper proves that the price of the leased assets is related to the interest force, the rent per period, and the numbers of payments and changes in rent when other factors remain unchanged. Our results prove that the risk of the P2P platform docking finance lease and the transfer of the creditor’s rights investment mode are low. The proposed scheme is verified through hypothesis testing and model simulation. When the lease term is longer and the interest rate is higher, the difference between the two function surfaces is larger. Thus, the business model of financial leasing in the P2P platform has more obvious business advantages. It provides better business macro direction and business micro-management guidance for the leasing industry, P2P platforms and financial leasing companies.

Pharmaceutical Data Integrity: issues, challenges and proposed solutions for manufacturers and inspectors

Data Integrity, which is data deemed Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available (ALCOA-plus), has been the focus of the pharmaceutical industry in recent years. With the growing use of computerized systems and rising prevalence of outsourcing manufacturing processes, ensuring data integrity is becoming more challenging in an increasingly complex pharmaceutical manufacturing industry. To address this issue, multiple legislation and guidance documents such as ‘Data Integrity and Compliance with CGMP Guidance for Industry’ from the US Food and Drug Administration (FDA), ‘GxP’ Data Integrity Guidance and Definitions from the UK Medicines & Healthcare products Regulatory Agency (MHRA), and ‘Guidance on Good Data and Record Management Practices’ from the World Health Organization (WHO), have been published in recent years. However, with rising data integrity issues observed by FDA, WHO, MHRA and other pharmaceutical inspectors even after these guidance documents have been published, their overall effectiveness is yet to be determined. This paper compares and evaluates the legislation and guidance currently in existence; and discusses some of the potential challenges pharmaceutical manufacturers face in maintaining data integrity with such legislation and guidance in place. It appears that these legislation and guidance are insufficient in maintaining data integrity in the industry when used alone. Last, but not least, this paper also reviews other solutions, such as the need for a company culture of integrity, a good database management system, education and training, robust quality agreements between contract givers and acceptors, and performance of effective audits and inspections, to aid in maintaining data integrity in the manufacturing industry. These proposed solutions, if successfully implemented, can address the issues associated with data integrity, and raise the standard of pharmaceutical and biopharmaceutical manufacturing worldwide.

Perspectives on updates, clarifications and controversies in chromatographic assay guidance for bioanalytical method validation from major regulatory agencies and organizations.

Bioanalysis, a key supporting function for generating data for pre-clinical and clinical studies in drug development, is under the regulation of local agencies as well as global organizations to ensure the data integrity and quality in submission. As major regulatory agencies and organizations, the US Food and Drug Administration, the European Medicines Agency and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use have been updating their industry guidance for bioanalytical method validation, to keep up with the development new modalities, technologies and regulations. This article summarizes the recent updates and any clarifications and controversies triggered by those updates. Perspectives and recommendations are given based on our own experience as well as commonly accepted practice in the bioanalytical community.

Attitude of building experts towards novel biobased wood-polymer façades under various properties: A choice-based experiment and impact analysis

Façade products made of Wood-Polymer Composites (WPC) have been on the market for 10 years, but with only moderate success. This study investigated the willingness-to-pay in the construction industry for WPC façades equipped with different utility bundles. For this purpose, an auction-like, choice-based survey was conducted among 212 building experts. It was found that 65% are open to consider such a biobased façade in planning. The consent was not dependent on the social-normative company conditions, but significantly associated with personal attitude and age. The greatest demand is expected when WPC façades with an initially small bending-strength should first or simultaneously become regulated by technical approvals and given higher strength as part of further development works. Eco-certification is the second best alternative, although further developments will quickly reduce turnover again. Developing only bending-strength for higher load-capacity, as is currently the case in the market, leads to the worst results. The findings provide guidance for the WPC industry.

