Digital design of an integrated purification system for continuous pharmaceutical manufacturing.

In this work dynamic models of the continuous crystallization, filtration, deliquoring, washing, and drying steps are introduced, which are developed in the open-source pharmaceutical modeling tool PharmaPy. These models enable the simulation and digital design of an integrated continuous two-stage crystallization and filtration-drying carousel system. The carousel offers an intensified process that can manufacture products with tailored properties through optimal design and control. Results show that improved crystallization design enhances overall process efficiency by improving critical material attributes of the crystal slurry for downstream filtration and drying operations. The digital design of the integrated process achieves enhanced productivity while satisfying multiple design and product quality constraints. Additionally, the impact of model uncertainty on the optimal operating conditions is investigated. The findings demonstrate the systematic process development potential of PharmaPy, providing improved process understanding, design space identification, and optimized robust operation.

A novel approach for perfusion process design based on a "Grey-Box" kinetic model.

Perfusion cell-culture mode has caught industrial interest in the field of biomanufacturing in recent years. Thanks to new technology, perfusion-culture processes can support higher cell densities, higher productivities and longer process times. However, due to the inherent operational complexity and high running costs, the development and design of perfusion-culture processes remain challenging. Here, we present a model-based approach to design optimized perfusion cultures of Chinese Hamster Ovary cells. Initially, four batches of bench-top reactor continuous-perfusion-culture data were used to fit the model parameters. Then, we proposed the model-based process design approach, aiming to quickly find out the "theoretically optimal" operational parameters combinations (perfusion rate and the proportion of feed medium in perfusion medium) which could achieve the target steady-state VCD while minimizing both medium cost and perfusion rate during steady state. Meanwhile, we proposed a model-based dynamic operational parameters-adjustment strategy to address the issue of cell-growth inhibition due to the high osmolality of concentrated perfusion medium. In addition, we employed a dynamic feedback control method to aid this strategy in preventing potential nutrient depletion scenarios. Finally, we test the feasibility of the model-based process design approach in both shake flask semi-perfusion culture (targeted at 5 × 107 cells/ml) and bench-top reactor continuous perfusion culture (targeted at 1.1 × 108 cells/ml). This approach significantly reduces the number of experiments needed for process design and development, thereby accelerating the advancement of perfusion-mode cell-culture processes.

Process design and techno-economic analysis of activated carbon derived from anthracite coal.

Activated carbon (AC), renowned for its versatile applications in water treatment, air purification, and industrial processes, is a critical component in environmental remediation and resource recovery strategies. This study encompasses the process modeling of AC production using anthracite coal as a precursor, involving multiple activation stages at different operating conditions, coupled with a detailed techno-economic analysis aimed at assessing the operational feasibility and financial viability of the plant. The economic analysis explores the investigation of economic feasibility by performing a detailed cashflow and sensitivity analysis to identify key parameters influencing the plant's economic performance, including raw material and energy prices, operational and process parameters. Capital and operational costs are meticulously evaluated, encompassing raw material acquisition, labor, energy consumption, and equipment investment. Financial metrics like Net Present Value (NPV), Internal Rate of Return (IRR), and payout period (POP) are employed, and the results show that AC selling price, raw material cost and plant capacity are the most influential parameters determining the plant's feasibility. The minimum AC production cost of 1.28 $/kg is obtained, corresponding to coal flow rate of 14,550 kg/h. These findings provide valuable insights for stakeholders, policymakers, and investors seeking to engage in activated carbon production from anthracite.

Exploration and evaluation of modular concepts for the design of full-scale pharmaceutical manufacturing facilities.

The design of biopharmaceutical processes is predominantly driven by the domain of experimental process design. This approach can be further improved by combining multiple domain information such as experiments, unit models, and flowsheet models. Approaches consisting of methods and flowsheet models provide the framework for exploring, analyzing, and ultimately evaluating the combinatorial space of all possible designs within the molecule-to-manufacturing value chain. In recent years, modular process designs are of interest in the pharmaceutical industry because of the shift toward multiproduct, mutiprocess processes. Therefore, a systematic approach for how to evaluate the utilization of the modular plug-n-play concept provides metrics that can propel modular design from a viable design alternative to the selected alternative for full-scale manufacturing. The objective of this paper is to present such an in silico approach for the evaluation of modular designs. The approach is presented as a systematic method and then, is exemplified through the manufacture of an active pharmaceutical ingredient (API). The application of the method shows how to transition from a typical design-for-purpose design alternative to a modular design through the utilization of data, modeling, simulation, and uncertainty/sensitivity analyses for quantification of various selection metrics such as process robustness and flexibility.

