Green metrics for biologics

Biologics are the fastest growing segment of the pharmaceutical market, therefore, the environmental impact of manufacturing these drugs needs to be fully characterized. For monoclonal antibodies, in particular, several metrics have been identified as the manufacturing process is quite standardized for batch processes. This paper will provide an overview of carbon footprint analysis, process mass intensity (PMI), water related impact of energy (WARIEN) and life cycle assessment (LCA) as they have been applied to monoclonal antibody production. Further development and standardization of these tools will allow the industry to identify and implement new technologies that significantly lower the environmental impact of not only monoclonal antibody production but other modalities as well.     

Clinical grade lentiviral vector purification and quality control requirements

Lentiviral vectors have been proven to be a powerful tool in gene therapies that includes the ability to perform long-term gene editing in both dividing and non-dividing cells. In order to meet the rising demand for clinical-grade lentiviral vectors for future clinical trials and requirements by regulatory agencies, new methods and technologies were developed, including the rapid optimization of production and purification processes. However, gaps still exist in achieving ideal yields and recovery rates in large-scale manufacturing process steps. The downstream purification process is a critical step required to obtain a sufficient quantity and high-quality lentiviral vectors products, which is challenged by the low stability of the lentiviral vector particles and large production volumes associated with the manufacturing process. This review summarizes the most recent and promising technologies and enhancements used in the large-scale purification process step of lentiviral vector manufacturing and aims to provide a significant contribution towards the achievement of providing sufficient quantity and quality of lentiviral vectors in scalable processes.     

From experimental design to quality by design in pharmaceutical legislation

Quality by design (QbD) is a concept first outlined by Juran, who believed that quality could be planned and that most quality crises and problems relate to the way in which quality was planned in the first place. Experimental design is a powerful technique and tool for QbD, used for exploring new processes, gaining increased knowledge of the existing processes and optimizing these processes for achieving internationally competitive performance. It is also used for the investigation of relationship between parameters of ill-defined process. In this paper, the experimental design principles in pharmaceutical development and impact of these principles on pharmaceutical legislation have been reviewed. Also, slow implementation of QbD in pharmaceutical industries has been discussed. Pharmaceutical legislation is necessary for companies to continue benefiting from knowledge gained and to continually improve throughout the process lifecycle by making adaptations to assure that root causes of manufacturing problems are quickly corrected.     

Enzyme-immobilized microfluidic process reactors

Microreaction technology, which is an interdisciplinary science and engineering area, has been the focus of different fields of research in the past few years. Several microreactors have been developed. Enzymes are a type of catalyst, which are useful in the production of substance in an environmentally friendly way, and they also have high potential for analytical applications. However, not many enzymatic processes have been commercialized, because of problems in stability of the enzymes, cost, and efficiency of the reactions. Thus, there have been demands for innovation in process engineering, particularly for enzymatic reactions, and microreaction devices represent important tools for the development of enzyme processes. In this review, we summarize the recent advances of microchannel reaction technologies especially for enzyme immobilized microreactors. We discuss the manufacturing process of microreaction devices and the advantages of microreactors compared to conventional reaction devices. Fundamental techniques for enzyme immobilized microreactors and important applications of this multidisciplinary technology are also included in our topics.     

A survey on cobalt metallurgical processes and its application

The Cobalt (Co) transition element in the recent years have been a new research area with increased trends in inorganic chemistry. The Co is used in several areas for example ceramics, technologies, additive manufacturing, rechargeable batteries in manufacturing firms. The magnets, and alloys, digital processing, bio-essentiality, Healthcare computing, sustainable development, storage of renewable energy, biogas amongst others are entailed. In this study, the Co Metallurgical processes are presented and how they are used. This is because of its low resistance in smaller geometries and capacity to work through a thinner barrier. This paper avails the purification process of Co from its ores. Presented a diagrammatic illustration of Co within an adverse aspect. This in return avails all fundamental research content that can facilitate the researchers in opposing models and frame works that are state-of-art in elements purification processes.     

New approaches to the industrial synthesis of HIV protease inhibitors

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from l-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to l-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.     

Dropping mode chemiluminescence system with a poly(dimethylsiloxane) cell for applications to semiconductor processes.