PIH36 Content Validity and Scoring of Intrauterine System Daily Bleeding Diary (IUS-DBD) for Women Using Ius for Contraception

The IUS Daily Bleeding Diary (IUS-DBD) is a single-item patient-reported outcome (PRO) measure with a 5-point Likert response scale and a 24-hour recall period, designed to evaluate the intensity and frequency of uterine bleeding. In accordance with United States (US) Food and Drug Administration (FDA) PRO Guidance for Industry 2009 requirements, this study evaluated the content validity (relevance, appropriateness, and understandability) and scoring of the IUS-DBD in a sample of women using IUS for contraception. This was a non-interventional, qualitative interview study. Participants were identified by clinicians in the US; women were eligible if they had used IUS contraception for 2–6 months and had experienced bleeding during this time or had the IUS removed due to bleeding. Interviews utilized a semi-structured interview guide with concept elicitation and cognitive debriefing methodology to evaluate the content validity of the IUS-DBD. Hypothetical bleeding profiles were assessed to explore clinically meaningful differences. Transcripts were analysed using framework analysis techniques in ATLAS.ti v7. Twenty women were interviewed. Participants (n=16/20, 80%) reported experiencing initial bothersome bleeding/spotting following IUS insertion and stated that fewer days of bleeding/spotting during the initial 3 months would be an important and meaningful improvement (n=18/18, 100%). Participants (n=20/20, 100%) interpreted the meaning of the IUS-DBD correctly (n=20/20, 100%) and found it easy to understand (n=18/19, 95%). Most correctly interpreted the recall period (n=17/20, 85%) and found the response options to be appropriate, distinct and usable (n=17/20, 85%). Based on hypothetical bleeding profiles, participants perceived a 10% reduction in days of bleeding/spotting per 30 days to be minimally improved (20%-42% participants), a 30% reduction to be minimally/much improved (>85% participants), and a 50% reduction to be much/very much improved (>75% participants). The IUS-DBD is a content valid PRO to evaluate uterine bleeding in clinical studies with women using IUS for contraception.

Assessment of rVWF Pharmacokinetics in Overweight and Obese VWD Patients Using a Population Pharmacokinetic Model

