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This paper presents the cross validation of two aerodynamic shape optimization methodologies in order to validate, characterize, and compare the two methodologies. Both methodologies use gradient-b...

The pharmaceutical industry and regulatory agencies rely on dissolution similarity testing to make critical product decisions as part of drug product life cycle management. Accordingly, the application of mathematical approaches to evaluate dissolution profile similarity is described in regulatory guidance with the emphasis given to the similarity factor f

The determination of the variability of critical dosage form attributes has been a challenge in establishing the quality of pharmaceutical products. During the development process knowledge is minimal. Consequently, ad hoc statistical tools such as hypothesis or significance tests, with calibrated decision error rates are often used in an effort to vet CQAs (Critical Quality Attributes) and keep their levels "between the curbs". As progress moves towards product launch, process and mechanistic understanding grows considerably and there are opportunities to leverage that knowledge for predictive modeling. Bayesian models offer a coherent strategy for integrating prior knowledge into both experimental design as well as predictive analysis for optimal risk-based decision making. This is because the Bayesian paradigm, unlike the frequentist paradigm, can assign probabilities to underlying states of nature that directly impact safety and efficacy such as the population distribution of tablet potencies or dissolution profiles in a batch. However, there are challenges and reluctance in switching to a predictive modeling quality framework once regulatory approval has been attained. This paper offers encouragement to make this switch. In this paper, we review a joint Long Island University - Purdue University (LIU-PU) FDA funded project whose purpose was to further integrate the concepts of this adaptive approach to lot release with the rationale and methods for data generation and curation and to extend the testing of this approach. We discuss the utility of the approach in product development. We consider the regulatory compliance implications, with examples, and establish a potential way forward toward implementation of this approach for both industry and regulatory stake-holders.

To determine whether the duration of noninvasive respiratory support exposure is associated with bronchopulmonary dysplasia (BPD) or death in preterm infants.Multicenter, retrospective study of infants born at29 weeks' gestation. The association between days on noninvasive respiratory support and BPD or death was determined using instrumental variable techniques and generalized propensity score matching to account for potential confounding by illness severity.Among 6268 infants 36% developed BPD or died. The median duration of noninvasive respiratory support was 18 days. There was inconsistency in the association between noninvasive support and BPD or death when analyzed by instrumental variable techniques (Average Marginal Effect -0.37; 95% CI -1.23 to 0.50) and generalized propensity score matching (Average Marginal Effect 0.46; 95% CI 0.33 to 0.60).Findings on the association between duration of exposure to noninvasive respiratory support and the development of BPD or death were inconclusive.Generic Database:NCT00063063.

The pharmaceutical industry and regulatory agencies rely on dissolution similarity testing to make critical product performance decisions as part of drug product life cycle management. Accordingly, the application of mathematical approaches to evaluate dissolution profile similarity is described in regulatory guidance. However, the requirements (e.g., which time points, number of time points, %CV) to apply the widely known similarity factor f2 and other alternative statistical approaches diverge noticeably across regulatory agencies. In an effort to highlight current practices to assess dissolution profile similarity and to strive towards global harmonization, a workshop entitled "in vitro dissolution similarity assessment in support of drug product quality: what, how, when" was held May 21-22, 2019, at the University of Maryland, Baltimore. This article summarizes key points from the podium presentations and breakout (BO) sessions focusing on (1) contrasting the advantages and disadvantages of several statistical methods; (2) the importance of experimental design for successful similarity evaluation; (3) the value of similarity evaluation in light of clinically relevant specifications; and (4) the need for creating a robust and scientifically appropriate path (e.g., non-prescriptive decision tree) for dissolution profile similarity assessment as a stepping stone for global harmonization.

This paper presents the development of a new framework of multiblock structured elliptic grid smoothing for full-aircraft configurations. The framework is fully automated and applies different solv...

During assay development, one of the key steps in designing a quantitative assay procedure is to choose an appropriate calibration model for the standard curve. A recent draft USP general c...

To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P .001) and pervasive developmental problems (P .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values .05).BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

OBJECTIVE: To compare in-hospital outcomes after umbilical cord milking versus delayed cord clamping among infants

In this work we develop a Bayesian framework for building surrogate stochastic models of complex multi-step processes for which tractable mechanistic models are difficult to construct. The probabilistic process envelope defined by the design space provides an extra level of assurance of product quality over and above that provided by traditional process control. While the application we report is specific to drug products manufactured using traditional batch processing, the proposed framework is applicable in general to batch and continuous manufacturing of products that must meet a set of critical product quality specifications.