A lab-made chemiluminescence system with a polymer cell for the dropping mode was used to determine ultra-trace metal ions in hydrofluoric acid (HF) and the standard cleaning solution-1 (SC-1) used in semiconductor manufacturing processes. The cell was made of poly(dimethylsiloxane) (PDMS) with dimensions of about 10 mm i.d. and 8 mm in height, was cheap, disposable, chemically inert to alkalis and acids, especially HF, and was optically transparent in the visible region. A dropping method for sample injection was adopted to minimize pulsation and the dramatic pH change of the luminol-H2O2 reagent when adding the sample. The average sample weight of a single drop was 7.17 microg with a remarkable reproducibility of +/-0.37% relative standard deviation (RSD). This very small sample volume compared to the reagent volume made it possible to avoid any precipitation being formed when HF was added. For an application, Fe was determined in deionized (d.i.) water, sulfuric acid, SC-1, and a diluted HF (1:200 DHF) solution, which have been commonly used in semiconductor manufacturing processes. The limits of detections for Fe2+ in those solutions were found to be in the range of 42 to 62 pg ml(-1). Based on the analytical results, this chemiluminescence system with the PDMS cell was reproducible, resistant to HF, had less sample consumption and waste generation, and was sensitive enough to apply to the semiconductor industry as an on-line monitoring sensor. Although this chemiluminescence system does not have selectivity for each specific metal ion, it can be used as an on-line sensor to monitor the metal contamination level of Fe, Cu, Co, etc., which are major elements of concern in the semiconductor manufacturing process.     

A review on key aspects of wet granulation process for continuous pharmaceutical manufacturing of solid dosage oral formulations

Wet granulation process is a major unit operation in production of pharmaceuticals as solid dosage oral formulation. Indeed, granulation is used to improve the formulation properties such as flowability, compressibility, and so on for pharmaceutical manufacturing. Different types of granulations can be used in pharmaceutical manufacturing in which the selection of proper process depends on the operational conditions as well as formulation properties. In current decades, twin-screw wet granulation has been of paramount interest owing to its superior properties. Pharmaceutical manufacturing industry are trying to move towards continuous mode by which the efficiency can be improved compared to the batch mode. Therefore, development of continuous granulation process is of great importance. In this review article, various processing units applicable for wet granulation of pharmaceutical formulations for solid dosage forms are reviewed and discussed. The advantages and disadvantages of the processes are discussed and listed along with modeling approaches for simulation of process. The governing models and numerical schemes applicable for design of wet granulation are also critically discussed. The main focus is on wet granulation as this method has attracted much attention in pharmaceutical processing.     

Applications of TGA in quality control of SWCNTs

Carbon nanotubes exhibit a range of chemistries, including mixtures of different nanotube diameters, lengths, and chiralities coupled with various concentrations of metallic and non-nanotube-carbon impurities. The performance of a given material for a specific application depends on the chemistry, which is dictated in large part by the manufacturing process. Here, thermogravimetric analysis is utilized as a bulk characterization method for determining nanotube quality after manufacturing. The application of thermogravimetric analysis for quantifying basic nanotube chemistry is described (e.g., carbon-to-metal content, homogeneity). In addition, extension of the method to analyze specific nanotube properties (i.e., length and diameter) is reported. Results indicate that thermogravimetric analysis is sufficiently sensitive to enable quality control at both the macro-scale (carbon-to-metal ratio) and nano-scale (single-walled to multi-walled) and can detect subtle modifications in manufacturing processes.     

Die Herstellung von Reinstsiliciumscheiben: Mehr Chemie als man glaubt

Monocrystalline semiconductor wafers made of silicon represent the base material for microelectronic devices. The transfer of the precursor material quartz into a 300 mm wafer deposited with an epitaxial layer requires a multitude of process steps, part of which are determined by chemical reactions. This article has introduced into the manufacturing of semiconductor silicon and the processes etching, polishing, cleaning and epitaxy. This technology branch, though, is distinguished by extreme requirements regarding surface perfection and cleanliness, which may be expressed in atomic layers (surface roughness of the wafers) and ppt (contamination of chemicals)     

Chlorherstellung mit Sauerstoffverzehrkathoden. Energieeinsparung bei der Elektrolyse

