Narrow band imaging for detection of gastric intestinal metaplasia and dysplasia: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Gastric intestinal metaplasia (GIM), a precursor of gastric adenocarcinoma, is challenging to diagnose with white light endoscopy (WLE) and can be missed by random gastric biopsies. Narrowband imaging (NBI) may potentially improve the detection of GIM. However, pooled estimates from prospective studies are lacking. METHODS: Electronic databases were searched for studies comparing NBI and WLE alone for detection of GIM and synchronous dysplasia. Primary outcome was pooled detection rate of GIM by NBI compared with WLE in prospective studies. The secondary outcome was concurrent dysplasia detection. RESULTS: Ten studies were found eligible from 306 articles screened. Eight prospective studies were found eligible for primary endpoint of GIM detection. Two other retrospective studies were included for dysplasia detection. A total of 1366 subjects (694 males, 54.4 ± 5.08 years) underwent upper endoscopy. GIM was detected in 482 (35.3%) subjects. NBI detected GIM in 32% additional subjects (70% vs 38%, RR 1.79; 95% CI 1.34-2.37; P < 0.01). Subgroup analysis revealed newer NBI scopes (GIF260) detected significantly more GIM than WLE (RR 2.47; 95% CI 1.63-3.76; P < 0.01) but not the older (H180) NBI endoscopes (RR 1.33; 95% CI 0.93-1.88; P = 0.11). There was moderate heterogeneity between the studies (I2  = 63%). In five studies (n = 628) that reported dysplasia, there was no significant difference between NBI and WLE in dysplasia detection (RR 1.09; 95% CI 0.81-1.47; P = 0.58). CONCLUSION: Narrowband imaging can significantly increase the detection of GIM when used in addition to standard white light exam during an upper endoscopy.

Passive, wireless transduction of electrochemical impedance across thin-film microfabricated coils using reflected impedance.

A new method of wirelessly transducing electrochemical impedance without integrated circuits or discrete electrical components was developed and characterized. The resonant frequency and impedance magnitude at resonance of a planar inductive coil is affected by the load on a secondary coil terminating in sensing electrodes exposed to solution (reflected impedance), allowing the transduction of the high-frequency electrochemical impedance between the two electrodes. Biocompatible, flexible secondary coils with sensing electrodes made from gold and Parylene C were microfabricated and the reflected impedance in response to phosphate-buffered saline solutions of varying concentrations was characterized. Both the resonant frequency and impedance at resonance were highly sensitive to changes in solution conductivity at the secondary electrodes, and the effects of vertical separation, lateral misalignment, and temperature changes were also characterized. Two applications of reflected impedance in biomedical sensors for hydrocephalus shunts and glucose sensing are discussed.

Impact of the US FDA "Biopharmaceutics Classification System" (BCS) Guidance on Global Drug Development.

The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided. Results show that greater than 160 applications were approved, or tentatively approved, based on the BCS approach across multiple therapeutic areas; an additional significant finding was that at least 50% of these approvals were in the central nervous system (CNS) area. These findings indicate a robust utilization of the BCS approach toward reducing unnecessary in vivo BE studies and speeding up availability of high quality pharmaceutical products. The article concludes with a look at the adoption of this framework by regulatory and health policy organizations across the globe, and FDA's current thinking on areas of improvement of this guidance.

Parylene MEMS patency sensor for assessment of hydrocephalus shunt obstruction.

Neurosurgical ventricular shunts inserted to treat hydrocephalus experience a cumulative failure rate of 80 % over 12 years; obstruction is responsible for most failures with a majority occurring at the proximal catheter. Current diagnosis of shunt malfunction is imprecise and involves neuroimaging studies and shunt tapping, an invasive measurement of intracranial pressure and shunt patency. These patients often present emergently and a delay in care has dire consequences. A microelectromechanical systems (MEMS) patency sensor was developed to enable direct and quantitative tracking of shunt patency in order to detect proximal shunt occlusion prior to the development of clinical symptoms thereby avoiding delays in treatment. The sensor was fabricated on a flexible polymer substrate to eventually allow integration into a shunt. In this study, the sensor was packaged for use with external ventricular drainage systems for clinical validation. Insights into the transduction mechanism of the sensor were obtained. The impact of electrode size, clinically relevant temperatures and flows, and hydrogen peroxide (H2O2) plasma sterilization on sensor function were evaluated. Sensor performance in the presence of static and dynamic obstruction was demonstrated using 3 different models of obstruction. Electrode size was found to have a minimal effect on sensor performance and increased temperature and flow resulted in a slight decrease in the baseline impedance due to an increase in ionic mobility. However, sensor response did not vary within clinically relevant temperature and flow ranges. H2O2 plasma sterilization also had no effect on sensor performance. This low power and simple format sensor was developed with the intention of future integration into shunts for wireless monitoring of shunt state and more importantly, a more accurate and timely diagnosis of shunt failure.

