Preserving the food preservation legacy.

This paper deals with the question about how early humans managed to feed themselves, and how they preserved and stored food for times of need. It attempts to show how humans interacted with their environments and demonstrate what lessons can be learnt from the about 3.4 million years of food processing and preservation. It includes a discussion about how hominins shifted from consumption of nuts and berries toward meat and learnt to control and use fire. Cooking with fire generated more food-related energy and enabled humans to have more mobility. The main trust of the paper is on historical food preservations, organized from the perspectives of key mechanical, thermal, biological and chemical processes. Emerging food processes are also highlighted. Furthermore, how humans historically dealt with food storage and packaging and how early humans interacted with their given environments are discussed. Learnings from the history of food preservation and culinary practices of our ancestors provide us with an understanding of their culture and how they adapted and lived with their given environments to ensure adequacy of food supply. Collaboration between food scientists and anthropologists is advocated as this adds another dimension to building resilient and sustainable food systems for the future.

Digitizing Chemical Synthesis in 3D Printed Reactionware.

Chemistry digitization requires an unambiguous link between experiments and the code used to generate the experimental conditions and outcomes, yet this process is not standardized, limiting the portability of any chemical code. What is needed is a universal approach to aid this process using a well-defined standard that is composed of syntheses that are employed in modular hardware. Herein we present a new approach to the digitization of organic synthesis that combines process chemistry principles with 3D printed reactionware. This approach outlines the process for transforming unit operations into digitized hardware and well-defined instructions that ensure effective synthesis. To demonstrate this, we outline the process for digitizing 3 MIDA boronate building blocks, an ester hydrolysis, a Wittig olefination, a Suzuki-Miyaura coupling reaction, and synthesis of the drug sulfanilamide.

Impact of Critical Material Attributes (CMAs)-Particle Shape on Miniature Pharmaceutical Unit Operations.

The U.S. Food and Drug Administration (FDA) emphasizes drug product development by Quality by Design (QbD). Critical material attributes (CMAs) are a QbD element that has an impact on pharmaceutical operations and product quality. Pharmaceutical drugs often crystallize as needle-shaped (a CMA) particles and affect the process due to poor flowability, low bulk density, and high compressibility, and eventually the product performance. In this study, the product obtained from crystallization was needle-shaped Ciprofloxacin HCl (CIPRO), formed lumps during drying, and compacted during processing through feeders. To delump small amounts of materials and break the needles, multiple available devices (mortar-pestle, Krups grinder) and custom-made grinder were assessed before formulation. The processed CIPRO powder was then used to make tablets in the miniature tablet manufacturing unit developed by the team at MIT. The critical quality attributes (CQA) of the tablets, set by the United States Pharmacopeia (USP), were then assessed for the drug powder processed with each of these devices. Powder properties comparable to commercial CIPRO were obtained when the custom MIT-designed grinder was used, leading to tablets that meet the USP criteria, with comparable dissolution profiles of those for marketed CIPRO tablets. This study demonstrates how needle-shaped crystals have an impact on pharmaceutical operations, even if it is on a miniature scale, and how proper shape and subsequent flow properties can be obtained by processing the particles through the MIT team-designed grinder.

Development of in situ product removal strategies in biocatalysis applying scaled-down unit operations.

An experimental platform based on scaled-down unit operations combined in a plug-and-play manner enables easy and highly flexible testing of advanced biocatalytic process options such as in situ product removal (ISPR) process strategies. In such a platform, it is possible to compartmentalize different process steps while operating it as a combined system, giving the possibility to test and characterize the performance of novel process concepts and biocatalysts with minimal influence of inhibitory products. Here the capabilities of performing process development by applying scaled-down unit operations are highlighted through a case study investigating the asymmetric synthesis of 1-methyl-3-phenylpropylamine (MPPA) using ω-transaminase, an enzyme in the sub-family of amino transferases (ATAs). An on-line HPLC system was applied to avoid manual sample handling and to semi-automatically characterize ω-transaminases in a scaled-down packed-bed reactor (PBR) module, showing MPPA as a strong inhibitor. To overcome the inhibition, a two-step liquid-liquid extraction (LLE) ISPR concept was tested using scaled-down unit operations combined in a plug-and-play manner. Through the tested ISPR concept, it was possible to continuously feed the main substrate benzylacetone (BA) and extract the main product MPPA throughout the reaction, thereby overcoming the challenges of low substrate solubility and product inhibition. The tested ISPR concept achieved a product concentration of 26.5 gMPPA · L-1 , a purity up to 70% gMPPA · gtot-1 and a recovery in the range of 80% mol · mol-1 of MPPA in 20 h, with the possibility to increase the concentration, purity, and recovery further. Biotechnol. Bioeng. 2017;114: 600-609. © 2016 Wiley Periodicals, Inc.