Chlorine is one of the most important base chemicals and is required for the manufacture of about two‐thirds of all chemical products such as polymers, crop protection and pharmaceutical products, products for drinking water purification, and ultrapure silicon for photovoltaics and electronics applications. The industrial chlorine production through the chlor‐alkali electrolysis has since 1975 mainly been based on the advanced membrane process. Chlorine recycling by manufacturing processes based on hydrogen chloride has also become increasingly important. The still very high energy demand for the electrochemical chlorine synthesis can be significantly reduced by up to 30 % if the hydrogen evolving cathodes in the classical processes are replaced by oxygen depolarized cathodes (ODC) which are well known from fuel cells. Hydrogen chloride electrolysis with ODCs is already carried out in world‐scale plants. The more important chlor‐alkali process with ODCs will be realized for the first time in 2011 in a demonstration unit with a chlorine capacity of 20000 tons per year in Uerdingen, Germany.     

A Versatile 3D and 4D Printing System through Photocontrolled RAFT Polymerization

Reversible addition‐fragmentation chain‐transfer (RAFT) polymerization is a valuable tool for synthesizing macromolecules with controlled topologies and diverse chemical functionalities. However, the application of RAFT polymerization to additive‐manufacturing processes has been prevented due to the slow polymerization rates of typical systems. In this work, we developed and optimized a rapid visible (green) light mediated RAFT polymerization process and applied it to an open‐air 3D printing system. The reaction components are non‐toxic, metal free and environmentally friendly, which tailors these systems toward biomaterial fabrication. The inclusion of RAFT agent in the photosensitive resin provided control over the mechanical properties of 3D printed materials and allowed these materials to be post‐functionalized after 3D printing. Additionally, photoinduced spatiotemporal control of the network structure provided a one‐pass approach to 4D printed materials. This RAFT‐mediated 3D and 4D printing process should provide access to a range of new functional and stimuli‐responsive materials.     

Reactive separation processes for the production of PEGylated proteins

Protein PEGylation plays an important role in the whole panel of reactions used for the modification and improvement of therapeutic proteins. The classic production process consists of a batch reactor followed by a purification unit. In this review, we show that other processes smartly combining the separation and the reaction unit operations within a single process can bring a competitive advantage in terms of yield, conversion and productivity. This represents an alternative approach to the development of new ad-hoc specific chemistries. In the following, in addition to provide an overview of processes described in the literature and discuss advantages and disadvantages of each, we propose innovative solutions which include continuous manufacturing technologies.     

Deep Eutectic Solvents: Alternative Solvents for Biomass-Based Waste Valorization

Innovative technologies can transform what are now considered “waste streams” into feedstocks for a range of products. Indeed, the use of biomass as a source of biopolymers and chemicals currently has a consolidated economic dimension, with well-developed and regulated markets, in which the evaluation of the manufacturing processes relies on specific criteria such as purity and yield, and respects defined regulatory parameters for the process safety. In this context, ionic liquids and deep eutectic solvents have been proposed as environmentally friendly solvents for applications related to biomass waste valorization. This mini-review draws attention to some recent advancements in the use of a series of new-solvent technologies, with an emphasis on deep eutectic solvents (DESs) as key players in the development of new processes for biomass waste valorization. This work aims to highlight the role and importance of DESs in the following three strategic areas: chitin recovery from biomass and isolation of valuable chemicals and biofuels from biomass waste streams.     

MANUFACTURING OF LOW-PHOSPHORUS-DETERGENTS

Changes in composition of household washing detergents are reviewed, with emphasis on the importance of STPP

As by law or voluntary agreement the STPP content in detergents has dropped during the last years in some countries, it will be shown that the quality of the used phosphates is of great influence on the quality of the final product

In manufacturing detergents with low phosphate content it is important to use special STPP-types for every process

The process technology of the manufacture of phosphate-containing powdered detergents can be divided into processes in which the individual components are worked up Into agglomeration products (spray mixing plants) and processes In which the individual components are combined to form a slurry of several substances (spray drying plants).     

