D-Optimal Optimization and Data-Analysis Comparison Between a DoE Software and Artificial Neural Networks of a Chitosan Coating Process onto PLGA Nanoparticles for Lung and Cervical Cancer Treatment Abstract Purpose A common approach to “Quality-by-Design” is to employ quality software(s) to characterize the impacts of input parameters on output-critical quality attributes. In this study, paclitaxel (PTX), a common chemotherapeutic agent, was loaded into poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs), and the coating process of chitosan (CS) onto PLGA NPs was focused for optimization. Method Experiments were designed using Modde 8.0 to set up a D-optimal design for inputs (CS/PLGA ratios, temperature, and pH), and particle size (Z), zeta potential (Zeta), polydispersity index (PDI), encapsulation efficiency (EE), and loading capacity (LC) were the selected outputs. Data analysis was performed using Modde 8.0 concurrently with artificial neural networks such as INform 3.1 and FormRules 2.0. Furthermore, enhancement of cytotoxicity, cellular uptake, and apoptosis by CS coating were also determined. Results The results confirmed the influence of inputs on output ones (R2 > 90%). The optimized formulation showed Z of 161.53 ± 0.97 nm, PDI of 0.270 ± 0.007, Zeta of 41.87 ± 1.42 mV, and EE of 98.59 ± 0.22%; the results were close to the predicted calculations. The optimal formulation, CS-PLGA NPs, showed higher cytotoxicity than PLGA NPs in Hela and SK-LU-1 cell-lines (cell viability assay). Furthermore, apoptosis and intracellular uptake studies confirmed enhancement of the CS layer. Conclusion The data reveal the validity of optimization models and their potential in anti-cancer therapy, especially for lung and cervical cancer treatment.

Effect of Human Error, Inhalation Flow, and Inhalation Volume on Dose Delivery from Ellipta® Dry-Powder Inhaler Abstract Purpose Ellipta® is a new dry-powder inhaler (DPI), with medium flow resistance. The present study aimed to evaluate Ellipta® dose preparation and inhalation technique and determine the effect of human factor, inhalation flow, and inhalation volume on total emitted dose (TED). Methods Two-hundred obstructive lung disease patients were asked to load Ellipta® dose and inhale from placebo Ellipta®, without receiving counseling (first attempt). They were divided into patients who previously used DPI (100 patients) and others who never used DPI before (100 patients). Secondly, TED of single-loaded dose from Relvar-Ellipta® was determined at different inhalation flows (20, 40, and 60 L/min) and inhalation volumes (2 and 4 L). TED was also determined after loading the dose twice at inhalation flows of 40 and 60 L/min and inhalation volume of 4 L. Doses were prepared while Ellipta® is in upright and horizontal positions. Results The number of handling errors performed by patients who previously used DPI was lower compared to others who never used DPI before. No significant difference was found between TEDs of 40 and 60 L/min inhalation flow at 2 or 4 L inhalation volume when loading Ellipta®, once or twice, in an upright or horizontal position. TED at inhalation flow of 20 L/min was significantly lower than at 40 and 60 L/min (p < 0.001). A 4-L inhalation volume significantly increased TED than 2 L/min only at inhalation flow of 20 L/min (p = 0.001). Conclusions Ellipta® is a consistent DPI. It can be used to deliver inhaled medication at a flow of ≥ 40 L/min without fear of not receiving the needed dose. It does not allow delivering double dosing.

Manufacturing of Pharmaceuticals by Impregnation of an Active Pharmaceutical Ingredient onto a Mesoporous Carrier: Impact of Solvent and Loading Abstract Purpose In this study, an active pharmaceutical ingredient (API) was impregnated onto a mesoporous carrier (excipient) in a fluidized bed. Impregnating APIs in porous carriers has the potential to simplify the drug substance development process and leads to the elimination of the blending and granulation unit operations. Impregnation and drying occur simultaneously in fluidized-bed impregnation, and this method precludes several challenges encountered in other impregnation methods. Furthermore, the process ensures a uniform distribution of APIs within the porous carriers. This method also allows for a variety of solvents to be used in the impregnation. Methods Using a batch fluidized-bed dryer, impregnation of acetaminophen (APAP) onto a magnesium/aluminum metasilicate (Neusilin R) was studied. Water and methanol were used as transport solvents to impregnate different loadings (w/w) of APAP, namely, ranging from 24 to 0.1%. Results Uniformity tests indicated that APAP loadings of all impregnated products are close to their target loadings across carrier size classes. Tests before and after impregnation showed that there were no changes observed in the physical properties of the carrier, such as particle size, compressibility, and flow properties. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis performed on the samples indicated that the low loadings APAP was present in the carrier pores in its amorphous state. At high loadings, we observed that APAP was mainly present in its amorphous state, however, some degree of crystallinity was observed. Lastly, dissolution tests on the impregnated product showed enhanced dissolution rates in acidic media, and comparable dissolution rate in de-ionized (DI) water, compared to the pure drug crystals. Conclusion Our results show that the method of fluidized-bed impregnation yields a product with high uniformity and overcomes several challenges presented by traditional physical blends. Graphical Abstract ᅟ

