Quality Control Considerations Research Articles

Manufacturing Bacteriophages (Part 2 of 2): Formulation, Analytics and Quality Control Considerations.

Within this second piece of the two-part series of phage manufacturing considerations, we are examining the creation of a drug product from a drug substance in the form of formulation, through to fill-finish. Formulation of a drug product, in the case of bacteriophage products, is often considered only after many choices have been made in the development and manufacture of a drug substance, increasing the final product development timeline and difficulty of achieving necessary performance parameters. As with the preceding review in this sequence, we aim to provide the reader with a framework to be able to consider pharmaceutical development choices for the formulation of a bacteriophage-based drug product. The intent is to sensitize and highlight the tradeoffs that are necessary in the development of a finished drug product, and to be able to take the entire spectrum of tradeoffs into account, starting with early-stage R&D efforts. Furthermore, we are arming the reader with an overview of historical and current analytical methods with a special emphasis on most relevant and most widely available methods. Bacteriophages pose some challenges that are related to but also separate from eukaryotic viruses. Last, but not least, we close this two-part series by briefly discussing quality control (QC) aspects of a bacteriophage-based product, taking into consideration the opportunities and challenges that engineered bacteriophages uniquely present and offer.

Haplotype-resolved de novo assembly of the Vero cell line genome

The Vero cell line is the most used continuous cell line for viral vaccine manufacturing with more than 40 years of accumulated experience in the vaccine industry. Additionally, the Vero cell line has shown a high affinity for infection by MERS-CoV, SARS-CoV, and recently SARS-CoV-2, emerging as an important discovery and screening tool to support the global research and development efforts in this COVID-19 pandemic. However, the lack of a reference genome for the Vero cell line has limited our understanding of host–virus interactions underlying such affinity of the Vero cell towards key emerging pathogens, and more importantly our ability to redesign high-yield vaccine production processes using Vero genome editing. In this paper, we present an annotated highly contiguous 2.9 Gb assembly of the Vero cell genome. In addition, several viral genome insertions, including Adeno-associated virus serotypes 3, 4, 7, and 8, have been identified, giving valuable insights into quality control considerations for cell-based vaccine production systems. Variant calling revealed that, in addition to interferon, chemokines, and caspases-related genes lost their functions. Surprisingly, the ACE2 gene, which was previously identified as the host cell entry receptor for SARS-CoV and SARS-CoV-2, also lost function in the Vero genome due to structural variations.

Untargeted Metabolomics Workshop Report: Quality Control Considerations from Sample Preparation to Data Analysis.

The Proteomics Society, India (PSI), hosted the Metabolomics workshop on experimental and data analysis training for untargeted metabolomics in December 2019. The workshop included six tutorial lectures and hands-on data analysis training sessions presented by seven speakers from across the globe. The tutorials and hands-on data analysis sessions focused on workflows for liquid chromatography-mass spectrometry (LC-MS) based on untargeted metabolomics. We review here three main topics from the workshop, which were uniquely identified as bottlenecks for new researchers: (a) experimental design, (b) quality controls during sample preparation and instrumental analysis, and (c) data quality evaluation using open source tools. Our objective here is to present common challenges faced by novice researchers and present guidelines to address them. We provide resources and good practices for researchers who are at the initial stage of setting up metabolomics workflows in their laboratories.

The impact of UAV flight planning parameters on topographic mapping quality control

There is a growing need for up-to-date data for rapid decision making in the modern digital age. Recently, the need for high-resolution topographic maps is highly demanding by most mapping clients. With the maturing automatic structure from mobile and multi-view stereoscopy software, small organizations and individuals now have the ability to make their own surveys based on mobile mapping devices. This study looks at how feasible using low-cost Unmanned Aerial Vehicle (UAV) as a mobile mapping device for photogrammetric topographical surveys. It is showing the impact of different UAV flight settings and parameters on the accuracy of mapping products. An automatic scenario for photogrammetric flight mission and its execution are proposed and described. The focus of this research is to generate 3D point clouds from digital imagery using low-cost UAV and showing the relationship between flight mission settings and the quality of the delivered 3D data. Automatic solution is presented and analysed, which automatically generate 3D point clouds from arbitrary image configurations. Results delivered within millimetres based on specific flight setting and optimal quality control considerations. Accuracy assessment and validation process was adopted based on statistical assessments according to ground truth 3D adjusted measurements to assure validity.