In this work, a novel risk-based methodology for lot release is proposed. Its objective is to assess the risk that a lot declared to have passed truly meets product specifications. The methodology consists of 3 parts: adaptive sample size determination, estimation of the probability that the product was within specifications, and the lot-release decision. The methodology provides a probabilistic statement about the true quality of the batch. Having a probability estimate is the essential condition of risk-based decision-making. We demonstrate the proposed methodology on experimental data generated from 17 immediate-release solid oral drug products from a number of different manufacturers with 5 to 10 lots per manufacturer.

Release of manufactured lots is a major decision point in reaching the goal of a customer – the product quality is reasonably good – and of manufacture – no rework/scrap/lost revenue. In this study we will focus on pharmaceutical industry (solid dosage form). Adaptive Bayesian sample size determination. In this study we used adaptive Bayesian approach to determine the number of lots needed to estimate inter/intra lot variability. This was dictated by limited number of lots available in the study. Specifically, a linear random effects model was built and fitted to tablet data from multiple lots. The estimate was considered accurate enough when change in signal (or variability estimates) disappeared within noise. In our case we considered 1% of label claim as noise level. However, if signal to noise ratio was high, additional lot was sampled. Sampling included traditional content uniformity and dissolution testing. In order to be consistent with pharmacopeia 10 tablets from a lot were used for content uniformity testing while 12 tablets from the same lot were used for dissolution testing. Manufacturer, however, may not need this step since historical production information may be used to estimate the inter/intra lot variability by employing Bayesian methodology. It is important to note that analytical variability component was factored out which is not easily done with traditional frequentist methodology. Estimation of probability that product is within specifications at given confidence level. The next step was to estimate the probability of product being within specifications at a given confidence level which is metrics used for lot release by ASTM E2709–12 standard. However, the approach delineated in the standard was extended by Bayesian treatment. Specifically, inter/intra lot variability estimates were used to determine the probability while confidence level was replaced by the Bayesian credible interval concept. As delineated in ASTM E2709–12 standard this non-trivial task using frequentist methodology was very straightforward when using Bayesian methodology. We propose that lot can be released (consistently with ASTM E2709–12 standard) when the probability of product being within specifications at a given confidence level is high enough not to cause any harm to the patient. In order to determine the probability threshold, we propose to perform virtual clinical study with Simcyp or PK-Sim to determine if there is no harm to the patient and drug product is efficacious, i.e. drug plasma levels are within therapeutic window for prescribed dosing regimen. We verified the proposed methodology on seven immediate release products from different manufactures. We found that there are large differences in inter/intra lot variability between different manufacturers. Based on our experience more than six lots are typically required to establish accurate variability estimate. The current pharmacopeia doesn’t incorporate inter lot variability and therefore our proposed approach is more restrictive in the sense that it allows releasing lots that contain safer and more efficacious product than using existing lot release criteria. It is based on FDA’s risk based approach. From manufacturers perspective it supports the FDA’s quality metrics initiative to assure that only safe and quality medicine is being produced. While this study considered solid dosage form the proposed methodology could be easily generalized for different dosage forms and any batch processing industries.

Validation of linearity is a regulatory requirement. Although many methods are proposed, they suffer from several deficiencies including difficulties of setting fit-for-purpose acceptable limits, dependency on concentration levels used in linearity experiment, and challenges in implementation for statistically lay users. In this article, a statistical procedure for testing linearity is proposed. The method uses a two one-sided test (TOST) of equivalence to evaluate the bias that can result from approximating a higher-order polynomial response with a linear function. By using orthogonal polynomials and generalized pivotal quantity analysis, the method provides a closed-form solution, thus making linearity testing easy to implement.

A compendial standard is a function of data generated by one or more quality testing procedures. Since the data are sampled from an underlying distribution, the probability of passing a compendial test (Pa) can be expressed as a function of the distribution's model parameters. Applying Bayesian methodology to such a function, we show how to compute the posterior distribution of Pa and other quantities of interest. We apply this methodology to the USP compendial standard and illustrate the importance of considering interbatch variance. We show that the operating characteristics of this Bayesian approach depend on the underlying model parameters almost exclusively through the population Pa and use this to develop a simple univariate procedure to determine the number of batches needed for a process qualification. We note some advantages of this Bayesian approach compared to current approaches. To show the simplicity of the approach and encourage its use, example R and WinBUGS code are provided.