Condensed milk storage and evaporation affect the flavor of nonfat dry milk.

Unit operations in nonfat dry milk (NFDM) manufacture influence sensory properties, and consequently, its use and acceptance in ingredient applications. Condensed skim milk may be stored at refrigeration temperatures for extended periods before spray drying due to shipping or lack of drying capacity. Currently, NFDM processors have 2 options for milk concentration up to 30% solids: evaporation (E) or reverse osmosis (RO). The objective of this study was to determine the effect of condensed milk storage and milk concentration method (E vs. RO) on the flavor of NFDM and investigate mechanisms behind flavor differences. For experiment 1, skim milk was pasteurized and concentrated to 30% solids by E or RO and then either stored for 24h at 4°C or concentrated to 50% solids by E and spray dried immediately. To investigate mechanisms behind the results from experiment 1, experiment 2 was constructed. In experiment 2, pasteurized skim milk was subjected to 1 of 4 treatments: control (no E), heated in the evaporator without vacuum, E concentration to 30% solids, or E concentration to 40% solids. The milks were then diluted to the same solids content and evaluated. Volatile compounds were also measured during concentration in the vapor separator of the evaporator. Sensory properties were evaluated by descriptive sensory analysis and instrumental volatile compound analysis was conducted to evaluate volatile compounds. Interaction effects between storage and method of concentration were investigated. In experiment 1, E decreased sweet aromatic flavor and many characteristic milk flavor compounds and increased cardboard and cooked flavors in NFDM compared with RO. Liquid storage increased cardboard flavor and hexanal and octanal and decreased sweet aromatic flavors and vanillin concentration. Results from experiment 2 indicated that the characteristic milk flavors and their associated volatile compounds were removed by the vapor separator in the evaporator due to the heat and vacuum applied during concentration. These results demonstrate that off-flavors are significantly reduced when RO is used in place of E and storage of condensed milk is avoided.

Rationalisation of the purification process for a phage active pharmaceutical ingredient.

The resurgence of phage therapy, once abandoned in the early 20th century in part due to issues related to the purification process and stability, is spurred by the global threat of antibiotic resistance. Engineering advances have enabled more precise separation unit operations, improving overall purification efficiency. The present review discusses the physicochemical properties of impurities commonly found in a phage lysate, e.g., contaminants, phage-related impurities, and propagation-related impurities. Differences in phages and bacterial impurities properties are leveraged to elaborate a four-step phage purification process: clarification, capture and concentration, subsequent purification and polishing. Ultimately, a framework for rationalising the development of a purification process is proposed, considering three operational characteristics, i.e., scalability, transferability to various phages and duration. This guide facilitates the preselection of a sequence of unit operations, which can then be confronted with the expected impurities to validate the theoretical capacity of the process to purify the phage lysate.

Advances in numerical simulation of unit operations for tablet preparation.

Recently, there has been an increase in the use of numerical simulation technology in pharmaceutical preparation processes. Numerical simulation can contribute to a better understanding of processes, reduce experimental costs, optimize preparation processes, and improve product quality. The intermediate material of most dosage forms is powder or granules, especially in the case of solid preparations. The macroscopic behavior of particle materials is controlled by the interactions of individual particles with each other and surrounding fluids. Therefore, it is very important to analyze and control the microscopic details of the preparation process for solid preparations. Since tablets are one of the most widely used oral solid preparations, and the preparation process is relatively complex and involves numerous units of operation, it is especially important to analyze and control the tablet production process. The present paper discusses recent advances in numerical simulation technology for the preparation of tablets, including drying, mixing, granulation, tableting, and coating. It covers computational fluid dynamics (CFD), discrete element method (DEM), population balance model (PBM), finite element method (FEM), Lattice-Boltzmann model (LBM), and Monte Carlo model (MC). The application and deficiencies of these models in tablet preparation unit operations are discussed. Furthermore, the paper provides a systematic reference for the control and analysis of the tablet preparation process and provides insight into the future direction of numerical simulation technology in the pharmaceutical industry.

Predicting Formulation Conditions During Ultrafiltration and Dilution to Drug Substance Using a Donnan Model with Homology-Model Based Protein Charge.