Quality by design approach for understanding the critical quality attributes of cyclosporine ophthalmic emulsion.

Restasis is an ophthalmic cyclosporine emulsion used for the treatment of dry eye syndrome. There are no generic products for this product, probably because of the limitations on establishing in vivo bioequivalence methods and lack of alternative in vitro bioequivalence testing methods. The present investigation was carried out to understand and identify the appropriate in vitro methods that can discriminate the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion formulations having the same qualitative (Q1) and quantitative (Q2) composition as that of Restasis. Quality by design (QbD) approach was used to understand the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion. The formulation variables chosen were mixing order method, phase volume ratio, and pH adjustment method, while the process variables were temperature of primary and raw emulsion formation, microfluidizer pressure, and number of pressure cycles. The responses selected were particle size, turbidity, zeta potential, viscosity, osmolality, surface tension, contact angle, pH, and drug diffusion. The selected independent variables showed statistically significant (p < 0.05) effect on droplet size, zeta potential, viscosity, turbidity, and osmolality. However, the surface tension, contact angle, pH, and drug diffusion were not significantly affected by independent variables. In summary, in vitro methods can detect formulation and manufacturing changes and would thus be important for quality control or sameness of cyclosporine ophthalmic products.

Basal cell carcinosarcoma: a report of 4 cases and review of the literature.

BACKGROUND: To describe the features of 4 cases of basal cell carcinosarcoma and systematically review previously reported cases. METHODS: Four cases of basal cell carcinosarcoma were identified from the practice of the authors. A search of the literature revealed an additional 40 cases, variously described in small series and single case reports. The clinical and pathological features of these 44 cases are described. RESULTS: Basal cell carcinosarcoma is largely a tumor of elderly men (male:female 3:1, average age: 76 years). The majority of these lesions are relatively small (<25 mm). Heterologous elements are common, particularly an osteosarcomatous component, which is present in 45% of cases. Although there are relatively limited follow-up data, only 1 case formally reported in the literature has shown distant metastasis. CONCLUSIONS: Despite relatively high reported rates of local recurrence and metastasis for "carcinosarcoma" as an unrefined entity, it seems that the subgroup of basal cell carcinosarcoma has a relatively good prognosis, with adequate local excision being curative in the majority of cases. Recognition of this entity is critical for accurate diagnosis and its separation from other types of carcinosarcoma may have significant prognostic implications.

Chronically implanted pressure sensors: challenges and state of the field.

Several conditions and diseases are linked to the elevation or depression of internal pressures from a healthy, normal range, motivating the need for chronic implantable pressure sensors. A simple implantable pressure transduction system consists of a pressure-sensing element with a method to transmit the data to an external unit. The biological environment presents a host of engineering issues that must be considered for long term monitoring. Therefore, the design of such systems must carefully consider interactions between the implanted system and the body, including biocompatibility, surgical placement, and patient comfort. Here we review research developments on implantable sensors for chronic pressure monitoring within the body, focusing on general design requirements for implantable pressure sensors as well as specifications for different medical applications. We also discuss recent efforts to address biocompatibility, efficient telemetry, and drift management, and explore emerging trends.

A network of regulatory innovations to improve FDA quality assessments of human drug applications.