Practical Advice on Scientific Design of Freeze-Drying Process: 2023 Update.

OBJECTIVE: The purpose of this paper is to re-visit the design of three steps in the freeze-drying process, namely freezing, primary drying, and secondary drying steps. Specifically, up-to-date recommendations for selecting freeze-drying conditions are provided based on the physical-chemical properties of formulations and engineering considerations. METHODS AND RESULTS: This paper discusses the fundamental factors to consider when selecting freezing, primary drying, and secondary drying conditions, and offers mathematical models for predicting the duration of each segment and product temperature during primary drying. Three simple heat/mass transfer primary drying (PD) models were tested, and their ability to predict product temperature and sublimation time showed good agreement. The PD models were validated based on the experimental data and utilized to tabulate the primary drying conditions for common pharmaceutical formulations, including amorphous and partially crystalline products. Examples of calculated drying cycles, including all steps, for typical amorphous and crystalline formulations are provided. CONCLUSIONS: The authors revisited advice from a seminal paper by Tang and Pikal (Pharm Res. 21(2):191-200, 2004) on selecting freeze-drying process conditions and found that the majority of recommendations are still applicable today. There have been a number of advancements, including methods to promote ice nucleation and computer modeling for all steps of freeze-drying process. The authors created a database for primary drying and provided examples of complete freeze-drying cycles design. The paper may supplement the knowledge of scientists and formulators and serve as a user-friendly tool for quickly estimating the design space.

Facile preparation of sisal-Fe/Zn layered double hydroxide bio-nanocomposites for the efficient removal of rifampin from aqueous solution: kinetic, equilibrium, and thermodynamic studies.

In the present study, sisal-Fe/Zn LDH bio-nanocomposite for efficiently removing rifampin was synthesized using a simple co-precipitation method. SEM, XRD, and FTIR analyses were applied to characterize the prepared composite. In the following, different factors that are affecting the adsorption of rifampin, including contact time, initial rifampin concentration, adsorbent dosage, and temperature were evaluated. Also, the kinetic, isotherm, and thermodynamic studies were investigated. The results indicated that Freundlich (R2 = 0.9976) was a suitable model for describing the adsorption equilibrium and adsorption kinetic showed that the data are in maximum agreement with the pseudo-second-order kinetic model (R2 = 0.9931). According to the Langmuir isotherm model, the maximum adsorption capacity of rifampin was found to be 40.00 mg/g. The main mechanisms for rifampin elimination were introduced as electrostatic attraction and physical adsorption. Moreover, the spontaneity and nature of the reaction were analyzed by elucidating thermodynamic factors that indicated the adsorption process was exothermic and spontaneous. Also, the batch process design indicated that for treating 10 L wastewater containing 100 mg/L rifampin with a removal efficiency of 96%, the needed amount of sisal-Fe/Zn LDH is 51.6 g. This study revealed that the sisal-Fe/Zn LDH bio-nanocomposites as a low-cost adsorbent have promising adsorption potential.

In this study, an innovative bio-nanocomposite (sisal­Fe/Zn layered double hydroxide) has been synthesized using a co-precipitation method for the first time and was used for the removal of pharmaceutical pollutants. Sisal­Fe/Zn LDH exhibited an excellent adsorption capacity of 40.00 mg/g to remove rifampin from the aqueous solution. The main mechanisms for rifampin elimination were introduced as electrostatic attraction and physical adsorption. Also, the batch process design showed that for treating 10 L wastewater containing 100 mg/L rifampin with a removal rate of 96%, the amount of sisal­LDH bio-nanocomposite required is about 51.6 g. Therefore, sisal­Fe/Zn layered double hydroxide as an eco-friendly biosorbent can be considered for future water treatment.

[Manufacturing classification system for oral solid dosage forms of traditional Chinese medicines(â ): classification of processing routes].