The role of Fc glycans on clearance of IgG molecule has been examined by various groups in experiments where specific glycans have been enriched or the entire spectrum of glycans was studied after administration in pre-clinical or clinical pharmacokinetic (PK) studies. The overall conclusions from these studies are inconsistent, which may result from differences in antibody structure or experimental design. In the present study a well-characterized recombinant monoclonal IgG1 molecule (mAb-1) was analyzed from serum samples obtained from a human PK study. mAb-1 was recovered from serum using its ligand cross-linked to Sepharose beads. The overall purity and recovery of all isoforms were carefully evaluated using a variety of methods. Glycans were then enzymatically cleaved, labeled using 2-aminobenzamide and analyzed by normal phase high performance liquid chromatography. The assays for recovering mAb-1 from serum and subsequent glycan analysis were rigorously qualified at a lower limit of quantitation of 15 μg/mL, thus permitting analysis to day 14 of the clinical PK study. Eight glycans were monitored and classified into two groups: (1) the oligomannose type structures (M5, M6 and M7) and (2) fucosylated biantennary oligosaccharides (FBO) structures (NGA2F, NA1F, NA2F, NA1F-GlcNAc and NGA2F-GlcNAc). We observed that the oligomannose species were cleared at a much faster rate (40%) than FBOs and conclude that high mannose species should be carefully monitored and controlled as they may affect PK of the therapeutic; they should thus be considered an important quality attribute. These observations were only possible through the application of rigorous analytical methods that we believe will need to be employed when comparing innovator and biosimilar molecules.

Background β-amyloid peptide (Aβ) is associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Aβ levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aβ production or Aβ clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aβ are consistent between sampling intervals to determine whether Aβ can be used as a pharmacodynamic biomarker for drug candidates. Previous studies have produced seemingly conflicting observations for the intrasubject stability of CSF Aβ levels; we attempt to reconcile these conflicting observations. Methods The current study examined the Aβ levels in CSF collected with various sampling frequencies from three clinical studies conducted in healthy young or elderly subjects at the same investigative site for the purpose of designing future studies. Results The results suggest that CSF sampling frequency and/or sampling volume contributes to intrasubject variability in CSF Aβ levels, and that lowering the CSF sampling frequency may help minimize this effect. Conclusion These results will help guide clinical trial design for Alzheimer's disease therapy.

As stipulated by ICH Q8 R2 (1), prediction of critical process parameters based on process modeling is a part of enhanced, quality by design approach to product development. In this work, we discuss a Bayesian model for the prediction of primary drying phase duration. The model is based on the premise that resistance to dry layer mass transfer is product specific, and is a function of nucleation temperature. The predicted duration of primary drying was experimentally verified on the lab scale lyophilizer. It is suggested that the model be used during scale-up activities in order to minimize trial and error and reduce costs associated with expensive large scale experiments. The proposed approach extends the work of Searles et al. (2) by adding a Bayesian treatment to primary drying modeling.

Dissolution (or in vitro release) studies play an important role during pharmaceutical drug development. They are useful as a quality control tool, establishing an IVIVC, justifying a biowaiver and supporting equivalence between generics and innovator products. This chapter provides an overview of regulatory guidances related to dissolution testing. The important question of dissolution profile comparisons and the challenges of defining similarity are discussed. The limitations of the f 2 statistic, a regulatory driven test, are described, with emphasis on the lack of a statistical basis for the test. The strengths and weaknesses of alternative approaches are described. A Bayesian test procedure is given that mitigates to a large extent the weaknesses of other approaches by providing a coherent connection between a parameter defining “fit for use” to a statistical probability statement of similarity.