In the manufacturing of therapeutic monoclonal antibodies (mAbs), the final steps of the purification process are typically ultrafiltration/diafiltration (UF/DF), dilution, and conditioning. These steps are developed such that the final drug substance (DS) is formulated to the desired mAb, buffer, and excipient concentrations. To develop these processes, process and formulation development scientists often perform experiments to account for the Gibbs-Donnan and volume-exclusion effects during UF/DF, which affect the output pH and buffer concentration of the UF/DF process. This work describes the development of an in silico model for predicting the DS pH and buffer concentration after accounting for the Gibbs-Donnan and volume-exclusion effects during the UF/DF operation and the subsequent dilution and conditioning steps. The model was validated using statistical analysis to compare model predictions against experimental results for nine molecules of varying protein concentrations and formulations. In addition, our results showed that the structure-based in silico approach used to calculate the protein charge was more accurate than a sequence-based approach. Finally, we used the model to gain fundamental insights about the Gibbs-Donnan effect by highlighting the role of the protein charge concentration (the protein concentration multiplied with protein charge at the formulation pH) on the Gibbs-Donnan effect. Overall, this work demonstrates that the Gibbs-Donnan and volume-exclusions effects can be predicted using an in silico model, potentially alleviating the need for experiments.

Bacterial Retention During Filtration of a Live Attenuated Virus Vaccine Through the Sartobran P Sterile Filter.

Recent studies of sterile filtration of a Live Attenuated Virus (LAV) demonstrated that the Sartobran P sterile filter provided 80% yield of a LAV that was 100 - 400 nm in size, raising questions about the effectiveness of this filter in retaining the standard challenge bacterium, Brevundimonas diminuta. This study evaluated the retention of B. diminuta by the Sartobran P over a range of conditions appropriate for LAV filtration. The B. diminuta were characterized by dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), and scanning electron microscopy. The Sartobran P showed complete retention of B. diminuta under all conditions, even in the presence of additives like sucrose, surfactants, and high salt that have previously been hypothesized to increase the risk of bacterial breakthrough. The size of B. diminuta decreased when incubated in the nutrient poor media required by the ASTM challenge test. The addition of sucrose caused a further reduction in size as measured by NTA, although this was due to an increase in cell motility. There was no evidence of bacterial breakthrough at high loadings of either the LAV or B. diminuta, further demonstrating the effectiveness of the Sartobran P for sterile filtration of large viral vaccines.

The Impact of Delayed Symptomatic Treatment Implementation in the Intensive Care Unit.

We estimated the harm related to medication delivery delays across 12,474 medication administration instances in an intensive care unit using retrospective data in a large urban academic medical center between 2012 and 2015. We leveraged an instrumental variables (IV) approach that addresses unobserved confounds in this setting. We focused on nurse shift changes as disruptors of timely medication (vasodilators, antipyretics, and bronchodilators) delivery to estimate the impact of delay. The average delay around a nurse shift change was 60.8 min (p < 0.001) for antipyretics, 39.5 min (p < 0.001) for bronchodilators, and 57.1 min (p < 0.001) for vasodilators. This delay can increase the odds of developing a fever by 32.94%, tachypnea by 79.5%, and hypertension by 134%, respectively. Compared to estimates generated by a naïve regression approach, our IV estimates tend to be higher, suggesting the existence of a bias from providers prioritizing more critical patients.

Continuous Twin Screw Wet Granulation and Drying-Control Strategy for Drug Product Manufacturing.

The use of continuous manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density, and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This article focuses on development of appropriate control strategies for continuous wet granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The article also discusses the use of process analytical technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique, thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process such as wet granulation compared with direct compression process.

Tablet Compression Force as a Process Analytical Technology (PAT): 100% Inspection and Control of Tablet Weight Uniformity.

The modern rotary pharmaceutical tablet press is capable of accepting or rejecting individual tablets based on the measured compression force of the tablet. Because during steady operation, each tablet is compressed to the same thickness, a larger compression force implies a heavier tablet. Tablets that are too heavy likely contain more than the desired content of drug substance. The measured compression force thus becomes an important input to the overall control strategy, and variability in the compression force from one tablet to the next corresponds directly with the uniformity of dosage units. This provides an extraordinary opportunity to use the instantaneous compression force signal as a process analytical technology to make product collection decisions on every individual tablet. Only 1 question requires investigation: how to set the main compression force limits to achieve the desired tablet weights? In this work, a small-scale characterization method and associated mathematical model are developed to answer this question.

"Product on Stopper" in a Lyophilized Drug Product: Cosmetic Defect or a Product Quality Concern?