Digital Breast Tomosynthesis: Physics, Artifacts, and Quality Control Considerations.

As digital breast tomosynthesis (DBT) becomes widely used, radiologists must understand the basic principles of (a) image acquisition, (b) artifacts, and (c) quality control (QC) that are specific to DBT. Standard acquisition parameters common to both full-field digital mammography (FFDM) and DBT are combinations of x-ray tube voltage, current exposure time, and anode target and filter combinations. Image acquisition parameters specific to DBT include tube motion, sweep angle, and number of projections. Continuous tube motion or x-ray emission decreases imaging time but leads to focal spot blurring when compared with step-and-shoot techniques. The sweep angle and number of projections determines resolution. Wider sweep angles allow greater out-of-plane (z-axis) resolution, improving visualization of masses and architecture distortion. A greater number of projections increases in-plane or x-y axis resolution, improving visualization of microcalcifications. Artifacts related to DBT include blurring-ripple, truncation, and loss of skin and superficial tissue resolution. Motion artifacts are difficult to recognize because of inherent out-of-plane blurring. To maintain optimal image quality and an "as low as reasonably achievable" (ALARA) radiation dose, regular QC must be performed. DBT is considered a new imaging modality; therefore, breast imaging facilities are required to obtain a separate certification in addition to that in FFDM, and all personnel (radiologists, technologists, and medical physicists) are mandated to complete initial DBT training and maintain appropriate continuing medical education credits. ©RSNA, 2019.

Risk of excessive intake of vitamins and minerals delivered through public health interventions: objectives, results, conclusions of the meeting, and the way forward.

The excessive consumption of certain vitamins and minerals could have deleterious consequences on health and development of individuals and populations. Simultaneous micronutrient-delivery interventions could be challenging in terms of safety as the target populations may overlap, posing a risk of excessive intake of certain micronutrients. The Evidence and Programme Guidance Unit of the Department of Nutrition for Health and Development of the World Health Organization convened a technical consultation on the risk of excessive intake of vitamins and minerals delivered through public health interventions in October 2017. The technical consultation's working groups identified important and emerging technical issues, lessons learned, and research priorities related to (1) planning, implementing, monitoring, and evaluating nutrition programs for the detection and control of the risk of excessive intakes; (2) safety, quality control, and assurance considerations; (3) coordination between public health nutrition interventions and other interventions and sectors; and (4) the legislative framework and policy coherence needed for simultaneous nutrition interventions. This paper provides the background and rationale of the technical consultation, synopsizes the presentations, and provides a summary of the main considerations proposed by the working groups.

Additive Manufacturing with 3D Printing: Progress from Bench to Bedside.

Three-dimensional (3D) printing was discovered in the 1980s, and many industries have embraced it, but the pharmaceutical industry is slow or reluctant to adopt it. Spiritam® is the first and only 3D-printed drug product approved by FDA in 2015. Since then, the FDA has not approved any 3D-printed drug product due to technical and regulatory issues. The 3D printing process cannot compete with well-established and understood conventional processes for making solid dosage forms. However, pharmaceutical companies can utilize it where mass production is not required; rather, consistency, precision, and accuracy in quality are paramount. There are many 3D printing technologies available, and not all of them are amenable to pharmaceutical manufacturing. Each 3D technology has certain prerequisites in terms of material that it can handle. Some of the pertinent technical and regulatory issues are as follows: Current Good Manufacturing Practice, in-process tests and process control, and cleaning validation. Other promising area of 3D printing use is printing medications for patients with special needs in a hospital and/or pharmacy setting with minimum regulatory oversight. This technology provides a novel opportunity for in-hospital compounding of necessary medicines to support patient-specific medications. However, aspects of the manufacturing challenges and quality control considerations associated with the varying formulation and processing methods need to be fully understood before 3D printing can emerge as a therapeutic tool. With these points in mind, this review paper focuses on 3D technologies amenable for pharmaceutical manufacturing, excipient requirement, process understanding, and technical and regulatory challenges.