Advancements in the control of construction equipment can have significant benefits in the industry. Better control can lead to improvements in safety, cost, labor turnover, and productivity. It is helpful to characterize improvements in a control system using performance tests. Results of such tests provide a means of comparing control systems. Research at the University of Texas at Austin has resulted in the development of tests to characterize improvements in the control of a large-scale manipulator (LSM). Tests have shown that autonomous control of the LSM has better performance capability than manual control for well-defined movements or simple tasks. However, computer-enhanced manual control is still required for operation in a typical construction environment. Object-oriented programming was used to implement computer-assisted operation modes that enhance the LSM's performance. This paper discusses the development of performance tests for characterizing control systems for LSMs. The new computer-assisted operation modes also are explained. A description is included identifying lessons learned during this research that should be considered during future development of LSMs.

Every pharmaceutical product that is approved and released to the public is shaped by countless decisions made at the research and clinical stages of development. The efficacy and safety of these products depends on the quality of these decisions. In this paper we examine how modern probability tools might be used to raise the quality of such decisions. Specifically we are arguing for the greater use of Bayesian probability tools in pharmaceutical product development decision making. A case study on a novel Bayesian treatment of shelf life determination for lyophilized parenteral is presented.

The use of von Frey filaments, originally developed by Maximilian von Frey, has become the cornerstone for assaying mechanical sensitivity in animal models and is widely used for human assessment. While there are certain limitations associated with their use that make comparisons between studies not straightforward at times, such as stimulus duration and testing frequency, von Frey filaments provide a good measurement of mechanosensation. Here we describe the application of von Frey filaments to testing in animal models, specifically with respect to determining changes in sensory thresholds in a pain state using the Dixon up-down method. In a literature survey, we found that up to 75% of reports using this method analyze the data with parametric statistical analysis and of those that used nonparametric analysis, none took into account that mechanical sensation is perceived on a logarithmic scale (Weber's Law) when calculating efficacy. Here we outline a more rigorous analysis for calculating efficacy and ED 50 's from von Frey data that incorporates Weber's Law. We show that this analysis makes statistical and biological sense and provide a specific example of how this change affects data analysis that brings results from animal models more in line with clinical observations. Perspective This focus article argues that analyzing von Frey paw withdrawal threshold data obtained by using the Dixon up-down method without considering Weber's Law is inappropriate. An analysis method that incorporates how mechanical sensation is perceived and how its application brings results from animal models more in line with clinical data is presented.

Alzheimer's disease (AD), which is characterized by a degeneration of neurons and their synapses, is one of the most common forms of dementia. CSF levels of amyloid 𝛽 4 2 (A 𝛽 4 2 ) have been recognized as a strong candidate to serve as an AD biomarker. There are a number of commercial assays that are routinely employed for measuring A 𝛽 4 2 ; however, these assays give diverse ranges for the absolute levels of CSF A 𝛽 4 2 . In order to employ CSF A 𝛽 4 2 as a biomarker across multiple laboratories, studies need to be performed to understand the relationship between the different platforms. We have analyzed CSF samples from both diseased and nondiseased subjects with two different widely used assay platforms. The results showed that different values for the levels of CSF A 𝛽 4 2 were reported, depending on the assay used. Nonetheless, both assays clearly demonstrated statistically significant differences in the levels of A 𝛽 4 2 in CSF from AD relative to age-matched controls (AMC). This paper provides essential data for establishing the relationship between these assays and provides an important step towards the validation of A 𝛽 4 2 as a biomarker for AD.

We present a numerical study of sawtooth in ohmic tokamak plasmas with the XTOR-2F code. This study is, to our knowledge, the first to explore the long-term dynamics of the internal kink. Resistive MHD gives two regimes : stable oscillations or a saturated helicoidal state. Stabilizing diamagnetic drifts enable us to find sawteeth for pertinent experimental parameters. We also present the contributions made for the transition of the code toward the hybrid MHD-kinetic code XTOR-K, to include both kinetic and fluid effects. We chose a full-f, full-orbit kinetic model, coupled to the fluid part through a Newton-Krylov/Picard algorithm which is stable for the fundamental MHD modes. Orbit integration is done by the Boris algorithm, adapted in toroidal geometry. Invariants of motion do not accumulate numerically. Several methods, including a numerical temporal filter, are considered to reduce the noise on the particular pressure tensor.; Nous présentons une étude numérique des dents de scie dans un plasma de tokamak ohmique avec le code XTOR-2F. Cette étude est à notre connaissance la première à explorer la dynamique au long terme du kink interne. La MHD résistive prévoit deux régimes distincts : oscillations stables ou régime saturé hélicoïdal. Les dérives diamagnétiques stabilisantes permettent de retrouver des dents de scie pour des paramètres expérimentaux pertinents. On détaille aussi les contributions faites à la transition du code vers le code hybride MHD-cinétique XTOR-K, pour coupler effets cinétiques et fluides. On a choisi un modèle cinétique full-f, full-orbit couplé à la partie fluide par un algorithme Newton-Krylov/Picard stable vis-à-vis des modes MHD fondamentaux. L'avancée des particules est faite par l'algorithme de Boris, adapté en géométrie torique. Les invariants du mouvement ne dérivent pas numériquement. Différentes méthodes, entre autres un filtrage temporel numérique, sont envisagées pour réduire le bruit sur le tenseur de pression particulaire.