Introduction: Adequate treatment and prevention of bleeding in patients with von Willebrand disease (VWD) requires replacement of von Willebrand factor (VWF) to thresholds often dictated by the clinical situation. While weight (WT)-based dosing is widely used for calculation of clotting factor dose, its validity in all populations has been debated. Further questions have arisen regarding the use of ideal vs actual body weight to calculate dose, likely driven by the large interindividual variability between factor concentrations and associated pharmacokinetics (PK). Understanding the relationship between body size and VWF PK in overweight and obese patients could contribute to optimization of dosing in these populations. Here, we aimed to understand the relationship between body size metrics (body mass index [BMI] and WT) and PK parameters of recombinant VWF (rVWF) in overweight and obese patients, using a population model that described von Willebrand Ristocetin Cofactor (VWF:RCo) PK following rVWF administration. Methods: A previously developed 2-compartment population PK model, capturing the influence of body size on VWF:RCo PK by WT-based allometric scaling (Bauer A et al, Res Pract Thromb Haemost 2020;4[Suppl 1]), was utilized to investigate rVWF PK in overweight and obese VWD patients. VWF:RCo data used for model development originated from two phase 1 (study 070701 and 071104) and two phase 3 (study 071001 and 071101) VWD trials, for a total of 79 patients with a BMI and WT range of 16.6-47.8 kg/m2 and 43.8-144.8 kg, respectively. The model performance in the target subgroup of patients was qualified by means of visual predictive checks (VPC). The relationship between BMI/WT and individual PK parameters was then investigated graphically. Finally, an exposure-matching exercise was performed to assess whether VWF:RCo exposure following rVWF administration in overweight subjects was comparable to that of the reference population (Food and Drug Administration, Guidance for Industry, Exposure-Response Relationships: Study Design, Data Analysis, and Regulatory Applications, 2003); to this end, VWF:RCo area under the curve from time zero to infinity (AUCinf) for patients of 45-150 kg was simulated following a rVWF dose of 50 IU/kg. The AUCinf was then compared to the target AUCinf range, defined as the AUCinf of a 74-kg patient receiving 50 IU/kg rVWF +/- 20% (Weiner D, Improving the Drug Company Information to Real World Patient Drug Dosing: a Rivaroxaban AF Case Study, American College of Pharmacometrics 2019 Meeting). Results: The VPC stratified by BMI and WT showed satisfactory predictive performance of the model in overweight patients, with a slight underprediction of peak VWF:RCo activity in patients with BMI >25 kg/m2. As expected, graphical analyses indicated an increase in VWF:RCo clearance and volume of distribution with rising BMI and WT, whereas half-life (t1/2), incremental recovery (IR) and mean residence time appeared to be independent of body size. Trends in PK parameters vs. WT or BMI were similar because of the high correlation between the two body size indices (r=0.94 in the present data set). The simulations of VWF:RCo PK revealed that, for the typical patient, AUCinf was within the target exposure across the weight range of 45-150 kg. Deviations from the target AUCinf were observed when inter-individual variability was considered. Conclusions: The available PK model adequately described VWF:RCo activity in overweight patients with VWD. Overall, t1/2 and IR remained the same even as BMI or WT increased. Model-simulations indicated that, on average, WT-based dosing in patients of < 150 kg led to an AUCinf of VWF:RCo within the pre-defined target. These results support calculation of rVWF dosing based on actual WT in a patient population similar to the one included in the current analysis (BMI ≤ 47.8 kg/m2). However, PK assessments should remain regularly utilized by physicians to address any potential interindividual variability. Disclosures Hale: Takeda Pharmaceutical Company Limited: Current Employment. Bauer:Baxalta Innovations GmbH, a Takeda company, Vienna, Austria: Current Employment, Current equity holder in publicly-traded company. Smania:Pharmetheus: Current Employment; Baxalta/Takeda: Consultancy. Friberg-Hietala:Pharmetheus: Current Employment, Current equity holder in private company; Baxalta/Takeda: Consultancy. Wolfsegger:Baxalta Innovations GmbH, a Takeda company: Current Employment, Current equity holder in publicly-traded company.

Evidence supporting wound care end points relevant to clinical practice and patients' lives. Part 3: The Patient Survey.

The 2006 U.S. Food and Drug Administration Guidance for Industry emphasizes wound closure as the primary outcome for clinical trials in wound healing. Wound care professionals understand that complete wound healing is not always achievable when evaluating new treatments. FDA, Association for the Advancement of Wound Care, and Wound Healing Society are working collaboratively to identify scientifically achievable, clinically relevant, and patient-centered endpoints with sufficient support to serve as primary outcomes for clinical trials. The Opinion Survey from People with Wounds presented here addresses an important but understudied issue: the gap between clinician, healthcare insurance companies, government agencies, and patient perspectives regarding clinically meaningful and scientifically achievable primary endpoints for wound care. The survey, adapted from the clinician survey with adjustment for health literacy, was pilot tested and revised based on a limited number of patients in a single clinic. After central IRB approval, the on-line survey was administered in English and Spanish and submitted anonymously to a server with the cooperation of multiple wound clinics and societies. Four hundred and thirty-eight patients and caregivers from across the United States responded over a 10-month period. Based on this survey, the most valuable clinical endpoints were reduced infection, recurrence, and amputation. The most valuable quality of life outcomes were increased independence, reduced social isolation, and pain. The top five endpoints in terms of usefulness for measuring clinical trial success were time to heal, wound size, infection, recurrence, and pain. Narrative responses from wound patients emphasized the inability to perform activities of daily living and pain as major factors that impacted their daily lives. Engagement of patients in clinical trials and evaluation of potential treatments is critical to improving wound care. This survey provides insight into the needs of patients with wounds and provides a roadmap for structuring future clinical trials to better meet those needs.

