Product Quality Profiles Research Articles

A high-titer scalable Chinese hamster ovary transient expression platform for production of biotherapeutics.

Transient gene expression (TGE) in Chinese hamster ovary (CHO) cells offers a route to accelerate biologics development by delivering material weeks to months earlier than what is possible with conventional cell line development. However, low productivity, inconsistent product quality profiles, and scalability challenges have prevented its broader adoption. In this study, we develop a scalable CHO-based TGE system achieving 1.9 g/L of monoclonal antibody in an unmodified host. We integrated continuous flow-electroporation and alternate tangential flow (ATF) perfusion to enable an end-to-end closed system from N-1 perfusion to fed-batch 50-L bioreactor production. Optimization of both the ATF operation for three-in-one application-cell growth, buffer exchange, and cell mass concentration-and the flow-electroporation process, led to a platform for producing biotherapeutics using transiently transfected cells. We demonstrate scalability up to 50-L bioreactor, maintaining a titer over 1 g/L. We also show comparable quality between both transiently and stably produced material, and consistency across batches. The results confirm that purity, charge variants and N-glycan profiles are similar. Our study demonstrates the potential of CHO-based TGE platforms to accelerate biologics process development timelines and contributes evidence supporting its feasibility for manufacturing early clinical material, aiming to strengthen endorsement for TGE's wider implementation.

A comparison of different intensified upstream processes highlighting the advantage of WuXi Biologics' Ultra-high Productivity platform (WuXiUPTM) in improved product quality and purification yield.

WuXiUPTM, WuXi Biologics' Ultra-high Productivity platform, is an intensified and integrated continuous bioprocess platform developed for production of various biologics including monoclonal antibodies, fusion proteins, and bispecific antibodies. This process technology platform has manifested its remarkable capability in boosting the volumetric productivity of various biologics and has been implemented for large-scale clinical material productions. In this paper, case studies of the production of different pharmaceutical proteins using two high-producing and intensified culture modes of WuXiUPTM and the concentrated fed-batch (CFB), as well as the traditional fed-batch (TFB) are discussed from the perspectives of cell growth, productivity, and protein quality. Both WuXiUPTM and CFB outperformed TFB regarding volumetric productivity. Additionally, distinctive advantages in product quality profiles in the WuXiUPTM process, such as reduced acidic charge variants and fragmentation, are revealed. Therefore, a simplified downstream purification process with only two chromatographic steps can be developed to deliver the target product at a satisfactory purity and an extremely-high yield.

Raman-controlled pyruvate feeding to control metabolic activity and product quality in continuous biomanufacturing.

Despite technological advances ensuring stable cell culture perfusion operation over prolonged time, reaching a cellular steady-state metabolism remains a challenge for certain manufacturing cell lines. This study investigated the stabilization of a steady-state perfusion process producing a bispecific antibody with drifting product quality attributes, caused by shifting metabolic activity in the cell culture. A novel on-demand pyruvate feeding strategy was developed, leveraging lactate as an indicator for tricarboxylic acid (TCA) cycle saturation. Real-time lactate monitoring was achieved through in-line Raman spectroscopy, enabling accurate control at predefined target setpoints. The implemented feedback control strategy resulted in a three-fold reduction of ammonium accumulation and stabilized product quality profiles. Stable and flat glycosylation profiles were achieved with standard deviations below 0.2% for high mannose and fucosylation. Whereas galactosylation and sialylation were stabilized in a similar manner, varying lactate setpoints might allow for fine-tuning of these glycan forms. The Raman-controlled pyruvate feeding strategy represents a valuable tool for continuous manufacturing, stabilizing metabolic activity, and preventing product quality drifting in perfusion cell cultures. Additionally, this approach effectively reduced high mannose, helping to mitigate increases associated with process intensification, such as extended culture durations or elevated culture densities.

Utilizing targeted integration CHO pools to potentially accelerate the GMP manufacturing of monoclonal and bispecific antibodies.