Oral solid dosage(OSD) occupies a key position in the market of Chinese patent medicines and new traditional Chinese medicines. Processing route is the foundation for the research and development of traditional Chinese medicine OSDs. On the basis of prescriptions and preparation methods of 1 308 traditional Chinese medicine OSDs recorded in the Chinese Pharmacopoeia, we summarized the patterns of processing routes of both modern dosage forms(tablets, granules, and capsules) and traditional dosage forms(pills and powder) and constructed a manufacturing classification system(MCS) based on the processing routes. Based on the MCS, statistical analyses were conducted respectively on medicinal materials, pharmaceutical excipients, extraction solvents in the pretreatment process, crushed medicinal materials, methods of concentration and purification, and methods of drying and granulation, aiming to uncover the process features. The results showed that each dosage form can be prepared via different routes with different processing methods of decoction pieces and raw materials for dosage preparation. The raw materials for dosage form preparation of traditional Chinese medicine OSDs included total extract, semi-extract, and total crushed powder, which accounted for different proportions. The raw materials for traditional dosage forms are mainly decoction pieces powder. Semi-extracts are the main raw materials for tablets and capsules, which account for 64.8% and 56.3%, respectively. Total extracts are the main raw materials for granules, with a proportion of 77.8%. Compared with tablets and capsules, traditional Chinese medicine granules with dissolubility requirements had a larger proportion of water extraction process, a higher proportion of refining process(34.7%), and a lower proportion of crushed medicinal mate-rials in semi-extract granules. There are four ways to add volatile oil to the modern dosage forms of traditional Chinese medicine. In addition, some new technologies and processes have been used in concentration, filtration, and granulation processes of traditional Chinese medicine OSDs, and the application of pharmaceutical excipients is diversified. The results of this study are expected to provide reference for the processing route design and upgrading of OSDs for new traditional Chinese medicines.

Extrapolation of design strategies for lignocellulosic biomass conversion to the challenge of plastic waste.

The goal of cost-effective production of fuels and chemicals from biomass has been a substantial driver of the development of the field of metabolic engineering. The resulting design principles and procedures provide a guide for the development of cost-effective methods for degradation, and possibly even valorization, of plastic wastes. Here, we highlight these parallels, using the creative work of Lonnie O'Neal (Neal) Ingram in enabling production of fuels and chemicals from lignocellulosic biomass, with a focus on ethanol production as an exemplar process.

Design of a High Sensitivity Pirani Gauge Based on Vanadium Oxide Film for High Vacuum Measurement.

We have designed a hot-plate-type micro-Pirani vacuum gauge with a simple structure and compatibility with conventional semiconductor fabrication processes. In the Pirani gauge, we used a vanadium oxide (VOx) membrane as the thermosensitive component, taking advantage of the high temperature coefficient of resistance (TCR) of VOx. The TCR value of VOx is -2%K-1∼-3%K-1, an order of magnitude higher than those of other thermal-sensitive materials, such as platinum and titanium (0.3%K-1∼0.4%K-1). On one hand, we used the high TCR of VOx to increase the Pirani sensitivity. On the other hand, we optimized the floating structure to decrease the thermal conductivity so that the detecting range of the Pirani gauge was extended on the low-pressure end. We carried out simulation experiments on the thermal zone of the Pirani gauge, the width of the cantilever beam, the material and thickness of the supporting layer, the thickness of the thermal layer (VOx), the depth of the cavity, and the shape and size. Finally, we decided on the basic size of the Pirani gauge. The prepared Pirani gauge has a thermal sensitive area of 130 × 130 µm2, with a cantilever width of 13 µm, cavity depth of 5 µm, supporting layer thickness of 300 nm, and VOx layer thickness of 110 nm. It has a dynamic range of 10-1~104 Pa and a sensitivity of 1.23 V/lgPa. The VOx Pirani was designed using a structure and fabrication process compatible with a VOx-based uncooled infrared microbolometer so that it can be integrated by wafer level. This work contains only our MEMS Pirani gauge device design, preparation process design, and readout circuit design, while the characterization and relevant experimental results will be reported in the future.

Teaching PSE mastery during, and after, the COVID-19 pandemic.

After more than a year of online teaching resulting from the COVID-19 pandemic, it is time to take stock of the status quo in teaching practice in all things concerning process systems engineering (PSE), and to derive recommendations for the future to harness what we have experienced to improve the degree to which our students achieve mastery. This contribution presents the experiences and conclusions resulting from the first COVID-19 semester (spring 2020), and how the lessons learned were applied to the process design course taught in the second COVID-19 semester (winter 2020) to a class of 53 students. The paper concludes with general recommendations for fostering active learning by students in all PSE courses, whether taught online or face to face.

