Pharmaceutical Manufacturing Processes Research Articles

Dynamic Flowsheet Model Development and Sensitivity Analysis of a Continuous Pharmaceutical Tablet Manufacturing Process Using the Wet Granulation Route

In view of growing interest and investment in continuous manufacturing, the development and utilization of mathematical model(s) of the manufacturing line is of prime importance. These models are essential for understanding the complex interplay between process-wide critical process parameters (CPPs) and critical quality attributes (CQAs) beyond the individual process operations. In this work, a flowsheet model that is an approximate representation of the ConsiGma TM -25 line for continuous tablet manufacturing, including wet granulation, is developed. The manufacturing line involves various unit operations, i.e., feeders, blenders, a twin-screw wet granulator, a fluidized bed dryer, a mill, and a tablet press. The unit operations are simulated using various modeling approaches such as data-driven models, semi-empirical models, population balance models, and mechanistic models. Intermediate feeders, blenders, and transfer lines between the units are also simulated. The continuous process is simulated using the flowsheet model thus developed and case studies are provided to demonstrate its application for dynamic simulation. Finally, the flowsheet model is used to systematically identify critical process parameters (CPPs) that affect process responses of interest using global sensitivity analysis methods. Liquid feed rate to the granulator, and air temperature and drying time in the dryer are identified as CPPs affecting the tablet properties.

Improving the Transparency of the Pharmaceutical Supply Chain through the Adoption of Quick Response (QR) Code, Internet of Things (IoT), and Blockchain Technology: One Result: Ending the Opioid Crisis

Over the past two years, Americans in nearly every state have suffered adverse effects from counterfeit medications, many of whom have died. The main culprit is Fentanyl-tainted counterfeit opiates which often lead to fatal overdoses. The increasing epidemic of counterfeit prescription medications extends beyond social classes, gender, race, and age. For instance, pop star Prince recently overdosed on counterfeit Hydrocodone containing synthetic Fentanyl. Shockingly, one in ten medications sold in developing countries are counterfeit; either containing incorrect doses of active ingredients or containing toxic contaminants retained from the production process. The popularity of counterfeit medications stems from cheaper costs, but also because of the ease with which these counterfeit products can be purchased. While the blockchain has gained its fame from Bitcoin, its potential implications are far reaching. In this paper, I propose the use of QR code and the IoT (Internet of Things) sensor devices leveraging the blockchain for increased transparency of the pharmaceutical supply chain and manufacturing process. The data collected from the devices would then be transferred to the blockchain, enabling consumers to use an app to verify the provenance of their medication.

Methods to Assess Mixing of Pharmaceutical Powders.

The pharmaceutical manufacturing process consists of several steps, each of which must be monitored and controlled to ensure quality standards are met. The level of blending has an impact on the final product quality; therefore, it is important to be able to monitor blending progress and identify an end-point. Currently, the pharmaceutical industry assesses blend content and uniformity through the extraction of samples using thief probes followed by analytical methods, such as spectroscopy, to determine the sample composition. The development of process analytical technologies (PAT) can improve product monitoring with the aim of increasing efficiency, product quality and consistency, and creating a better understanding of the manufacturing process. Ideally, these are inline methods to remove issues related to extractive sampling and allow direct monitoring of the system using various sensors. Many technologies have been investigated, including spectroscopic techniques such as near-infrared spectroscopy, velocimetric techniques that may use tracers, tomographic techniques, and acoustic emissions monitoring. While some techniques have demonstrated potential, many have significant disadvantages including the need for equipment modification, specific requirements of the material, expensive equipment, extensive analysis, the location of the probes may be critical and/or invasive, and lastly, the technique may only be applicable to the development phase. Both the advantages and disadvantages of the technologies should be considered in application to a specific system.

In Situ Cocrystallization of Dapsone and Caffeine during Fluidized Bed Granulation Processing.

Different pharmaceutical manufacturing processes have been demonstrated to represent feasible platforms for the production of pharmaceutical cocrystals. However, new methods are needed for the manufacture of cocrystals on a large scale. In this work, the suitability of the use of a fluidized bed system for granulation and concomitant cocrystallization was investigated. Dapsone (DAP) and caffeine (CAF) have been shown to form a stable cocrystal by simple solvent evaporation. DAP is the active pharmaceutical ingredient (API) and CAF is the coformer. In the present study, DAP-CAF cocrystals were produced through liquid-assisted milling and the product obtained was used as a cocrystal reference. The granulation of DAP and CAF was carried out using four different experimental conditions. The solid-state properties of the constituents of the granules were characterised by differential scanning calorimetry (DSC) and x-ray powder diffraction (PXRD) analysis while the granule size distribution and morphology were investigated using laser diffraction and scanning electron microscopy (SEM), respectively. DAP-CAF cocrystal granules were successfully produced during fluidized bed granulation. The formation of cocrystals was possible only when the DAP and CAF were dissolved in the liquid phase and sprayed over the fluidized solid particles. Furthermore, the presence of polymers in solution interferes with the cocrystallization, resulting in the amorphization of the DAP and CAF. Cocrystallization via fluidized bed granulation represents a useful tool and a feasible alternative technique for the large scale manufacture of pharmaceutical cocrystals for solid dosage forms.