Monoclonal antibodies (mAbs) are effective therapeutic agents against many acute infectious diseases including COVID-19, Ebola, RSV, Clostridium difficile, and Anthrax. mAbs can therefore help combat a future pandemic. Unfortunately, mAb development typically takes years, limiting its potential to save lives during a pandemic. Therefore "pandemic mAb" timelines need to be shortened. One acceleration tool is "deferred cloning" and leverages new Chinese hamster ovary (CHO) technology based on targeted gene integration (TI). CHO pools, instead of CHO clones, can be used for Phase I/II clinical material production. A final CHO clone (producing the mAb with a similar product quality profile and preferably with a higher titer) can then be used for Phase III trials and commercial manufacturing. This substitution reduces timelines by ~3 months. We evaluated our novel CHO TI platform to enable deferred cloning. We created four unique CHO pools expressing three unique mAbs (mAb1, mAb2, and mAb3), and a bispecific mAb (BsAb1). We then performed single-cell cloning for mAb1 and mAb2, identifying three high-expressing clones from each pool. CHO pools and clones were inoculated side-by-side in ambr15 bioreactors. CHO pools yielded mAb titers as high as 10.4 g/L (mAb3) and 7.1 g/L (BsAb1). Subcloning yielded CHO clones expressing higher titers relative to the CHO pools while yielding similar product quality profiles. Finally, we showed that CHO TI pools were stable by performing a 3-month cell aging study. In summary, our CHO TI platform can increase the speed to clinic for a future "pandemic mAb."

Scalability of Sartobind® Rapid A Membrane for High Productivity Monoclonal Antibody Capture.

Improved upstream titres in therapeutic monoclonal antibody (mAb) production have shifted capacity constraints to the downstream process. The consideration of membrane-based chromatographic devices as a debottlenecking option is gaining increasing attention with the recent introduction of high-capacity bind and elute membranes. We have evaluated the performance and scalability of the Sartobind® Rapid A affinity membrane (1 mL) for high-productivity mAb capture. For scalability assessment, a 75 mL prototype device was used to process 100 L of clarified cell culture harvest (CH) on a novel multi-use rapid cycling chromatography system (MU-RCC). MabSelect™ PrismA (4.7 mL) was used as a benchmark comparator for Protein A (ProtA) resin studies. Results show that in addition to a productivity gain of >10×, process and product quality attributes were either improved or comparable to the benchmark. Concentrations of eluate pools were 7.5× less than that of the benchmark, with the comparatively higher bulk volume likely to cause handling challenges at process scale. The MU-RCC system is capable of membrane operation at pilot scale with comparable product quality profile to the 1 mL device. The Sartobind® Rapid A membrane is a scalable alternative to conventional ProtA resin chromatography for the isolation and purification of mAbs from harvested cell culture media.

A novel dual-plasmid platform provides scalable transfection yielding improved productivity and packaging across multiple AAV serotypes and genomes

Transient transfection of mammalian cells using plasmid DNA is a standard method to produce adeno-associated virus (AAV) vectors allowing for flexible and scalable manufacture. Typically, three plasmids are used to encode the necessary components to facilitate vector production; however, a dual-plasmid system, termed pDG, was introduced over 2 decades ago demonstrating two components could be combined resulting in comparable productivity to triple transfection. We have developed a novel dual-plasmid system, pOXB, with an alternative arrangement of sequences that results in significantly increased AAV vector productivity and percentage of full capsids packaged in comparison to the pDG dual design and triple transfection. Here, we demonstrate the reproducibility of these findings across seven recombinant AAV genomes and multiple capsid serotypes as well as the scalability of the pOXB dual-plasmid transfection at 50-L bioreactor scale. Purified drug substance showed a consistent product quality profile in line with triple-transfected vectors, except for a substantial improvement in intact genomes packaged using the pOXB dual- transfection system. Furthermore, pOXB dual- and triple-transfection-based vectors performed consistently invivo. The pOXB dual plasmid represents an innovation in AAV manufacturing resulting in significant process gains while maintaining the flexibility of a transient transfection platform.

An Overview on Quality by Design

Quality by Design (QbD) has as a new concept for the development of high-quality pharmaceutical products. It is an essential component of the modern approach to pharmaceutical quality. QbD is the best way to build quality into all pharmaceutical products, but it poses a significant challenge to the pharmaceutical industry, whose processes are time-bound, despite inherent process and material variability. Throughout the design and development of a product, it is critical to define the desired product performance profile [Target Product Profile (TPP), Target Product Quality Profile (TPQP)] and identify critical quality attributed to the product (CQA). Applications of QbD to pharmaceutical processes (formulation development) and analytical development are briefly discussed. A standardized pharmaceutical quality system that is applicable throughout the product's lifecycle and emphasizes an integrated approach to risk management and science should be developed, resulting in better quality medicines for patients.ICH documents such as ICH Q8, i.e. Pharmaceutical development; ICH Q9, i.e. Quality Risk Management; ICH Q10, i.e. Pharmaceutical Quality Systems, and FDA's Process Analytical Technology (PAT) were referred to in order to ensure drug product quality. QbD allows formulation and manufacturing variables to be properly understood and controlled.