A Paradigm Shift: Considerations in Prenatal Cell-Free DNA Screening.

Testing to determine the health of a fetus has undergone multiple iterations since the widespread adoption of amniocentesis in the 1970s, including several combinations of ultrasound and/or maternal serum screening. The clinical paradigm for prenatal screening for fetal chromosome aneuploidies was transformed by the introduction of cell-free DNA (cfDNA) screening or noninvasive prenatal screening in 2011. The clinical performance of cfDNA screening is well-established for the most common autosomal and sex chromosome aneuploidies with a detection rate exceeding 90% for all aneuploidies. One of the most significant advantages of cfDNA screening relative to maternal serum screening is the markedly reduced false-positive rate, which is <0.5%. The clinical implementation of cfDNA screening is discussed at length, including key biological, preanalytical, and analytical factors that affect test performance. cfDNA prenatal screening for whole chromosome aneuploidies has become routine in high-risk obstetric populations. There is tremendous interest in expanding cfDNA screening to the general obstetric population. Early studies suggest that routine application of cfDNA screening is both feasible and effective, although significant economic and quality control considerations remain.

AF4-ICPMS with the 300 Da Membrane To Resolve Metal-Bearing "Colloids" < 1 kDa: Optimization, Fractogram Deconvolution, and Advanced Quality Control.

The smallest colloids exert a disproportionately large influence on colloidal systems owing to their greater surface area; however, the challenges of working in the smaller size range have limited most field-flow fractionation-ICPMS analyses to sizes > ca. 1 kDa. We discuss considerations and present solutions for overcoming these challenges, including high pressures associated with using the 300-Da membrane, calibration in this small size range, accounting for drifting LODs and separation conditions during membrane aging, and optimizing the compromise between resolution and recovery. Necessary flow program ranges for observing pressure limits are discussed, and calibration is conducted using a combination of bromophenol blue and polystyrene size standards. The impact of membrane drift on size is demonstrated and effectively corrected by routine calibration. Separation conditions are optimized by monitoring the recovery and resolution of several trace metals. A precise, high-resolution separation is achieved using fractogram deconvolution to fully resolve overlapping peaks. Method effectiveness and precision are demonstrated through triplicate analyses of three natural water samples: Mp = 2.89 ± 0.04, 3.20 ± 0.03 and 3.50 ± 0.12 kDa for DOM-associated Fe in the three samples (±95% CI). A primarily inorganic Fe fraction with Mp = 14.7 ± 0.5 kDa was also resolved from the DOM-associated fraction. Quality control methods and considerations for optimizing flow conditions are detailed in the Supporting Information as a guide for researchers seeking to analyze colloids in this smallest size range using AF4-ICPMS with the 300-Da membrane.

When more really means more: WGS standards and quality control.

Next-generation sequencing (NGS) is reshaping the landscape of modern genetic diagnostic laboratories and their operational standards. NGS is gradually replacing the single-gene Sanger sequencing with targeted multigene panel-based resequencing for genes with variants implicated in any number of common diseases, from cardiovascular or neurological disorders to cancers or drug treatment response. Further advances in technology are positioning whole exome and ultimately whole genome sequencing (WES and WGS) for common diagnostic use. In a rapidly changing environment, quality control considerations are crucial. In this issue, Stephan White et al. (Hum Mutat 38: 912–921, 2017) discuss the critical steps that are required to properly perform WGS. They emphasize the key differences between WGS and WES, the important variables that need to be taken into serious consideration when performing NGS for both germline and somatic variants, the necessary quality control measures to monitor the entire process, and the standard operation procedures to ensure that NGS services will always be provided in a standardized manner. It is obvious that further technological advances in massively parallel DNA sequencing technology, accompanied by concomitant price reductions, will make WES and WGS more affordable and hence easier to become the ultimate genetic test in molecular diagnosis. Such advances must undoubtedly be accompanied with the necessary health technology assessment and economic evaluation analyses, demonstrating that such approaches are indeed cost-effective so that they can be adopted sooner and, most importantly, are covered by national healthcare systems. The points discussed in White et al., combined with those from recently published guidelines for variant calling, genomic databases, genomic data sharing and translational tools, should facilitate implementation of NGS services into the molecular diagnostic setting for routine clinical care.