Application of Shewhart Control Charts in the Inspection of Pharmaceutical Manufacturing Process

Control charts, also known as Shewhart Control charts, are used to determine if a manufacturing process is in a state of statistical control. This article illustrates the use of charts to evaluate pharmaceutical manufacturing process variability. According to the characteristics and control requirements of quality parameters, several types of typical parameters were introduced to illustrate the detection results and create the control charts in order to confirm whether the production was under control. Expedite the operator discovering the process variation caused by special factors, and taking corrective actions so that the products consistently complied with the regulatory specifications and production instructions.

Template-induced nucleation for controlling crystal polymorphism: from molecular mechanisms to applications in pharmaceutical processing

The major factors governing template-induced nucleation of molecular crystals are assessed, highlighting applications in pharmaceutical manufacturing and formulation processes where the templating effect is used to promote crystal nucleation and for controlling crystal polymorphism.

Simulation Modeling of a Pharmaceutical Tablet Manufacturing Process via Wet Granulation

The pharmaceutical tablet manufacturing process (PTMP) via wet granulation holds a critical position in pharmaceutical industry. The interest in integrating mechanistic process modeling into the pharmaceutical development has been increased because simulation model is a prerequisite for process design, analysis, control, and optimization. So the simulation modeling for PTMP via wet granulation is very necessary and significant. This study aims at proposing a simulation modeling framework for PTMP via spray fluidized bed granulation (SFBG), which is one of the most widely used wet granulation techniques in pharmaceutical industry. For SFBG, a simulation model that simultaneously involves the influences of operating variables and material attributes on average particle size (APS) is firstly developed, and then a drying model to determine the particle moisture content is introduced to be coupled with the established model predicting APS. For PTMP, considering the important effect of porosity on tablet qualities, a model describing the changes in tablet porosity is developed based on a promoted form of the Heckel equation, and then several recognized models that are all related to porosity are introduced or constructed to calculate important tablet quality indexes. The feasibility and effectiveness of the developed simulation models are validated by performing a computational experimental study to explore the scientific understanding of process and process quality control.

Generic gas chromatography flame ionization detection method using hydrogen as the carrier gas for the analysis of solvents in pharmaceuticals

Within the pharmaceutical industry, the determination of residual solvents by Gas Chromatography Flame Ionization Detection (GC-FID) is a highly utilized analytical test that often employs helium (He) as the carrier gas. However, many do not realize that helium is a non-renewable resource that will eventually become progressively more difficult to source. In recent years, analytical chemists are increasingly adopting hydrogen (H2) in place of helium for routine GC analysis. In this study, a simple and efficient generic/universal GC-FID method using H2 as the carrier gas has been developed with the capability of baseline resolution of over 30 of the most commonly used solvents in development and manufacturing with a method run time of less than eight minutes. The use of this method for the separation and analysis of solvents within a pharmaceutical manufacturing process is demonstrated with additional method validation data presented using five different diluents as a means to increase flexibility for the chromatographer. Furthermore, it is the recommendation of the authors that the current compendia for residual solvent analysis be updated to allow for hydrogen as a carrier gas. The similarity between He and H2 observed within this study supports the use of hydrogen as a suitable replacement for helium, and an update of the EU and USP compendia for residual solvent analysis should be made to reflect this.

Systematic Framework for Implementation of Material Traceability into Continuous Pharmaceutical Tablet Manufacturing Process

With the applications of more advanced manufacturing technologies being applied to the pharmaceutical industry, continuous processes are at the forefront of innovation. One area that is highly desired to be systematically investigated is material traceability in continuous manufacturing systems. By following federal guidelines already in place, the goal was to address the issue of material traceability in a continuous direct compression tablet manufacturing process. The residence time distribution (RTD) method has been used for material traceability in continuous pharmaceutical tablet manufacturing process. Utilizing the minimum and maximum residence times for the continuous line pre-production, raw material batch changes that occur during feeder refill can be traced at the outlet of the process. MATLAB programing was used to develop software prototype to trace material components. Developed framework for implementation of material traceability into continuous manufacturing pilot-plant. To demonstrate the application of this framework, a software prototype was developed, which allows the operator to input residence time attributes for each component in the formulation. Using the minimum and maximum residence time values for that component, the lot number is incremented when the change in material batch is predicted to be present in the tablets at the outlet. The tablet lot number is recorded by the control system in real-time. Developed framework and corresponding software allows the material traceability to be fully accounted for during a continuous drug product manufacturing process. A proof of concept was created to demonstrate feasibility of such a system, which has a wide range of applications.