Stability of Abuse-deterrent properties of PEO-based Abuse-deterrent formulation

Abuse of opioid drug products is a national health crisis in the US. To deter abuse, a number of drug products with abuse-deterrent (AD) properties have been approved by the US Food and Drug Administration (FDA). For abuse deterrence, it is critical to maintain the AD properties during the product shelf life. However, no information on the stability of AD properties during product shelf life is publicly available. In this study, stability of AD properties of surrogate AD formulation (ADF) of opioid active pharmaceutical ingredients (APIs) were studied. Surrogate extended release (ER) AD tablets were prepared by direct compression using Diltiazem HCl (model drug), polyethylene oxide (PEO WSR 301) polymer and magnesium stearate followed by curing at 70 °C for 30 mins. The stability studies were conducted at 25 °C/60 % RH and 40 °C/75 % RH storage conditions for 12 months (M) and 6 months (M), respectively. In vitro characterization and evaluation of AD properties of tablets were performed. As anticipated, the curing process increased the crushing strength of the tablets. However, the tablets could still be manipulated and compromised leading to an enhancement in the amount of drug extracted in solvents (e.g., water, alcohol), regardless of extraction temperature as well as tablet storage condition and time. Furthermore, the granule particle size as well as viscosity in water of manipulated samples were found to be lower for tablets stored at 25 °C/60 % RH or 40 °C/75 % RH for 12 M or 3 M/6M, respectively. The changes in AD properties eased the syringeability of hydrated samples and ultimately led to the withdrawal of higher amounts of drug into the syringe, thereby, impacting the abuse deterrence potential of the formulation by an IV route. These data demonstrated that the stability of AD properties (i.e., granule particle size, viscosity and syringeability-injectability) of PEO-based tablets was dependent on the storage condition. In conclusion, the design of AD formulation and setting of product quality profile should take into consideration the stability of AD properties during the product shelf life.

Modeling of three-phase radial flow reactor for diesel hydrotreating

• Mixing cell network model presented for industrial-scale three-phase Radial Flow Reactor for diesel hydrodesulfurization. • 2D MCN model was developed for Radial Flow Reactor (RFR) with one and five distributors to predict the product quality and bed temperature profiles. • Reactions like hydrodesulphurization (HDS), Hydrodearomatisation (HDA), and olefins saturation are taken into consideration. A mathematical model for a novel industrial-scale three-phase catalytic Radial Flow Reactor (RFR) has been developed using a two-dimensional mixing cell network (MCN) model. RFR is predominantly used for gaseous phase reactions in the petroleum refining industry. This work discusses the capabilities of three-phase RFR for diesel hydrodesulfurization. The reactions considered for the model development of diesel hydrodesulfurization are hydrodesulfurization, hydrodearomatisation, and olefins saturation. Apart from the well-known advantage of RFR, such as pressure drop, the analysis revealed other benefits such as better product quality, reduced H 2 S inhibition, no requirement of quench, high WABT. Simulations for RFR were performed for different gas distributors and results show that distributor design impacts the performance of reactor.

Quality By Design: A Review

Quality by Design is the most recent quality-related trend in pharmaceutical manufacturing (QbD). This paper discusses Pharmaceutical Quality by Design (QbD) as a way to guarantee high-quality pharmaceuticals. Details about Quality by Design are given in addition to a list of its components. The quality parameters and attributes of each unit operation are unique. Pharmaceutical products can benefit from Quality by Design and the steps that can be taken to implement it. High-quality pharmaceuticals and their manufacturing processes form the core of pharmaceutical R&D. It is impossible to verify the quality of a product because this document includes a breakdown of the product's quality profile and the most important aspects of Quality by Design. Comparing the quality of various products can be done in two ways: through Quality by Design and end-product testing (QbD). Quality by Design is based on the ICH Guidelines. ICH guidelines govern the development of pharmaceuticals and the implementation of quality assurance systems. Pharmaceutical development and production can benefit from Quality by Design (QbD).
 Keywords: Concept & background of QbD, Traditional vs QbD Approach, Key elements, PAT, Challenges, Current & Future perspective.