Bacterial Endotoxin Testing-Fast Endotoxin Masking Kinetics in the Presence of Lauryldimethylamine Oxide.

For release of parenteral drug products, bacterial endotoxin testing is one of a panel of necessary tests. In order to ensure the validity of such tests, various controls are performed, including demonstration of compendial method suitability or method qualification. In addition to compendial suitability testing, quality control (QC) sample hold-time studies are requested by authorities like the Food and Drug Administration (FDA) as described in “Guidance for Industry: Pyrogen and Endotoxins Testing.” It is requested to be determine whether the ability to detect endotoxins can be affected by storage and handling of the sample to be tested. To accomplish these studies, endotoxin is introduced or spiked into the undiluted product and held for a certain period of time in process-representative containers. This time period reflects procedural maximum QC sample hold time from sampling until analysis. Inadequate detection of endotoxin can be caused by adsorption of endotoxin to container surfaces or molecular masking effects, in which the binding sites on the endotoxin molecules are prevented from triggering the enzymatic cascade necessary in the assay, are obscured. The endotoxin may form macromolecular structures, such as sheets or blebs, or the binding sites may otherwise be rendered unavailable due to the sample matrix composition. In either case, the endotoxin assay may yield falsely low results if and when masking occurs. In this work, the QC sample hold times of different in-process controls within the production process of a biopharmaceutical product were analyzed. One out of eight different samples showed a strong masking of endotoxin. Analysis of the sample composition revealed that either kifunensine, mycophenolic acid (MPA), or lauryl-N, N-dimethylamine oxide (LDAO) was responsible for masking. Further analysis clearly identified LDAO as the root cause for masking. A novel one-step mechanism for LDAO-induced endotoxin masking is proposed. The principle is similar to an already-proposed two-step mechanism for endotoxin masking, but the LDAO case combines these two steps: the disturbance of the salt bridges and hydrophobic interactions with LPS in one molecule. These molecular interactions occur quickly when both endotoxin and LDAO are present in the same matrix. Thus, depending on the masking agents, low endotoxin recovery (LER) can occur regardless of the QC sample hold duration.

A level set based immersed boundary method for simulation of non-isothermal viscoelastic melt filling process

In this work, the polymer melt filling process is simulated by using a coupled finite volume and level-set based immersed boundary (LS-IB) method. Firstly, based on a shape level set (LS) function to represent the mold boundary, a LS-IB method is developed to model the complex mold walls. Then the non-isothermal melt filling process is simulated based on non-Newtonian viscoelastic equations with different Reynolds numbers in a circular cavity with a solid core, and the effects of Reynolds number on the flow patterns of polymer melt are presented and compared with each other. And then for a true polymer melt with a small Reynolds number that varies with melt viscosity, the moving interface, the temperature distributions and the molecular deformation are shown and analyzed in detail. At last, as a commonly used application case, a socket cavity with seven inserts is investigated. The corresponding physical quantities, such as the melt velocity, molecular deformation, normal stresses, first normal stress difference, temperature distributions and frozen layer are analyzed and discussed. The results could provide some predictions and guidance for the polymer processing industry.