Combining Morphological Population Balances with Face-Specific Growth Kinetics Data to Model and Predict the Crystallization Processes for Ibuprofen

A route map for modeling pharmaceutical manufacturing processes utilizing morphological population balance (MPB) is presented in terms of understanding and controlling particle shape and size for optimizing the efficiency of both the manufacturing process and final properties of the formulated drugs. This is applied to batch cooling crystallization of the pharmaceutical compound ibuprofen from supersaturated ethanolic solutions in which the MPB is combined with the known crystal morphology and associated face-specific growth kinetics (Nguyen et al. CrystEngComm 2014, 16, 4568–4586) to predict the temporal evolution of the shape and size distributions of all crystals. The MPB simulations capture the temporal evolution of the size and shape of ibuprofen crystals and their distributions at each time instance during the crystallization processes. The volume equivalent spherical diameter and crystal size distribution converted from MPB simulation are validated against the experimental studies on the 1 L scale size (Rashid et al. Chem. Eng. Res. Des. 2012, 90, 158–161), confirming the promise of this approach as a powerful simulation, optimization, and control tool for the digital design of precision pharmaceutical processes and products with the desirable properties, with potential applications in crystallization design for personalized medicines.

Process Innovation in the Pharmaceutical Industry

Problem definition: Process innovation is commonly claimed to be a major source of competitive advantage for firms. Despite this perceived influence it has received substantially less attention than product innovation and much uncertainty remains about its true association with firm performance. We investigate the relationship between a pharmaceutical manufacturing firm's process-innovation portfolio and its economic performance. Academic/Practical relevance: Our study uniquely conducts a multi-dimensional evaluation of a firm's portfolio of process innovations at the product level. This allows a quantitative evaluation of both the relative benefit of the different dimensions of a portfolio as well as the potential complementarities between these. Methodology: Through a collaboration with expert patent attorneys we develop a unique longitudinal dataset that combines secondary data and evaluations of a firm's portfolio of process patents along three key dimensions: novelty, scope, and locus. We conduct econometric analyses for a large-scale sample of drugs open to competition from generics, where process innovation is the main source of competitive advantage. Results: We find a positive association between overall process innovation and firm performance. When differentiating between dimensions of process innovation, results further suggest that high novelty is beneficial, and complemented by a broad scope, but only for patents applying to the later phase of the pharmaceutical manufacturing process. Managerial Implications: Our results provide important practical insights that can inform process-related R&D investments in the pharmaceutical sector. In particular, it may not be economically beneficial to invest in high-novelty process innovations in early production stages, which are characterized by numerous opportunities to innovate with potentially higher but less predictable economic payoffs. On the other hand, at later stages of the production process, where the opportunities to innovate are less numerous with potentially lower but more predictable economic payoffs, portfolios that are jointly characterized by high novelty and high scope could be more valuable.

Residence Time Distribution (RTD)-Based Control System for Continuous Pharmaceutical Manufacturing Process

During continuous manufacturing, there may be some out of specification tablets that need to be diverted in real time, in order to ensure the quality of the final product. Specifically, the content uniformity of each tablet must be guaranteed before it can be released to market. However, currently, no methods or tools are available that can assure the content uniformity and divert the non-confirming products in real time. The aim of this work is to develop and evaluate a strategy to divert the non-confirming tablets in real time and thereby assure drug concentration of final tablets. This work has been conducted in silico using a combination of MATLAB and Simulink. A methodology to implement a residence time distribution (RTD)-based control system for drug concentration-based tablet diversion which uses the convolution integral was developed and implemented in MATLAB. Comparisons between the performance of “fixed window” and “RTD-based” approaches for diversion have also been presented and used to assess optimal usability. In this work, two novel strategies namely, “fixed window approach” and “RTD-based approach” have been developed and evaluated for real-time diversion of non-confirming tablets. The RTD-based control system was designed, developed, and implemented in silico. A framework for its implementation in a real-time system has also been elaborated on. This methodology was compared to an alternative fixed window approach. The proposed control system is analyzed for various manufacturing scenarios, systems, and disturbances. A comparison of the two proposed strategies suggests that the “RTD-based control system” is more efficient in every simulated scenario. The relative performance is best when the disturbances in the system are characterized by short pulse-like changes.

