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.

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.

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.

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.

Understanding In Vivo Dissolution of Immediate Release (IR) Solid Oral Drug Products Containing Weak Acid BCS Class 2 (BCS Class 2a) Drugs.

In vivo drug dissolution kinetics of BCS Class 2a IR solid oral drug products remains largely unknown. An understanding to what extent the solubility influences in vivo dissolution is needed to design appropriate in vitro dissolution methods. In this study, nonsteroidal anti-inflammatory drugs (NSAIDs) are used to investigate the in vivo dissolution of BCS Class 2a drugs based on numerical deconvolution analyses. The PK data were obtained from published literature or drug applications submitted to the FDA. It has been hypothesized that the in vivo drug dissolution rate would likely correlate to the solubility of NSAIDs in the media at gastrointestinal pH. Our findings show a short lag time of absorption (Tlag), comparable to the liquid gastric emptying time and independent of the solubility and formulation. In Vivo drug dissolution of NSAIDs was generally rapid and complete within the regular drug residence time in the small intestine while multi-phase absorption was observed in some subjects for all the NSAIDs. The comparisons of in vivo drug dissolution rate, which was characterized by in vivo dissolution half-life (Thalf), indicate that solubility has a minimal impact on in vivo drug dissolution rate for NSAIDs. Gastric emptying regulated by migrating motor complex (MMC) under fasted state most likely governs drug dissolution and absorption of NSAIDs. For BCS Class 2a IR solid oral drug products, large variability of gastric emptying and MMC as well as the strong driving force of intestinal absorption probably outweigh the impact of solubility on drug in vivo dissolution.

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.

Industry 4.0 for pharmaceutical manufacturing: Preparing for the smart factories of the future.

Over the last two centuries, medicines have evolved from crude herbal and botanical preparations into more complex manufacturing of sophisticated drug products and dosage forms. Along with the evolution of medicines, the manufacturing practices for their production have advanced from small-scale manual processing with simple tools to large-scale production as part of a trillion-dollar pharmaceutical industry. Today's pharmaceutical manufacturing technologies continue to evolve as the internet of things, artificial intelligence, robotics, and advanced computing begin to challenge the traditional approaches, practices, and business models for the manufacture of pharmaceuticals. The application of these technologies has the potential to dramatically increase the agility, efficiency, flexibility, and quality of the industrial production of medicines. How these technologies are deployed on the journey from data collection to the hallmark digital maturity of Industry 4.0 will define the next generation of pharmaceutical manufacturing. Acheiving the benefits of this future requires a vision for it and an understanding of the extant regulatory, technical, and logistical barriers to realizing it.

Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs.

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment.Graphical abstract.

FDA's new pharmaceutical quality initiative: Knowledge-aided assessment & structured applications.

This paper describes a new FDA's pharmaceutical quality assessment system: Knowledge-aided Assessment & Structured Application (KASA). The KASA system is designed to: 1) capture and manage knowledge during the lifecycle of a drug product; 2) establish rules and algorithms for risk assessment, control, and communication; 3) perform computer-aided analyses of applications to compare regulatory standards and quality risks across applications and facilities; and 4) provide a structured assessment that minimizes text-based narratives and summarization of provided information. When fully developed and implemented, KASA will enrich the effectiveness, efficiency, and consistency of regulatory quality oversight through lifecycle management of products and facilities, and information sharing in a standardized and structured format. Ultimately, KASA will advance FDA's focus on pharmaceutical quality, the foundation for ensuring the safety and efficacy of drugs.

Dissolution Testing in Drug Product Development: Workshop Summary Report.

This publication summarizes the proceedings and key outcomes of the first day ("Day 1") of the 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." The overall aims of the workshop were to foster a productive dialog between industry and regulatory agencies and to discuss current strategies toward the development and implementation of clinically relevant dissolution specifications as an integral part of enhanced drug product understanding and effective drug product life-cycle management. The Day 1 podium presentations covered existing challenges and concerns for implementing highly valuable, yet often unique and novel experimental dissolution setups as quality control tools. In addition, several podium presentations highlighted opportunities to replace conventional dissolution testing with surrogate test methods to enable robust drug product and process understanding within the context of quality by design (QbD), new manufacturing technologies, and real-time release testing (RTRT). The topics covered on Day 1 laid the foundation for subsequent discussions which focused on the challenges related to establishing an in vitro-in vivo link and approaches for establishing clinically relevant drug product specifications which are becoming an expectation in regulatory submissions. Clarification of dissolution-related terminology used inconsistently among the scientific community, and the purpose of various testing approaches were key discussion topics of the Day 1 breakout sessions. The outcome of these discussions along with creative ways to overcome challenges related to bridging "exploratory dissolution approaches" with methods suitable for end-product control testing are captured within this report.