The Next One

Even as we continue to battle the scourge of COVID-19, there's a lot of hope that things eventually will return to normal. Moving forward, though, will there ever be a time when we aren't at the outset of another global pandemic, and should planning efforts more often consider strategies to address a pandemic on top of another disaster? COVID-19 has revealed many of the water industry's strengths and some areas that need improvement, but thankfully water professionals are used to planning for uncertainty. Accommodating the natural cycle of water moving through the environment with seasonal impacts, leaders and decision makers must also account for any significant negative events in their forecasts and plans. For example, utilities and the communities they serve must also address drought leading to wildfires, torrential rains producing floods, and deep freezes causing pipes to burst. Climate change increases the likelihood of those extremes, but even when facing a flood after a fire during a pandemic, water services must always continue. While most of us are focused on the COVID-19 pandemic, some of those in the trenches are already preparing for the next catastrophe—be it another pandemic or some other global disturbance. Regardless of challenges and their combinations, water experts are creating the policies, plans, and bases of design to account for whatever comes next. It's up to water professionals to know their systems, build in and expand resiliency, and guide a community's valuable assets through one event, then another, or sometimes two or more at the same time. However, the challenges that seem daunting today will catalyze understanding and innovation, leaving the industry better prepared for the future. We can't allow any natural or man-made force to overwhelm a community's water systems under normal conditions but especially not in times of crisis. In preparing for and dealing with large-scale threats, it's great to have relationships in place so responses and resources can be coordinated quickly. At the local level, teams must be properly equipped and prepared, and AWWA is ready and able to connect those who need help with the industry guidance and expertise they need. Responding to COVID-19, the water industry so far hasn't missed a beat, and those systems that faced wildfires or floods on top of this pandemic are learning lessons that will serve as future models for responding to compounding calamities. In preparing for the next one, the water industry will need to optimize available resources to ensure water systems and the professionals behind them can effectively face the next contagion combined with a natural disaster occurring alongside a man-made challenge, while always looking ahead for the next one. This month's Journal AWWA features articles on source water protection, water loss control, lead and copper control, and using inclusive language. If you are interested in submitting an article, contact me at journaleditor@awwa.org.

Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ).

Background and ObjectiveChronic insomnia has major consequences for daytime functioning, yet no fully validated patient-reported outcome instrument for once-daily assessments is available to measure these consequences. This study describes the development and psychometric evaluation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ).MethodsThe Daytime Insomnia Symptom Scale (DISS), an existing 20-item instrument for assessing daytime functioning, was modified to give an 18-item version of the IDSIQ (IDSIQ-18) based on iterative qualitative interviews with 54 subjects with insomnia and expert input. The construct validity and other psychometric properties of the IDSIQ-18 were analyzed based on an interventional study (NCT03056053) in which subjects with insomnia received zolpidem (5 or 10 mg) daily for 2 weeks and an observational study among subjects with no diagnosis of insomnia (good sleepers). Participants in both studies completed the IDSIQ-18 daily for 2 weeks. Exit interviews were conducted with a sample of subjects who completed the interventional study to elicit concepts defining the experience of insomnia, to assess understanding of the response scales, and to determine meaningful change thresholds. Exploratory factor analysis and Rasch analysis were conducted to further assess the structure and latent model for the scoring of the final IDSIQ instrument. Further psychometric evaluation of the final IDSIQ was then conducted.ResultsSubjects in both the interventional study (N = 114) and observational study (N = 103) were predominantly female (65% for subjects with insomnia and 60% for good sleepers). Mean age was 51 years for subjects with insomnia and 45 years for good sleepers. Subjects in the exit interviews (N = 41) demonstrated a good understanding of the IDSIQ-18 response scales. Day 1 mean scores were higher (worse) in subjects with insomnia compared with good sleepers. Based on inter-item correlation, exploratory factor, and Rasch analyses and review of the qualitative data, four items were removed. This yielded the final IDSIQ, with 14 items comprising three domains: Alert/Cognition, Mood, and Sleepiness. The domain structure was determined in a confirmatory factor analysis. Evidence of internal consistency reliability was strong: day 1 Cronbach’s alpha was 0.917 for IDSIQ total score and 0.806–0.918 for the domains. Test-retest reliability, assessed for subjects with insomnia with no change on the Patient Global Assessment of Disease Severity scale between day 1 and day 8, was also good (intra-class correlation coefficient 0.856–0.911). Meaningful change thresholds derived for this sample using anchor-based approaches were 20 for IDSIQ total score, 9 for the Alert/Cognition domain, 4 for the Mood domain, and 4 for the Sleepiness domain.ConclusionsThese studies, which closely followed Food and Drug Administration Guidance for Industry on patient-reported outcome measures, support use of the IDSIQ as a fit-for-purpose measure for deriving valid and reliable endpoints in insomnia clinical research trials and real-world studies.Electronic supplementary materialThe online version of this article (10.1007/s40271-020-00474-z) contains supplementary material, which is available to authorized users.