Relevance of regulatory constraints in designing pharmaceutical manufacturing processes: A case study on waste solvent recovery

This work deals with the relevance of regulatory constraints on the outcome of process design in pharmaceutical manufacturing with a case study on waste solvent recovery. The role of the investigated process was to separate and purify tetrahydrofuran from an azeotropic mixture with water and methanol. As the technologies to overcome the distillation boundary, zeolite membrane, pressure swing, azeotropic distillation, and entrainer processes were considered as alternatives, and were modeled and evaluated with regard to economy, environmental impact, and environmental, health, and safety hazards. The target concentration of recovered solvent, which cannot be altered because of regulations, was imagined to be modifiable, and two design problems, initial and extended, were formulated. A type of pressure swing process that was found to be optimal in the extended problem was equal to or better than any of the optimal alternatives in the initial design problem. Remarkably, the net present value of this alternative was about 17% larger than the maximum in the initial design problem. These results confirmed quantitatively that the way in which regulatory constraints are taken into account makes a difference in the outcome and that the appropriate formulation of a design problem is critical for pharmaceutical manufacturing processes.

Effective Role of Sodium Chloride as an Agglomeration Inhibitor or a Grinding Aid in Pharmaceutical Manufacturing Processes (特集 フロンティア研究論文(2))

Effective Role of Sodium Chloride as an Agglomeration Inhibitor or a Grinding Aid in Pharmaceutical Manufacturing Processes (特集 フロンティア研究論文(2))

Evaluating the Impact of a Decade of Funding from the Green Chemistry Institute Pharmaceutical Roundtable

Starting in 2007, the ACS Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) has invested in sustainable chemical reactions and technologies in order to positively impact the pharmaceutical manufacturing routes and processes of the future. It has done so by committing over $2 million to support a grant program focused on spurring innovative and sustainable solutions to industrially relevant problems with significant unmet need. This has resulted in the funding of 28 research programs from academic groups across the globe, spanning a wide range of greener chemical technologies such as C–H activation, flow chemistry, biocatalysis, novel catalytic transformations, base metal catalysis, and solvent substitution. The application of this work has encompassed a range of therapeutic modalities, from traditional small molecules to peptides and biologics. This manuscript reviews the impact of the GCIPR funding program in its first decade by drawing together in one place the outputs of each project funded, ...

Development of a Novel Continuous Filtration Unit for Pharmaceutical Process Development and Manufacturing

The lack of a commercial laboratory, pilot and small manufacturing scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufacturing processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chemical and physical attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical analytical methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20.

In-Depth Evaluation of Data Collected During a Continuous Pharmaceutical Manufacturing Process: A Multivariate Statistical Process Monitoring Approach

The present work presents an in-depth evaluation of continuously collected data during a twin-screw granulation and drying process performed on a continuous manufacturing line. During operation, the continuous line logs 49 univariate process variables, hence generating a large amount of data. Three identical 5-h continuous manufacturing runs were performed. Multivariate data analysis tools, more specifically latent variable modeling tools such as principal component analysis, were used to extract information from the generated data sets unveiling process trends and drifts. Furthermore, a statistical process monitoring strategy is presented. The approach is based on the application of multivariate statistical process monitoring to model the variables that remain around a steady state.

The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations

This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufacturing Organizations (CMOs). The survey includes staffing (personnel), chemistry, reaction platforms, postreaction processing, analytical, regulatory, and factors that influence the adoption of continuous manufacturing. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufacturing executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chemistry, while postprocessing and analytical remain in the very early stages of development and implementation.

Model development and prediction of particle size distribution, density and friability of a comilling operation in a continuous pharmaceutical manufacturing process

The comilling process plays an important role in solid oral dosage manufacturing. In this process, the granulated products are comminuted to the required size distribution through collisions created from a rotating impeller. In addition to predicting particle size distribution, there is a need to predict other critical quality attributes (CQAs) such as bulk density and tapped density, as these impact tablet compaction behavior. A comprehensive modeling approach to predict the CQAs is needed to aid continuous process modeling in order to simulate interaction with the tablet press operation. In the current work, a full factorial experiment design is implemented to understand the influence of granule strength, impeller speed and residual moisture content on the CQAs. A population balance modeling approach is applied to predict milled particle size distribution and a partial least squares modeling approach is used to predict bulk and tapped density of the milled granule product. Good agreement between predicted and experimental CQAs is achieved. An R2 value of 0.9787 and 0.7633 is obtained when fitting the mean particle diameters of the milled product and the time required to mill the granulated material respectively.

The Scattered Twelve Tribes of HEK293

Their ease of growth and transfection makes HEK293 cells a common cell culture in academic research. In addition, high transfection efficiency of HEK293 cells enable production of exogenous proteins or viruses for pharmaceutical and biomedical research purposes. Recently, HEK293 cells has gained attention due to it is versatility for transfection experiments, particularly the propagation of adenoviral-based and retroviral-based vectors during CART-T bioprocess. Since traceability is critical to pharmaceutical manufacturing process, we provide a mini review to clarify the historical development and intent use of different variants of HEK293 cells. This review should provide a key reference for the HEK293 variants’ historical and developmental background.