A network of regulatory innovations brings a holistic approach to improving the submission, assessment, and lifecycle management of pharmaceutical quality information in the U.S. This dedicated effort in the FDA's Center for Drug Evaluation and Research (CDER) aims to enhance the quality assessment of submissions for new drugs, generic drugs, and biological products including biosimilars. These regulatory innovations include developing or contributing: (i) the Knowledge-Aided Assessment and Structured Application (KASA), (ii) a new common technical document for quality (ICH M4Q(R2)), (iii) structured data on Pharmaceutical Quality/Chemistry, Manufacturing and Controls (PQ/CMC), (iv) Integrated Quality Assessment (IQA), (v) the Quality Surveillance Dashboard (QSD), and (vi) the Established Conditions tool from the ICH Q12 guideline. The innovations collectively drive CDER toward a more coordinated, effective, and efficient quality assessment. Improvements are made possible by structured regulatory submissions, a systems approach to quality risk management, and data-driven decisions based on science, risk, and effective knowledge management. The intended result is better availability of quality medicines for U.S. patients.

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters.

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters-OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using 3H-estrone sulfate, 3H-N-methyl quinidine, and 3H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC50 values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC50 values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC50 values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC50 values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants.

Antioxidants had No Effects on the In-Vitro Permeability of BCS III Model Drug Substances.

Reformulation with addition of antioxidants is one potential mitigation strategy to prevent or reduce nitrosamine drug substance-related impurities (NDSRIs) in drug products. To explore whether there could be other approaches to demonstrate bioequivalence for a reformulated oral product, which typically needs in vivo bioequivalence studies to support the changes after approval, the effects of antioxidant on the in vitro permeability of BCS III model drug substances were investigated to see whether there could be any potential impact on drug absorption. Six antioxidants were screened and four (ascorbic acid, cysteine, α-tocopherol and propyl gallate) were selected based on their nitrosamine inhibition efficiencies. The study demonstrated that these four antioxidants, at the tested amounts, did not have observable impact on the in vitro permeability of the BCS III model drug substances across Caco-2 cell monolayers in the In Vitro Dissolution Absorption System (IDAS). An in vitro permeability study could be considered as part of one potential bioequivalence bridging approach for reformulated low-risk immediate release solid oral products and oral suspension products. Other factors such as the influence of antioxidants on intestinal transporter activities should be considered where appropriate.

In vitro bioequivalence approach for a locally acting gastrointestinal drug: lanthanum carbonate.

A conventional human pharmacokinetic (PK) in vivo study is often considered as the "gold standard" to determine bioequivalence (BE) of drug products. However, this BE approach is not always applicable to the products not intended to be delivered into the systemic circulation. For locally acting gastrointestinal (GI) products, well designed in vitro approaches might be more practical in that they are able not only to qualitatively predict the presence of the active substance at the site of action but also to specifically assess the performance of the active substance. For example, lanthanum carbonate chewable tablet, a locally acting GI phosphate binder when orally administrated, can release free lanthanum ions in the acid environment of the upper GI tract. The lanthanum ions directly reach the site of action to bind with dietary phosphate released from food to form highly insoluble lanthanum-phosphate complexes. This prevents the absorption of phosphate consequently reducing the serum phosphate. Thus, using a conventional PK approach to demonstrate BE is meaningless since plasma levels are not relevant for local efficacy in the GI tract. Additionally the bioavailability of lanthanum carbonate is less than 0.002%, and therefore, the PK approach is not feasible. Therefore, an alternative assessment method is required. This paper presents an in vitro approach that can be used in lieu of PK or clinical studies to determine the BE of lanthanum carbonate chewable tablets. It is hoped that this information can be used to finalize an in vitro guidance for BE studies of lanthanum carbonate chewable tablets as well as to assist with "in vivo" biowaiver decision making. The scientific information might be useful to the pharmaceutical industry for the purpose of planning and designing future BE studies.

Endogenous MHC-related protein 1 is transiently expressed on the plasma membrane in a conformation that activates mucosal-associated invariant T cells.

The development of mucosal-associated invariant T (MAIT) cells is dependent upon the class Ib molecule MHC-related protein 1 (MR1), commensal bacteria, and a thymus. Furthermore, recent studies have implicated MR1 presentation to MAIT cells in bacteria recognition, although the mechanism remains undefined. Surprisingly, however, surface expression of MR1 has been difficult to detect serologically, despite ubiquitous detection of MR1 transcripts and intracellular protein. In this article, we define a unique mAb capable of stabilizing endogenous mouse MR1 at the cell surface, resulting in enhanced mouse MAIT cell activation. Our results demonstrated that under basal conditions, endogenous MR1 transiently visits the cell surface, thus reconciling the aforementioned serologic and functional studies. Furthermore, using this approach, double-positive thymocytes, macrophages, and dendritic cells were identified as potential APCs for MAIT cell development and activation. Based on this pattern of MR1 expression, it is intriguing to speculate that constitutive expression of MR1 may be detrimental for maintenance of immune homeostasis in the gut and/or detection of pathogenic bacteria in mucosal tissues.