Paclitaxel from primary taxanes: a perspective on creative invention in organozirconium chemistry

In this Perspective, which describes the achievements recognized by the 2007 ACS Award for Creative Invention, we discuss the discovery of a new synthetic reaction and its translation into a substantially improved method for manufacturing a major pharmaceutical product--the blockbuster anticancer drug, paclitaxel. The role of creativity in the discovery and invention processes is also discussed. As is often the case, chance discovery and serendipitous findings played a role in the evolution of this work. Translation of the basic research into a commercially viable paclitaxel semisynthesis is also described. The final manufacturing process illustrates the enormous impact that the globalization of markets has had on chemical and pharmaceutical manufacturing.     

Additive manufacturing approaches for biological power generation

As the consequences of global warming continue to affect the climate, there is an increased need for technologies that decrease dependence on fossil fuel consumption and promote sustainability. Additive manufacturing (AM) not only enables the scale-up and mass production of renewable energy technologies but also reduces cost and lead time, minimizes waste, and uses less energy than traditional manufacturing processes. Moreover, AM brings design and innovation to the forefront by allowing for design strategy revision and rapid prototyping. Herein, AM approaches used to fabricate devices that enable biological power generation are described. Biological power generation is a process through which biocatalysts – electroactive bacteria, enzymes, or cyanobacteria – harvest electrons from chemical substrates or light. Device engineering directs electron transfer events to a conductive material and maximizes power output. This review covers recent AM approaches for biological power generation in the form of microbial fuel cells (MFCs), enzymatic fuel cells, and biophotovoltaic cells with an emphasis on MFCs. Fabrication methods and materials for electrodes, chambers, inserts, membranes, and biofilms are described, along with impacts on device performance.     

Use of the bootstrap and permutation methods for a more robust variable importance in the projection metric for partial least squares regression

Bio-pharmaceutical manufacturing is a multifaceted and complex process wherein the manufacture of a single batch hundreds of processing variables and raw materials are monitored. In these processes, identifying the candidate variables responsible for any changes in process performance can prove to be extremely challenging. Within this context, partial least squares (PLS) has proven to be an important tool in helping determine the root cause for changes in biological performance, such as cellular growth or viral propagation. In spite of the positive impact PLS has had in helping understand bio-pharmaceutical process data, the high variability in measured response (Y) and predictor variables (X), and weak relationship between X and Y, has at times made root cause determination for process changes difficult. Our goal is to demonstrate how the use of bootstrapping, in conjunction with permutation tests, can provide avenues for improving the selection of variables responsible for manufacturing process changes via the variable importance in the projection (PLS-VIP) statistic. Although applied uniquely to the PLS-VIP in this article, the generality of the aforementioned methods can be used to improve other variable selection methods, in addition to increasing confidence around other estimates obtained from a PLS model.     

Process analytical technology for chromatography

A major United States Food and Drug Administration effort is devoted to process analytical technology (PAT), which is emerging as the likely "surprise" of the second half of the decade. PAT is an approach to monitoring, manufacturing, and other processes on a continuous rather than discrete basis. It carries the future promise of new methods of production. Building PAT into a chromatography system provides a significant cost and quality advantage to high volume multitest laboratories and provides a significant marketing advantage to the first suppliers able to implement such an approach.     

An Extreme Learning Machine Algorithm to Predict the In-flight Particle Characteristics of an Atmospheric Plasma Spray Process

A robust single hidden layer feed forward neural network (SLFN) is used in this study to model the in-flight particle characteristics of the atmospheric plasma spray (APS) process with regard to the input processing parameters. The in-flight particle characteristics influence the structure and properties of the APS coating and, thus, are considered important parameters to comprehend the manufacturing process. The training times of traditional back propagation algorithms, mostly used to model such processes, are far slower than desired for implementation of an on-line control system. Use of slow gradient based learning methods and iterative tuning of all network parameters during the learning process are the two major causes for such slower learning speed. An extreme learning machine (ELM) algorithm, which randomly selects the input weights and biases and analytically determines the output weights, is used in this work to train the SLFNs. Performance comparisons of the networks trained with ELM algorithm and standard error back propagation algorithms are presented. It is found that networks trained with ELM have good generalization performance, much shorter training times and stable performance with regard to the changes in number of hidden layer neurons. The trends represent robustness of the trained networks and enhance reliability of the application of the artificial neural network in modelling APS processes.