Algunos aspectos técnicos sobre la Estación Meteorológica Automática de la Reserva Biológica Alberto Manuel Brenes

The sitting, layout, data collection and maintenance aspects for Alberto Manuel Brenes Biological Reserve´s automatic weather station are described. This manuscript mentions metadata and quality control considerations for the weather station. Temperature, precipitation and wind speed basic analysis is done for the 2008 – 2016 period.

Managers of Molecular Imaging Laboratories (MOMIL) Interest Group.

The Managers of Molecular Imaging Laboratories (MOMIL) interest group in the World Molecular Imaging Society provides a forum for exchanging information between researchers who manage molecular imaging laboratories and institutional core facilities. This information exchange includes operational procedures for acquiring and analyzing imaging results, including considerations for quality assurance and quality control, and animal handling and care for imaging studies. MOMIL also exchanges administrative policies, interactions with collaborators and clients, and industry relations. In addition to this comprehensive review of MOMIL, more information is available at http://www.wmis.org /.

Optimization of a Relative Telomere Length Assay by Monochromatic Multiplex Real-Time Quantitative PCR on the LightCycler 480: Sources of Variability and Quality Control Considerations

Telomere length (TL) measurement is central to many biomedical research, population, and epidemiology studies, with promising potential as a clinical tool. Various assays are used to determine TL, depending on the type and size of the sample. We describe the detailed optimization of a monochromatic multiplex real-time quantitative PCR (MMqPCR) assay for relative TL using the LightCycler 480. MMqPCR was initially developed using a different instrument with many separate reagents. Differences in instrument performance, reagents, and workflow required substantial optimization for the assay to be compatible with the LightCycler 480. We optimized the chemistry of the assay using a purchased one-component reaction mix and herein describe sources of variability and quality control relevant to the MMqPCR TL assay on any instrument. Finally, the assay was validated against other TL assays, such as terminal restriction fragment, Southern blot, and flow fluorescent in situ hybridization. The correlations obtained between data from MMqPCR and these assays (R(2)=0.88 and 0.81) were comparable to those seen with the monoplex version (R(2)=0.85 and 0.82) when the same samples were assayed. The intrarun and interrun CV ranged from 4.2% to 6.2% and 3.2% to 4.9%, respectively. We describe a protocol for measuring TL on the LightCycler platform that provides a robust high-throughput method applicable to clinical diagnostics or large-scale studies of archived specimens.

Scientific and Regulatory Policy Committee (SRPC) Review*

Increased cell proliferation is a central key event in the mode of action for many non-genotoxic carcinogens, and quantitative cell proliferation data play an important role in the cancer risk assessment of many pharmaceutical and environmental compounds. Currently, there is limited unified information on assay standards, reference values, targeted applications, study design issues, and quality control considerations for proliferation data. Here, we review issues in measuring cell proliferation indices, considerations for targeted studies, and applications within current risk assessment frameworks. As the regulatory environment moves toward more prospective evaluations based on quantitative pathway-based models, standardization of proliferation assays will become an increasingly important part of cancer risk assessment. To help address this development, we also discuss the potential role for proliferation data as a component of alternative carcinogenicity testing models. This information should improve consistency of cell proliferation methods and increase efficiency of targeted testing strategies.

Isolation, cryopreservation and culture of human amnion epithelial cells for clinical applications.

Human amnion epithelial cells (hAECs) derived from term or pre-term amnion membranes have attracted attention from researchers and clinicians as a potential source of cells for regenerative medicine. The reason for this interest is evidence that these cells have highly multipotent differentiation ability, low immunogenicity, and anti-inflammatory functions. These properties have prompted researchers to investigate the potential of hAECs to be used to treat a variety of diseases and disorders in pre-clinical animal studies with much success. hAECs have found widespread application for the treatment of a range of diseases and disorders. Potential clinical applications of hAECs include the treatment of stroke, multiple sclerosis, liver disease, diabetes and chronic and acute lung diseases. Progressing from pre-clinical animal studies into clinical trials requires a higher standard of quality control and safety for cell therapy products. For safety and quality control considerations, it is preferred that cell isolation protocols use animal product-free reagents. We have developed protocols to allow researchers to isolate, cryopreserve and culture hAECs using animal product-free reagents. The advantage of this method is that these cells can be isolated, characterized, cryopreserved and cultured without the risk of delivering potentially harmful animal pathogens to humans, while maintaining suitable cell yields, viabilities and growth potential. For researchers moving from pre-clinical animal studies to clinical trials, these methodologies will greatly accelerate regulatory approval, decrease risks and improve the quality of their therapeutic cell population.