Comparison by Life-Cycle Assessment of Alternative Processes for Carvone and Verbenone Production.

Verbenone and carvone are allylic monoterpenoid ketones with many applications in the fine chemicals industry that can be obtained, respectively, from the allylic oxidation of α-pinene and limonene over a silica-supported iron hexadecachlorinated phthalocyanine (FePcCl16-NH2-SiO2) catalyst and with t-butyl hydroperoxide (TBHP) as oxidant. As there are no reported analyses of the environmental impacts associated with catalytic transformation of terpenes into value-added products that include the steps associated with synthesis of the catalyst and several options of raw materials in the process, this contribution reports the evaluation of the environmental impacts in the conceptual process to produce verbenone and carvone considering two scenarios (SI-raw-oils and SII-purified-oils). The impact categories were evaluated using ReCiPe and IPCC methods implemented in SimaPro 9.3 software. The environmental impacts in the synthesis of the heterogeneous catalyst FePcCl16-NH2-SiO2 showed that the highest burdens in terms of environmental impact come from the use of fossil fuel energy sources and solvents, which primarily affect human health. The most significant environmental impacts associated with carvone and verbenone production are global warming and fine particulate matter formation, with fewer environmental impacts associated with the process that starts directly from turpentine and orange oils (SI-raw-oils) instead of the previously extracted α-pinene and limonene (SII-purified-oils). As TBHP was identified as a hotspot in the production process of verbenone and carvone, it is necessary to choose a more environmentally friendly and energy-efficient oxidizing agent for the oxidation of turpentine and orange oils.

Process design and life cycle assessment of furfural and glucose co-production derived from palm oil empty fruit bunches.

In light of environmental issues, lignocellulosic empty fruit bunch (EFB) biomass is promoted as a carbon-neutral, environmentally friendly, and renewable alternative feedstock. A comprehensive environmental assessment of EFB biorefineries is critical for determining their sustainability in parallel with the bioeconomy policy. Nonetheless, no life cycle assessment (LCA) has been performed on co-producing food and biochemicals (furfural and glucose) derived from EFB biomass. This research is the first to evaluate the environmental performance of the furfural and glucose co-production processes from EFB biomass. Environmental analysis is conducted using a prospective gate-to-gate LCA for four impact categories, including global warming potential (GWP), acidification (ADP), eutrophication (EP), and human toxicity (HT). Aspen Plus is used to simulate the co-production process of furfural and glucose as well as generate mass and energy balances for LCA inventory data usage. The findings suggest that the environmental footprint in respect of GWP, ADP, EP, and HT is 4846.85 kg CO2 equivalent per ton EFB, 7.24 kg SO2 equivalent per ton EFB, 1.52 kg PO4 equivalent per ton EFB, and 2.62E-05 kg 1,4-DB equivalent per ton EFB, respectively. The normalized overall impact scores for GWP, ADP, EP, and HT are 1.16E-10, 2.28E-11, 6.12E-10, and 2.18E-17 years/ton of EFB, respectively. In summary, the proposed integrated plant is not only economically profitable but also environmentally sustainable. In the attempt to enhance the Malaysian economic sector based on the EFB, this study has the potential to serve as an indicator of the environmental sustainability of the palm oil industry. Supplementary Information: The online version contains supplementary material available at 10.1007/s10668-022-02633-8.

Gram-scale production of the sesquiterpene α-humulene with Cupriavidus necator.

Terpenoids have an impressive structural diversity and provide valuable substances for a variety of industrial applications. Among terpenes, the sesquiterpenes (C15 ) are the largest subclass with bioactivities ranging from aroma to health promotion. In this article, we show a gram-scale production of the sesquiterpene α-humulene in final aqueous concentrations of 2 g L-1 with the recombinant strain Cupriavidus necator pKR-hum in a fed-batch mode on fructose as carbon source and n-dodecane as an extracting organic phase for in situ product removal. Since C. necator is capable of both heterotrophic and autotrophic growth, we additionally modeled the theoretically possible yields of a heterotrophic versus an autotrophic process on CO2 in industrially relevant quantities. We compared the cost-effectiveness of both processes based on a production of 10 t α-humulene per year, with both processes performing equally with similar costs and gains. Furthermore, the expression and activity of 3-hydroxymethylglutaryl-CoA reductase (hmgR) from Myxococcus xanthus was identified as the main limitation of our constructed C. necator pKR-hum strain. Thus, we outlined possible solutions for further improvement of our production strain, for example, the replacement of the hmgR from M. xanthus by a plant-based variant to increase α-humulene production titers in the future.