Preliminary feasibility study using a novel narrow-band imaging system with dual focus magnification capability in Barrett's esophagus: is the time ripe to abandon random biopsies?

This preliminary feasibility study assessed the utility of a novel narrow-band imaging (NBI) system (Olympus Exera III; 190 series) both as a detection and as a characterization tool in patients undergoing surveillance endoscopy for Barrett's esophagus (BE). Two hundred and twenty-one areas in 40 patients with BE were examined prospectively. The BE segment was initially evaluated with NBI overview as a 'red flag' technique. Abnormal areas identified with NBI overview were then further interrogated with NBI and a dual focus (DF) magnification system (NBI-DF) in order to aid characterization. Normal areas on NBI overview were also systematically assessed with NBI-DF systematically (four quadrants every 2 cm). A confidence system was utilized when each area was assessed with NBI-DF. All areas on NBI-DF were classified into three easily distinguishable mucosal patterns: (i) regular pits with regular microvasculature (no dysplasia); (ii) irregular pits with irregular microvasculature (early cancer/high-grade dysplasia [HGD]); and (iii) equivocal, where the endoscopist was not sure about the pattern (this could be areas with increased brownish discoloration on NBI overview and dilated vasculature but no change in caliber on NBI-DF [likely inflammation or low-grade dysplasia: LGD]). Corresponding biopsies of each area were then taken. The sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of both modes (NBI overview and NBI-DF) were then compared with the final histopathological diagnosis. One hundred and eighty-three of 221 areas (82.8%) did not exhibit any dysplasia on final histopathological assessment. NBI overview and NBI-DF accurately called all these areas as non-dysplastic. The 38 areas that appeared suspicious on NBI overview were also further assessed with NBI-DF: seven of seven were accurately predicted as harboring no dysplasia; nine areas were predicted as irregular, of which four harbored early cancer, one HGD, three LGD and one inflammation on final histopathology assessment. Twenty-two areas were deemed to be equivocal (final histology: 18 LGD and four inflammation). The Sn, Sp, PPV and NPV for the prediction of dysplasia/early cancer using NBI overview and NBI-DF were thus 100%, 93.8%, 68.6%, 100% and 100%, 86.2%, 73.3%, 100%, respectively. If NBI-DF was used in addition to NBI overview, biopsies would have been avoided in 190 areas (86%). In addition, all early cancers and HGD could be accurately identified.

Batch-to-batch quality consistency evaluation of botanical drug products using multivariate statistical analysis of the chromatographic fingerprint.

Botanical drug products have batch-to-batch quality variability due to botanical raw materials and the current manufacturing process. The rational evaluation and control of product quality consistency are essential to ensure the efficacy and safety. Chromatographic fingerprinting is an important and widely used tool to characterize the chemical composition of botanical drug products. Multivariate statistical analysis has showed its efficacy and applicability in the quality evaluation of many kinds of industrial products. In this paper, the combined use of multivariate statistical analysis and chromatographic fingerprinting is presented here to evaluate batch-to-batch quality consistency of botanical drug products. A typical botanical drug product in China, Shenmai injection, was selected as the example to demonstrate the feasibility of this approach. The high-performance liquid chromatographic fingerprint data of historical batches were collected from a traditional Chinese medicine manufacturing factory. Characteristic peaks were weighted by their variability among production batches. A principal component analysis model was established after outliers were modified or removed. Multivariate (Hotelling T(2) and DModX) control charts were finally successfully applied to evaluate the quality consistency. The results suggest useful applications for a combination of multivariate statistical analysis with chromatographic fingerprinting in batch-to-batch quality consistency evaluation for the manufacture of botanical drug products.

Application of quality by design to the process development of botanical drug products: a case study.