A Radial Clutch Needle for Facile and Safe Tissue Compartment Access.

Efficient and safe access to targeted therapeutic sites is a universal challenge in minimally invasive medical intervention. Percutaneous and transluminal needle insertion is often performed blindly and requires significant user skill and experience to avoid complications associated with the damage of underlying tissues or organs. Here, we report on the advancement of a safer needle with a radial mechanical clutch, which is designed to prevent overshoot injuries through the automatic stopping of the needle once a target cavity is reached. The stylet-mounted clutch system is inexpensive to manufacture and compatible with standard hypodermic or endoscopic needles, and therefore can be adapted to achieve safe access in a myriad of minimally invasive procedures, including targeted drug delivery, at-home and in-hospital intravenous access, laparoscopic and endo- and trans-luminal interventions. Here, we demonstrate the clutch needle design optimization and illustrate its potential for rapid and safe minimally invasive cannulation.

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.

A multiple biomarker assay for quality assessment of botanical drugs using a versatile microfluidic chip.

Quality control is critical for ensuring the safety and effectiveness of drugs. Current quality control method for botanical drugs is mainly based on chemical testing. However, chemical testing alone may not be sufficient as it may not capture all constituents of botanical drugs. Therefore, it is necessary to establish a bioassay correlating with the drug's known mechanism of action to ensure its potency and activity. Herein we developed a multiple biomarker assay to assess the quality of botanicals using microfluidics, where enzyme inhibition was employed to indicate the drug's activity and thereby evaluate biological consistency. This approach was exemplified on QiShenYiQi Pills using thrombin and angiotensin converting enzyme as "quality biomarkers". Our results demonstrated that there existed variations in potency across different batches of the intermediates and preparations. Compared with chromatographic fingerprinting, the bioassay provided better discrimination ability for some abnormal samples. Moreover, the chip could function as "affinity chromatography" to identify bioactive phytochemicals bound to the enzymes. This work proposed a multiple-biomarker strategy for quality assessment of botanical drugs, while demonstrating for the first time the feasibility of microfluidics in this field.

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.

The future of pharmaceutical quality and the path to get there.

While six sigma quality has long been achieved in other industries, it is rarely seen in the pharmaceutical sector. However, consumers and patients deserve six sigma quality pharmaceuticals with minimal risks of shortages or recalls. We propose that the future of pharmaceutical quality is six sigma, meaning that no more than 3.4 defects occur per million opportunities. We discuss the path to get there, including economic drivers, performance-based regulation, Quality by Design, advanced manufacturing technologies, and continuous improvement and operational excellence. This article outlines an ambitious goal and is intended to be thought-provoking in spite of the challenging path to get there. This goal is envisioned because it is in the best interest of patients and consumers and is realizable with continued advances and investments in science and technology. The fundamental destination of pharmaceutical quality has been long envisioned: a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight.

Building parity between brand and generic peptide products: Regulatory and scientific considerations for quality of synthetic peptides.

Peptides are a fast growing segment in the pharmaceutical industry. Consequently, the industry and regulatory agencies are increasing their focus on the regulatory path and quality considerations for peptide development and manufacturing. Although most peptides are synthetic, manufactured by solid phase synthesis, nevertheless they are complex molecules with challenging quality and regulatory aspects. This paper provides a structured overview of relevant quality issues for chemically synthesized peptides used as active pharmaceutical ingredients (API) in drug products. It addresses the unique characteristics of peptides pertaining to structural and physicochemical characterization, manufacturing and in process controls, impurities and aggregates arising from manufacturing and storage, along with their potential impact on safety (including immunogenicity) and efficacy of the peptide drug products.

Advancing pharmaceutical quality: An overview of science and research in the U.S. FDA's Office of Pharmaceutical Quality.

Failures surrounding pharmaceutical quality, particularly with respect to product manufacturing issues and facility remediation, account for the majority of drug shortages and product recalls in the United States. Major scientific advancements pressure established regulatory paradigms, especially in the areas of biosimilars, precision medicine, combination products, emerging manufacturing technologies, and the use of real-world data. Pharmaceutical manufacturing is increasingly globalized, prompting the need for more efficient surveillance systems for monitoring product quality. Furthermore, increasing scrutiny and accelerated approval pathways provide a driving force to be even more efficient with limited regulatory resources. To address these regulatory challenges, the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) harbors a rigorous science and research program in core areas that support drug quality review, inspection, surveillance, standards, and policy development. Science and research is the foundation of risk-based quality assessment of new drugs, generic drugs, over-the-counter drugs, and biotechnology products including biosimilars. This is an overview of the science and research activities in OPQ that support the mission of ensuring that safe, effective, and high-quality drugs are available to the American public.

Scientific and Regulatory Considerations in Solid Oral Modified Release Drug Product Development.

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increasing the detectability of CQA failures.

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.