First time ß-farnesene production by the versatile bacterium Cupriavidus necator.

BACKGROUND: Terpenes are remarkably diverse natural structures, which can be formed via two different pathways leading to two common intermediates. Among those, sesquiterpenes represent a variety of industrially relevant products. One important industrially produced product is ß-farnesene as a precursor for a jet fuel additive. So far, microbial terpene production has been mostly limited to known production hosts, which are only able to grow on heterotrophic substrates. RESULTS: In this paper, we for the first time describe ß-farnesene production by the versatile bacterial host Cupriavidus necator on fructose, which is known to grow hetero- and autotrophically and even in bioelectrochemical systems. We were able to show a growth-dependent production of ß-farnesene by expressing the ß-farnesene synthase from Artemisia annua in C. necator H16 PHB-4. Additionally, we performed a scale-up in a parallel reactor system with production titers of 26.3 ± 1.3 µM ß-farnesene with a fed-batch process. CONCLUSIONS: The ß-farnesene production titers reported in this paper are not in the same range as titers published with known heterotrophic producers E. coli or S. cerevisiae. However, this proof-of-principle study with C. necator as production host opens new synthesis routes toward a sustainable economy and leaves room for further optimizations, which have been already performed with the known production strains.

Micro Freeze-Dryer and Infrared-Based PAT: Novel Tools for Primary Drying Design Space Determination of Freeze-Drying Processes.

PURPOSE: Present (i) an infrared (IR)-based Process Analytical Technology (PAT) installed in a lab-scale freeze-dryer and (ii) a micro freeze-dryer (MicroFD®) as effective tools for freeze-drying design space calculation of the primary drying stage. METHODS: The case studies investigated are the freeze-drying of a crystalline (5% mannitol) and of an amorphous (5% sucrose) solution processed in 6R vials. The heat (Kv) and the mass (Rp) transfer coefficients were estimated: tests at 8, 13 and 26 Pa were carried out to assess the chamber pressure effect on Kv. The design space of the primary drying stage was calculated using these parameters and a well-established model-based approach. The results obtained using the proposed tools were compared to the ones in case Kv and Rp were estimated in a lab-scale unit through gravimetric tests and a thermocouple-based method, respectively. RESULTS: The IR-based method allows a non-gravimetric estimation of the Kv values while with the micro freeze-dryer gravimetric tests require a very small number of vials. In both cases, the obtained values of Kv and Rp, as well as the resulting design spaces, were all in very good agreement with those obtained in a lab-scale unit through the gravimetric tests (Kv) and the thermocouple-based method (Rp). CONCLUSIONS: The proposed tools can be effectively used for design space calculation in substitution of other well-spread methods. Their advantages are mainly the less laborious Kv estimation process and, as far as the MicroFD® is concerned, the possibility of saving time and formulation material when evaluating Rp.

Process scale-up and technoeconomic analysis of phospholipid extraction from a dairy byproduct (whey protein phospholipid concentrate).

Dairy byproducts such as whey protein phospholipid concentrate (WPPC) and buttermilk contain phospholipids (PL). A solvent extraction process (simultaneous texturization and extraction of phospholipids, STEP method) to extract PL present in WPPC, using ethanol, recovers about 70% of PL in the raw material. To understand the commercial feasibility of this technology, we simulated a scaled-up version of the process to industrial production of 3.26 kt/yr in the SuperPro Designer (version 10, http://www.intelligen.com) process simulation platform. Economic analysis revealed that PL can be produced at a minimum selling price (MSP) of $92.98/kg, using the scaled-up STEP method. The total investment on capital and annual operating costs were $15.51 million and $14.49 million, respectively. The uncertainty in product cost due to variations in process variables, including PL composition in raw material, product recovery, labor, and raw material costs was analyzed through sensitivity analysis. Phospholipids MSP was most sensitive to product recovery and its composition in WPPC. A reduction of almost 5% in MSP was achieved by improving either of the process parameters by 10%. By increasing the plant size 1.5 times, the product MSP could be decreased by 30% to $65.14/kg. Finally, based on our analysis, recommendations were made for scale-up and commercialization of PL extraction using the STEP method.

Screening biorefinery pathways to biodiesel, green-diesel and propylene-glycol: A hierarchical sustainability assessment of process.