This paper was designed to assess the value of quality by design (QbD) to improve the manufacturing process understanding of botanical drug products. Ethanol precipitation, a widely used unit operation in the manufacture of botanical drug products was employed to illustrate the use of QbD, taking the process of danshen (the dry root of Salvia miltiorrhiza Bunge) as an example. The recovery of four active pharmaceutical ingredients (APIs) and the removal of saccharides were used to represent the performance of ethanol precipitation. Potentially critical variables, including density of concentrate, ethanol consumption, and settling temperature were identified through risk assessment methods. Design of experiments (DOE) was used to evaluate the effects of the potentially critical factors on the performance of ethanol precipitation. It was observed that higher density of concentrate leads to higher removal of saccharides, but results in lower recovery of APIs. With the rise of ethanol consumption, the recovery of different APIs behaves in different ways. A potential design space of ethanol precipitation operation was established through DOE studies. The results in this work facilitate the enhanced understanding of the relationships between multiple factors (material attributes and process parameters) and the performance of ethanol precipitation. This case study demonstrated that QbD is a powerful tool to develop manufacturing process of botanical drug products.

Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.

PURPOSE: FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times. METHODS: Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations. RESULTS: The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test. CONCLUSIONS: In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.

Preclinical pharmacokinetics of MI-219, a novel human double minute 2 (HDM2) inhibitor and prediction of human pharmacokinetics.

PURPOSE: The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. METHODS: Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration-time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima's method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration-time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). RESULTS: Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h⁻¹*kg⁻¹. Human Vdss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fuT) method was between 0.93-1.40 L*kg⁻¹. Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima's transformations. CONCLUSIONS: The predicted human pharmacokinetics is useful for the design of first-in-human study.

MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution.

Several nonclassical major histocompatibilty antigens (class Ib molecules) have emerged as key players in the early immune response to pathogens or stress. Class Ib molecules activate subsets of T cells that mount effector responses before the adaptive immune system, and thus are called innate T cells. MR1 is a novel class Ib molecule with properties highly suggestive of its regulation of mucosal immunity. The Mr1 gene is evolutionarily conserved, is non-Mhc linked, and controls the development of mucosal-associated invariant T (MAIT) cells. MAIT cells preferentially reside in the gut, and their development is dependent on commensal microbiota. Although these properties suggest that MAIT cells function as innate T cells in the mucosa, this has been difficult to test, due to the (i) paucity of MAIT cells that display MR1-specific activation in vitro and (ii) lack of knowledge of whether or not MR1 presents antigen. Here we show that both mouse and human MAIT cells display a high level of cross-reactivity on mammalian MR1 orthologs, but with differences consistent with limited ligand discrimination. Furthermore, acid eluates from recombinant or cellular MR1 proteins enhance MAIT cell activation in an MR1-specific and cross-species manner. Our findings demonstrate that the presentation pathway of MR1 to MAIT cells is highly evolutionarily conserved.

Drug-induced dermatomyositis after zoledronic acid.

A 57-year-old woman with prior exposure to bisphosphonates developed myalgia, proximal muscle weakness and lichenoid rash over the upper extremities and face 3 days after infusion of zoledronic acid for the management of osteoporosis. The diagnosis of dermatomyositis was made on the basis of clinical, laboratory and histological findings. This is the first report of drug-induced dermatomyositis secondary to zoledronic acid.

Profiling the process development of Wurster coating for modified release capsule products in approved drug product applications.

In this paper, we have studied Wurster Coating operation for the manufacture of modified release (MR) capsule products submitted to FDA as New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) by using a data-driven approach. We have collected and classified information into Wurster coating associated process variables, quality attributes, and scale up strategies under Quality by Design (QbD) paradigm. We have quantified the importance and risk of the process variables and quality attributes by analyzing reported frequencies and risk factors, respectively. We have also included analysis of quality attributes listed with high risk factors, such as weight gain, particle size, assay, dissolution of coated beads, and water content/ Loss on drying (LOD) and the process variables with higher risk factors, such as product temperature, spray rate, atomization air pressure, Inlet air volume and Inlet air temperature, etc. We believe that the knowledge obtained through profiling Wurster coating operation will help the industry to further improve the quality of drug product applications regarding the development of this unit operation. We hope systematic profiling of pharmaceutical unit operations under QbD paradigm can provide support for FDA's IT  initiatives aiming at improving the efficiency and consistency of FDA's quality assessment.