Analytical Method Development Using Transmission Raman Spectroscopy for Pharmaceutical Assays and Compliance with Regulatory Guidelines—Part II: Practical Implementation Considerations Abstract Transmission Raman spectroscopy is a relatively new technique for quantitative analysis of pharmaceutical products, either during manufacturing or as a finished product test. As with any new analytical tool, several requirements need to be met for widespread application. These include assessment of technical capability, integration with quality and manufacturing processes and successful deployment in a quality-controlled environment. In the first paper of a two-part series, regulatory guidelines and method development were discussed for the creation of transmission Raman spectroscopic methods for content uniformity (CU), assay and drug product identity (ID) applications. In this part II, the practicalities of method development are addressed, and an example of the development of a quantitative method for the determination of drug content uniformity in individual tablet cores using partial least-squares is presented.

Combined Feedforward/Feedback Control of an Integrated Continuous Granulation Process Abstract Purpose Continuous manufacturing offers shorter processing times and increased product quality assurance, among several other advantages. This makes it an ever-growing interest among pharmaceutical companies. A suitable efficient control system is however desired for continuous pharmaceutical manufacturing to achieve a consistent predefined end product quality. Methods In order to control product quality more accurately, the effects of input disturbances need to be proactively mitigated. Therefore, it is desired that a combined feedforward/feedback control system integrated with suitable process analytical technology (PAT) be implemented over a traditional feedback-only control system. The feedforward controller measures and takes corrective actions for disturbances proactively before they affect the process and thereby product quality. The feedback controller considers the real-time deviation of control variable from a pre-specified set point and keeps it at a minimum possible value. The deviation of a control variable from the set point could be due to both measurable and unmeasurable disturbances. Results In this work, a combined control strategy has been developed for a continuous twin screw wet granulation (WG) process. An integrated flowsheet model was developed and simulated in order to evaluate the effect of control loops on critical quality attributes (CQAs). Different strategies of manipulation were evaluated and the best strategy was identified. Conclusions In silico study on the combined feedforward/feedback control strategy and feedback-only control strategy demonstrates that the combined loop results in diminished variability of the CQAs.

Steady-State Data Reconciliation Framework for a Direct Continuous Tableting Line Abstract Purpose Reliable process monitoring in real-time remains a challenge for the pharmaceutical industry. Dealing with random and gross errors in the process measurements in a systematic way is a potential solution. In this paper, we present a process model-based framework, which for given sensor network and measurement uncertainties will predict the most likely state of the process. Thus, real-time process decisions, whether for process control or exceptional events management, can be based on the most reliable estimate of the process state. Methods Reliable process monitoring is achieved by using data reconciliation (DR) and gross error detection (GED) to mitigate the effects of random measurement errors and non-random sensor malfunctions. Steady-state data reconciliation (SSDR) is the simplest forms of DR but offers the benefits of short computational times. We also compare and contrast the model-based DR approach (SSDR-M) to the purely data-driven approach (SSDR-D) based on the use of principal component constructions. Results We report the results of studies on a pilot plant-scale continuous direct compression-based tableting line at steady-state in two subsystems. If the process is linear or mildly nonlinear, SSDR-M and SSDR-D give comparable results for the variables estimation and GED. SSDR-M also complies with mass balances and estimate unmeasured variables. Conclusions SSDR successfully estimates the true state of the process in presence of gross errors, as long as steady state is maintained and the redundancy requirement is met. Gross errors are also detected while using SSDR-M or SSDR-D. Process monitoring is more reliable while using the SSDR framework.

Evaluation of a Dry Coating Technology as a Substitute for Roller Compaction for Dry Agglomeration Applications in the Pharmaceutical Industry Abstract Purpose A dry coating technology has been evaluated as a dry agglomeration technique for a typical pharmaceutical formulation. Its efficiency was compared with that of the more commonly used roller compaction dry granulation. Methods A commercially available system was selected as a representative technology. The selection was based on batch size, processing time, unit size, vendor support, preventive maintenance requirements, development stage, and maturity for pharmaceutical industry requirements. The comparison targets the behavior of the resulting materials in terms of flowability, compressibility, mixing efficiency, and prevention of segregation. Particle size distribution, bulk density, scanning electron microscopy, FT4 powder rheometer, and hardness were used for the characterization of the powders. A design of experiment was used to evaluate the impact of the dry coating equipment operating parameters (rotor speed and processing time) as well as the impact of formulation (grade of microcrystalline cellulose and ratio between dibasic calcium phosphate and lactose). Results The tested dry coating technology shows (1) an improved compressibility, (2) that the powders are homogenous, and (3) that they do not have a tendency to segregate in downstream process steps and during handling and storage. The impact of the rotor speed is proven statistically not significant, but it seems that a lower rotor speed might lead to less attrition and better flow properties. Processing time does not seem to have an impact for the range of processing times evaluated. Compared to roller compaction, the main advantages of the tested technology are the shape and surface enhancement and the absence of work hardening. Conclusions This work has shown that the blends produced by the targeted dry coating equipment has equal or better results than the powders processed by roller compaction for all the critical quality attributes that were evaluated.