Plant design implies the best choice among a set of feedstock-to-product process pathways. Multiple sustainability performance indicators can blur the decision, and existing sustainability assessment methods usually focus only on environmental life-cycle performance and corporate metrics or solely on the gate-to-gate process. It is relevant to incorporate integrated system analysis to address sustainability comprehensively. To this end, the Sustainable Process Systems Engineering (S-PSE) method was previously introduced to select the most sustainable feedstock-process-product configuration via four-dimensional indicators (environment, efficiency, health-&-safety, and economic), and then pinpoint the sustainability hotspots of the best design to unveil possible improvements. This work expands S-PSE by adding new features: (i) cradle-to-gate environmental assessment; (ii) composition of flowsheets; (iii) new indicators; (iv) statistical screening of indicators; and (v) 2030 Agenda compliance. A biorefinery case-study demonstrates S-PSE: to select the best pathway from soybean-oil, palm-oil, and microalgae-oil to biodiesel, green-diesel, and propylene-glycol. Firstly, statistical screening reduces the indicator set by 62%. Results evince all routes from microalgae-oil as economically unfeasible due to oil cost, despite superior environmental performance. S-PSE evinces palm-oil-to-biodiesel as the most sustainable due to lower cradle-to-gate emissions and manufacturing cost, with sustainability hotspots associated to hazardous methanol input and energy-intensive distillations. 2030 Agenda analysis also outlines palm-oil-to-biodiesel as best for 5 out of 10 Sustainable Development Goals linked to the reduced indicator set.

Recommended Best Practices for Lyophilization Validation-2021 Part I: Process Design and Modeling.

This work describes lyophilization process validation and consists of two parts. Part I focuses on the process design and is described in the current paper, while part II is devoted to process qualification and continued process verification. The intent of these articles is to provide readers with recent updates on lyophilization validation in the light of community-based combined opinion on the process and reflect the industrial prospective. In this paper, the design space approach for process design is described in details, and examples from practice are provided. The approach shows the relationship between the process inputs; it is based on first principles and gives a thorough scientific understanding of process and product. The lyophilization process modeling and scale-up are also presented showing the impact of facility, equipment, and vial heat transfer coefficient. The case studies demonstrating the effect of batch sizes, fill volume, and dose strength to show the importance of modeling as well as the effect of controlled nucleation on product resistance are discussed.

Waste respirator processing system for public health protection and climate change mitigation under COVID-19 pandemic: Novel process design and energy, environmental, and techno-economic perspectives.

The ongoing COVID-19 pandemic leads to a surge on consumption of respirators. This study proposes a novel and effective waste respirator processing system for protecting public health and mitigating climate change. Respirator sterilization and pre-processing technologies are included in the system to resist viral infection and facilitate unit processes for respirator pyrolysis, product separation, and downstream processing for greenhouse gas (GHG) emission reduction. We evaluate the system's environmental performance through high-fidelity process simulations and detailed life cycle assessment. Techno-economic analysis results show that the payback time of the waste respirator processing system is seven years with an internal rate of return of 21.5%. The tipping fee and discount rate are the most influential economic factors. Moreover, the unit life cycle GHG emissions from the waste respirator processing system are 12.93 kg CO2-eq per thousand waste respirators treated, which reduces GHG emissions by 59.08% compared to incineration-based system so as to mitigate climate change.

Metabolic modeling for predicting VFA production from protein-rich substrates by mixed-culture fermentation.

Proteinaceous organic wastes are suitable substrates to produce high added-value products in anaerobic mixed-culture fermentations. In these processes, the stoichiometry of the biotransformation depends highly on operational conditions such as pH or feeding characteristics and there are still no tools that allow the process to be directed toward those products of interest. Indeed, the lack of product selectivity strongly limits the potential industrial development of these bioprocesses. In this work, we developed a mathematical metabolic model for the production of volatile fatty acids from protein-rich wastes. In particular, the effect of pH on the product yields is analyzed and, for the first time, the observed changes are mechanistically explained. The model reproduces experimental results at both neutral and acidic pH and it is also capable of predicting the tendencies in product yields observed with a pH drop. It also offers mechanistic insights into the interaction among the different amino acids (AAs) of a particular protein and how an AA might yield different products depending on the relative abundance of other AAs. Particular emphasis is placed on the utility of this mathematical model as a process design tool and different examples are given on how to use the model for this purpose.