all biomarkers considered for this review. Six percent of studies included more than 500 patients. It was unclear whether scan/test interpretation was conducted blind to knowledge of conversion to dementia in 62% of reports. Similarly, it was unclear whether decisions about conversion to dementia were made without knowledge of scan/test results in 63% of reports. Uninterpretable or intermediate test results were either not reported, or reported unclearly in 79% of cases. It was rarely possible to make an assessment, on the basis of the report, that the spectrum of patients in the cohort was representative of the patients whowould receive the test in practice. 21 studies of CSF or plasma Abeta reported conversion in 1128 patients. 26 studies of CSF tau reported conversion in 1054 patients. 22 structural MRI studies reported conversion in 1343 patients. 11 studies of FDG-PET reported conversion in 270 patients. 5 studies of PET based amyloid imaging reported conversion in 27 patients.Conclusions: The quality of reporting of longitudinal studies of biomarkers raises the possibility that substantial biases may be present. Multiple publication is commonplace in studies of diagnostic accuracy in dementia. Whilst this reflects developing techniques and continuing monitoring of subjects for outcomes, greater transparency is required so as to allow easier compilation of these data. A more formal process with cohort registration, reporting of ’intention to diagnose’ data, and clear independence of clinical and test evaluations is required. PET-based tests have the smallest evidence base. The small sample size of most studies limits their overall generalizeabilty. Funders, including those seeking licences for new products, should support large-scale, representative evaluations in that part of the population who would be most likely to utilize the test. Critical evaluation of the evidence base for diagnostic biomarkers is of major importance to the field of dementia. Without it, there is a risk that future clinical care and research will be built on assumptions about diagnostic validity that are wrong.

We present a numerical study of sawtooth in ohmic tokamak plasmas with the XTOR-2F code. This study is, to our knowledge, the first to explore the long-term dynamics of the internal kink. Resistive MHD gives two regimes : stable oscillations or a saturated helicoidal state. Stabilizing diamagnetic drifts enable us to find sawteeth for pertinent experimental parameters. We also present the contributions made for the transition of the code toward the hybrid MHD-kinetic code XTOR-K, to include both kinetic and fluid effects. We chose a full-f, full-orbit kinetic model, coupled to the fluid part through a Newton-Krylov/Picard algorithm which is stable for the fundamental MHD modes. Orbit integration is done by the Boris algorithm, adapted in toroidal geometry. Invariants of motion do not accumulate numerically. Several methods, including a numerical temporal filter, are considered to reduce the noise on the particular pressure tensor., Nous présentons une étude numérique des dents de scie dans un plasma de tokamak ohmique avec le code XTOR-2F. Cette étude est à notre connaissance la première à explorer la dynamique au long terme du kink interne. La MHD résistive prévoit deux régimes distincts : oscillations stables ou régime saturé hélicoïdal. Les dérives diamagnétiques stabilisantes permettent de retrouver des dents de scie pour des paramètres expérimentaux pertinents. On détaille aussi les contributions faites à la transition du code vers le code hybride MHD-cinétique XTOR-K, pour coupler effets cinétiques et fluides. On a choisi un modèle cinétique full-f, full-orbit couplé à la partie fluide par un algorithme Newton-Krylov/Picard stable vis-à-vis des modes MHD fondamentaux. L'avancée des particules est faite par l'algorithme de Boris, adapté en géométrie torique. Les invariants du mouvement ne dérivent pas numériquement. Différentes méthodes, entre autres un filtrage temporel numérique, sont envisagées pour réduire le bruit sur le tenseur de pression particulaire.