Patient-Centric Strategies for Drug Re-innovation Abstract Drug repurposing, often achieved via the FDA’s 505(b) (2) pathway, is an increasingly popular approach in today’s pharmaceutical environment. Repurposing or “re-innovation” comprises a multitude of techniques, which have resulted in wide-ranging commercial success. This article explores the diverse strategies that have been taken to repurpose drugs, and distinguishes a unifying theme among the most commercially successful examples—the ability to address significant unmet needs. The examples listed in this paper relate to small molecules drugs and certainly not exhaustive, however provide some of the key strategies that have been successful using “re-innovation” pathway.

Optimization of Unidirectional Mucoadhesive Buccal Patches Based on Chitosan and Pluronic® F-127 for Metoprolol Controlled Release: In Vitro and Ex Vivo Evaluations Abstract Purpose The aim of this work was to optimize unidirectional buccal patches loaded with metoprolol (MT-MBPs) to provide adequate mucoadhesive and water uptake properties as well as controlled drug release for the effective treatment of different cardiovascular diseases. Methods The patches were prepared layer-by-layer using the solvent casting method. A central composite design was employed to statistically optimize the formulation variables. Chitosan and Pluronic® F-127 (poloxamer 407) concentrations were chosen as the independent variables, while ex vivo mucoadhesive force, ex vivo residence time, in vitro water uptake (%), and in vitro drug release (%) were to be considered the dependent variables. The optimized formulation was also characterized and evaluated in terms of morphology, thermal behavior, tensile strength, elongation at break, and ex vivo drug permeation. Results The optimized MT-MBPs were successful in terms of mucoadhesive force (3.58 ± 0.62 N), residence time (342.67 ± 17.21 min), and water uptake at 1 h (24.53 ± 3.62%). A controlled drug release was obtained for 8 h. Thermal and morphologic analyses demonstrated that metoprolol was homogeneously distributed throughout the microporous chitosan-based polymer matrix. Furthermore, the MT-MBPs exhibited a tensile strength of 3.76 ± 0.55 N/mm2 and an elongation at break of 36.52 ± 13.88%. The results of ex vivo permeation through pig buccal mucosa indicated that therapeutic metoprolol concentrations can be reached by using a patch of 5.62 cm2. Conclusions Optimal composition of the MT-MBPs included 2.9% (w/v) and 2.6% (w/v) of chitosan and Pluronic® F-127, respectively, which constitutes the most suitable makeup for metoprolol buccal delivery. Graphical Abstract

Assessment of Applications of Design of Experiments in Pharmaceutical Development for Oral Solid Dosage Forms Abstract Purpose The concept of quality by design (QbD) was introduced to the pharmaceutical industry about a decade ago. Design of experiments (DoE) is an excellent and important tool for a QbD approach. This project’s aim is to obtain an overview of how DoE is being applied to assist pharmaceutical development in New Drug Application (NDA) and Abbreviated New Drug Application (ANDA) submissions for oral solid dosage forms including immediate release (IR) tablet, extended release (ER) tablet, IR capsule, and ER capsule. Methods A total of 131 NDA submissions and 606 randomly selected ANDA submissions with submission dates between 2012 and 2016 were chosen based on the Biopharmaceutics Classification System (BCS) of drug substances. The ratios of applying DoE studies in NDA and ANDA submissions were calculated and compared based on the BCS classes of the active pharmaceutical ingredients (APIs). Results For the Reference Listed Drug (RLD)-based cluster ANDA submissions, the percentage of applying DoE studies in BCS II ANDA submissions is statistically higher than those of the ANDA submissions in the other three BCS classes. Some common issues of the DoE studies were found in the selected submissions. Conclusions DoE has been used as an important tool for QbD approach in NDA submissions but has not yet become a routine common practice to assist the implementation of QbD approach during the pharmaceutical development for NDA and ANDA submissions for oral solid dosage forms. By conducting DoE studies, researchers can gather critical information (i.e., CMAs, CQAs, CPPs, potential interactions) during the pharmaceutical development which can help to improve the quality of applications.