During manufacturing of a lyophilized drug product, operator errors in product handling during loading of product filled vials onto the lyophilizer can lead to a seemingly cosmetic defect which can impact certain critical quality attributes of finished product. In this study, filling of a formulated monoclonal antibody in vials was performed using a peristaltic pump filling unit, and subsequently, the product was lyophilized. After lyophilization, upon visual inspection, around 40% of vials had cosmetic defect with residual product around stopper of the vial and were categorized as "product on stopper" vials, whereas remaining 60% vials with no cosmetic defect were called "acceptable vials." Both groups of vials from 1 single batch were tested for critical quality attributes including protein concentration (ultraviolet absorbance at 280), residual moisture (Karl Fischer), sterility (membrane filtration), and container closure integrity (CCI) (blue dye ingress). Analysis of protein quality attributes such as aggregation, protein concentration, residual moisture showed no significant difference between vials with "product on stopper" and "acceptable vials." However, CCI of the "product on stopper" vials was compromised due to the presence of product around stopper of the vial. The results from this case study demonstrate the following 2 important findings: (1) that a seemingly cosmetic defect may impact product quality, compromising the integrity of the product and (2) that CCI test method can be used as an orthogonal method to sterility testing to evaluate sterility assurance of the product. The corrective action proposed to mitigate this defect is use of a larger sized vial that can potentially minimize this defect that arises because of product handling errors.

Understanding the Delamination Risk of a Trilayer Tablet Using Minipiloting Tools.

A multilayer tablet is one of the formulation options used to mitigate chemical and physical incompatibility between different drug substances. Feasibility studies of multilayer tablets are often conducted using round flat-faced punch tooling. However, the link between different tooling designs and multilayer tablet performance is not well established. This study uses a prototype trilayer tablet and examines tooling design considerations when conducting small-scale studies to gauge the risk of interfacial defects. The impact of tablet weight and dimensions was evaluated to gain understanding of the effect of scale-up/down of tablet size. The factors in tooling selection, including tablet shape, cup depth, and size of embossing were evaluated to gain insight on the impact of tooling design on the interfacial strength of the trilayer tablet. It was found that tablet weight and dimensions can significantly affect the interfacial strength due to their impact on force transmission during compression and the retardation force from the die wall during ejection. Round flat-faced tooling generated trilayer tablets of the strongest interfacial strength compared to typical commercial tablets-oval shaped with concave surfaces. These factors should be accounted for when using round flat compacts to assess the interface risks of a multilayer tablet.

A Demonstration of Mixing Robustness in a Direct Compression Continuous Manufacturing Process.

The purpose of this work was to assess the impact of continuous mixing on tablet critical quality attributes (CQAs) manufactured using a continuous, direct compression process. A 9-run design of experiments (DoE) that bracketed the range of commercially relevant mixer speeds, mixer orientations, and mass flow rates was executed using a formulation containing a cohesive drug substance at relatively low drug load. Drug substance dispensed concentration using loss-in-weight feeders was within 1% of target for each experiment with 30-s mass flow relative standard deviation values of 3.5% or less. Higher mass flow rates resulted in first off tablets closer to target potency, a shorter tablet potency startup phase, and greater assurance of passing content uniformity testing. Dissolution profiles from the DoE runs that bracketed mixer shear conditions were similar, indicating mixing had minimal impact on drug substance release from the tablets. None of the DoE parameters had a practical impact on the description CQA (tablet breaking force, friability, and appearance). Collectively, these results highlight that for this study continuous mixing within a direct compression process is robust and is assessed as low risk of adversely impacting drug product CQAs provided there is appropriate control of the continuous feeders.

Application of In-line Focused Beam Reflectance Measurement to Brivanib Alaninate Wet Granulation Process to Enable Scale-up and Attribute-based Monitoring and Control Strategies.

Application of in-line real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design development of a drug product and enable attribute-based monitoring and control strategies. In this study, an in-line laser focused beam reflectance measurement (FBRM) C35 probe was used to investigate the effect of formulation and process parameters on the granule growth profile over time during the high shear wet granulation of a high drug load formulation of brivanib alaninate. The probe quantitatively captured changes in the granule chord length distribution (CLD) with the progress of granulation and delineated the impact of water concentration used during granulation. The results correlated well with offline particle size distribution measured by nested sieve analyses. An end point indication algorithm was developed that was able to successfully track the process time needed to reach the target CLD. Testing of the brivanib alaninate granulation through 25-fold scale-up of the batch process indicated that the FBRM CLD profile can provide a scale-independent granule attribute-based process fingerprint. These studies highlight the ability of FBRM to quantitate a granule attribute of interest during wet granulation that can be used as an attribute-based scale-up and process monitoring and control parameter.