An implementation for Smart Manufacturing Information System (SMIS) from an industrial practice survey

Countries around the world have put forward the Smart Manufacturing System (SMS), and described its implementation process from different dimensions. Even though, there is not much research on more specific and further in-depth application scenarios for Smart Manufacturing Information System (SMIS). Scholars’ research on smart manufacturing is focus on a part of the production system, but there is little research on top-level design from the perspective of the overall system to outline most of the elements covered by enterprises in the implementation of smart manufacturing process and the relationship between them. Especially, there is little research on the detailed step-by-step implementation steps of top-level planning and design for the implementation of smart manufacturing system in enterprises. Therefore, a general reference architecture for SMIS (Smart Manufacturing Information System) is proposed in this paper through a detailed survey of 42 enterprises in the information dimension of smart manufacturing. Then, the implementation path of SMIS is deduced from the connecting of the above integrated subsystems of SMIS. Finally, a comprehensive case study for SMIS in automobile manufacturing industry is given. This study can provide some guidance for enterprises to gradually carry out smart manufacturing system from the perspective of information technology. The SMIS’ reference general architecture, related reference subsystems, and implementation can be used as a guidance for Industry and government in designing, planning, setting up and implementing SMIS. At the same time, based on the existing smart manufacturing system framework, it has some complementary value.

Statistical Considerations in Assessing In Vivo Adhesion with Transdermal and Topical Delivery Systems for New Drug Applications.

Proper adhesion plays a critical role in maintaining a consistent, efficacious, and safe drug delivery profile for transdermal and topical delivery systems (TDS). As such, in vivo skin adhesion studies are recommended by regulatory agencies to support the approval of TDS in new drug applications (NDAs). A draft guidance for industry by the US Food and Drug Administration outlines a non-inferiority comparison between a test product and its reference product for generic TDS in abbreviated new drug applications (ANDAs). However, the statistical method is not applicable for evaluating adhesion of TDS for NDAs, because no reference product exists. In this article, we explore an alternative primary endpoint and a one-sided binomial test to evaluate in vivo adhesion of TDS in NDAs. Statistical considerations related to the proposed approach are discussed. To understand its potential use, the proposed approach is applied to data sets of in vivo adhesion studies from selected NDAs and ANDAs.

The Role of Patients in Alopecia Areata Endpoint Development: Understanding Physical Signs and Symptoms.

Meaningful patient input to understand disease experience and patient expectations for improvement with treatment is essential for the selection and development of outcome measures for alopecia areata (AA) clinical trials. This study explored the physical signs and symptoms of AA through 30 semistructured interviews with adult (n= 25) and adolescent (n= 5) patients experienced with severe or very severe AA. Scalp hair loss was overwhelmingly the most important sign and symptom of AA. Nearly all patients (90%) considered scalp hair loss in their top three most bothersome physical signs and symptoms of AA, with 77% (n= 23) naming scalp hair loss as the most bothersome symptom. Other identified signs and symptoms in the top three most bothersome included eyebrow, eyelash, nose, body, and facial hair loss, as well as eye irritation and nail damage and/or appearance. Eyebrow (16%, n= 4), eyelash (4%, n= 1), nasal (4%, n= 1), and body (4%, n= 1) hair loss were identified by seven adult patients as the most bothersome signs and symptoms of AA. Conceptual saturation confirmed that a comprehensive understanding of this patient population's physical AA-related signs and symptoms was obtained. These findings indicate that the primary objective for new AA treatments for this patient population should be meaningful improvement in scalp hair growth to address the most troubling unmet need.