Quality control considerations for the KM3NeT Very Large Volume Neutrino Telescope

Within the KM3NeT project a quality management system was proposed that included a qualification process and a database to store information on the design. This paper highlights quality control procedures applicable to KM3NeT and describes the database.

Quality control considerations for size exclusion chromatography with online ICP-MS: a powerful tool for evaluating the size dependence of metal-organic matter complexation.

Size exclusion chromatography (SEC), which separates molecules based on molecular volume, can be coupled with online inductively coupled plasma mass spectrometry (ICP-MS) to explore size-dependent metal-natural organic matter (NOM) complexation. To make effective use of this analytical dual detector system, the operator should be mindful of quality control measures. Al, Cr, Fe, Se, and Sn all exhibited columnless attenuation, which indicated unintended interactions with system components. Based on signal-to-noise ratio and peak reproducibility between duplicate analyses of environmental samples, consistent peak time and height were observed for Mg, Cl, Mn, Cu, Br, and Pb. Al, V, Fe, Co, Ni, Zn, Se, Cd, Sn, and Sb were less consistent overall, but produced consistent measurements in select samples. Ultrafiltering and centrifuging produced similar peak distributions, but glass fiber filtration produced more high molecular weight (MW) peaks. Storage in glass also produced more high MW peaks than did plastic bottles.

Role of second‐trimester ultrasound in screening for Down syndrome

Role of second‐trimester ultrasound in screening for Down syndrome

Current quality assurance concepts and considerations for quality control of in-clinic biochemistry testing

Quality assurance is an implied concept inherent in every consumer's purchase of a product or service. In laboratory testing, quality assurance encompasses preanalytic (sampling, transport, and handling prior to testing), analytic (measurement), and postanalytic (reporting and interpretation) factors. Quality-assurance programs require that procedures are in place to detect errors in all 3 components and that the procedures are characterized by both documentation and correction of errors. There are regulatory bodies that provide mandatory standards for and regulation of human medical laboratories. No such regulations exist for veterinary laboratory testing. The American Society for Veterinary Clinical Pathology (ASVCP) Quality Assurance and Laboratory Standards Committee was formed in 1996 in response to concerns of ASVCP members about quality assurance and quality control in laboratories performing veterinary testing. Guidelines for veterinary laboratory testing have been developed by the ASVCP. The purpose of this report was to provide an overview of selected quality-assurance concepts and to provide recommendations for quality control for in-clinic biochemistry testing in general veterinary practice.

Blast Furnace Slag as Sustainable Material in Concrete Pavements

Slag materials are byproducts of metallurgical processes that include metal production from ore and refinement of impure metals. Air-cooled blast furnace slag (ACBFS) has been used for different pavement-related applications. Appropriate use of ACBFS can significantly enhance sustainability, rather than disposing of it, by effectively contributing to all aspects of the “triple bottom line.” Proper use of ACBFS can also result in economic, environmental, and social benefits as long as the performance of the concrete structure is not compromised through such use because any short-term economic and environmental gain would be rapidly eclipsed by the economic, environmental, and social costs of poor pavement performance. Thus, it is essential that engineers and contractors who use ACBFS aggregates in concrete understand its unique properties to make sure that the expected performance of the pavement over its design life is achieved. The chemical composition of ACBFS may affect its performance and has to be considered when ACBFS is used as a coarse aggregate. Physical properties of ACBFS, such as texture, absorption, and specific gravity, also have to be considered when ACBFS is used in concrete. ACBFS also affects fresh and hardened properties of concrete. Specific design, construction, and quality control considerations have to be taken into account when ACBFS is used. In this paper, sustainability aspects of using ACBFS as a coarse aggregate in concrete pavements and considerations for its use in this application are presented. A best practices guideline recently published by FHWA presents the same discussions in more detail.