Degradation Kinetics and Mechanism of a ß-Lactam Antibiotic Intermediate, 6-Aminopenicillanic Acid, in a New Integrated Production Process.

In an effort to promote sustainability and to reduce manufacturing costs, the traditional production process for 6-aminopenicillanic acid (6-APA) has been modified to include less processing units. The objectives of this study are to investigate the degradation kinetics of 6-APA, to propose a reasonable degradation mechanism, and to optimize the manufacturing conditions within this new process. A series of degradation kinetic studies were conducted in the presence of impurities, as well as at various chemical and physical conditions. The concentrations of 6-APA were determined by high-performance liquid chromatography. An Arrhenius-type kinetic model was established to give a more accurate prediction on the degradation rates of 6-APA. A hydrolysis degradation mechanism is shown to be the major pathway for 6-APA. The degradation mechanisms and the kinetic models for 6-APA in the new system enable the design of a good manufacturing process with optimized parameters.

Engineering Digestion: Multiscale Processes of Food Digestion.

Food digestion is a complex, multiscale process that has recently become of interest to the food industry due to the developing links between food and health or disease. Food digestion can be studied by using either in vitro or in vivo models, each having certain advantages or disadvantages. The recent interest in food digestion has resulted in a large number of studies in this area, yet few have provided an in-depth, quantitative description of digestion processes. To provide a framework to develop these quantitative comparisons, a summary is given here between digestion processes and parallel unit operations in the food and chemical industry. Characterization parameters and phenomena are suggested for each step of digestion. In addition to the quantitative characterization of digestion processes, the multiscale aspect of digestion must also be considered. In both food systems and the gastrointestinal tract, multiple length scales are involved in food breakdown, mixing, absorption. These different length scales influence digestion processes independently as well as through interrelated mechanisms. To facilitate optimized development of functional food products, a multiscale, engineering approach may be taken to describe food digestion processes. A framework for this approach is described in this review, as well as examples that demonstrate the importance of process characterization as well as the multiple, interrelated length scales in the digestion process.

Determination of the Nip Angle in Roller Compactors With Serrated Rolls.

In roller compaction, the nip angle defines the critical transition interface between the slip and nip regions which is used to model material densification behavior and the properties of compacted ribbons. Current methods to determine the nip angle require either sophisticated instrumentation on smooth rolls or input parameters that are difficult to obtain experimentally. In this study, a practical method to determine nip angles for serrated rolls was developed based on mass balance considerations established around the nip region. Experimental input relating to roll geometry, powder density, and mass output from the compactor were required and they could be obtained reliably. The calculated nip angles were validated against those obtained from physical measurements during actual roll compaction. These nip angles were in agreement for various powder formulations containing plastic and brittle materials. The nip angles ranged from 4° to 12° and decreased significantly when the proportion of brittle material increased. Nip angles were also calculated using the widely used Johanson model. However, wall friction measurement on serrated roll surfaces could be impractical. The Johanson model-derived nip angles could differ by 3°-8° just by altering the roughness of the reference wall and this had compromised their reliability.

Process Analytical Technology for High Shear Wet Granulation: Wet Mass Consistency Reported by In-Line Drag Flow Force Sensor Is Consistent With Powder Rheology Measured by At-Line FT4 Powder Rheometer.

Drag flow force (DFF) sensor that measures the force exerted by wet mass in a granulator on a thin cylindrical probe was shown as a promising process analytical technology for real-time in-line high-resolution monitoring of wet mass consistency during high shear wet granulation. Our previous studies indicated that this process analytical technology tool could be correlated to granulation end point established independently through drug product critical quality attributes. In this study, the measurements of flow force by a DFF sensor, taken during wet granulation of 3 placebo formulations with different binder content, are compared with concurrent at line FT4 Powder Rheometer characterization of wet granules collected at different time points of the processing. The wet mass consistency measured by the DFF sensor correlated well with the granulation's resistance to flow and interparticulate interactions as measured by FT4 Powder Rheometer. This indicated that the force pulse magnitude measured by the DFF sensor was indicative of fundamental material properties (e.g., shear viscosity and granule size/density), as they were changing during the granulation process. These studies indicate that DFF sensor can be a valuable tool for wet granulation formulation and process development and scale up, as well as for routine monitoring and control during manufacturing.