Biopharmaceutical Manufacturing: Historical Perspectives and Future Directions.

This review describes key milestones related to the production of biopharmaceuticals-therapies manufactured using recombinant DNA technology. The market for biopharmaceuticals has grown significantly since the first biopharmaceutical approval in 1982, and the scientific maturity of the technologies used in their manufacturing processes has grown concomitantly. Early processes relied on established unit operations, with research focused on process scale-up and improved culture productivity. In the early 2000s, changes in regulatory frameworks and the introduction of Quality by Design emphasized the importance of developing manufacturing processes to deliver a desired product quality profile. As a result, companies adopted platform processes and focused on understanding the dynamic interplay between product quality and processing conditions. The consistent and reproducible manufacturing processes of today's biopharmaceutical industry have set high standards for product efficacy, quality, and safety, and as the industry continues to evolve in the coming decade, intensified processing capabilities for an expanded range of therapeutic modalities will likely become routine.

Engineering redox sensors into CHO cells enables near-real-time quantification of intracellular redox in bioprocesses.

The production of biologics that treat complex diseases, such as cancer, autoimmune, and infectious disease, requires careful monitoring and control of cell cultures. While bioprocess optimizations have dramatically improved production yields, a lack of analytical tools has made it challenging to identify accompanying intracellular improvements. Intracellular redox can diminish the growth and productivity of biologics-producing cells and adversely impact product quality profiles yet characterizing redox is challenging due to its complex and highly transient nature. In this study, we integrated a fluorescent thiol-based redox biosensor to monitor intracellular redox in one bisAb- and two monoclonal antibody-producing clonal cell lines in a 14-day fed-batch bioreactor. We characterized biosensor functionality using three fluorescence measurement techniques and determined sensor oxidation correlates with the intracellular ratio of reduced (GSH)and oxidized glutathione (GSSG), an important cellular antioxidant. Our fed-batch bioreactor studies showed that sensor expression minimally affected bioprocess outcomes, including growth, productivity, product quality attributes, or intracellular redox attributes, including mitochondrial reactive oxygen species and total cellular GSH levels in all cell lines tested. Biosensor measurements taken throughout the culture revealed that the intracellular environment in these cell lines became more reduced throughout the culture, with the exception of a high pH condition which became more oxidized. Our results demonstrate the potential of using biosensors to monitor intracellular changes in near-real-time with minimal process effects, thus potentially improving future bioprocess optimizations.

Substantiation of the target quality profile and risk assessment in the development of a combined drug for injection

Aim. To substantiate the target quality profile for planning the development of a combined drug for injection based on sodium hyaluronate (SH) and dihydroquercetin (DHQ) with an expanded spectrum of the specific activity, as well as to determine the risk factors affecting the quality of the combined drug for injections at the stage of pharmaceuticaldevelopment (PD). Materials and methods. The study objects were the active pharmaceutical ingredients (АРІ) of SH, DHQ and a drug in the form of a solution for injection based on them, as well as potential risk factors affecting the quality of the product. The target product quality profile (QTPP) was developed based on the review and analysis of scientific literature, materials of the State Register of Medicines of Ukraine, pharmacopoeias of the leading countries of the world, articles of scientific publications. The Ishikawa diagram was used to analyze potential risk factors for a drug for injection at the stage of PD. Results and discussion. The application of scientific approaches to the analysis of scientific materials from various information sources on combination therapy with drugs with multidirectional medicinal substances and the availability of information on parenteral medicines (PM) allowed us to plan a QTPP for the development of a combined drug for injection for intradermal administration. In order to identify the most dangerous factors affecting the quality of the drug, the causal analysis of these factors at the PD stage of the combined drug for injection was carried out, and an Ishikawa diagram was constructed. Conclusions. The QTPP has been developed. The expected set of quality indicators that would ideally be achieved to ensure the required quality of the drug has been determined taking into account its safety and efficacy. Based on the risk assessment methodology, the Ishikawa diagram for a combined drug for injection has been constructed; potential risks associated with the quality of active ingredients (AI) and excipients, quality of primary packaging, production conditions, quality control of the drug, the technological process affecting the quality of the combined drug for injection and the causes leading to deviations from these indicators have been identified. This diagram is used as a baseline for the overall assessment of quality risks at the stage of drug development.

Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants' Effect in Direct Compressible Formulation.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

Elemental metal variance in cell culture raw materials for process risk profiling.

Elemental metals are critical raw material attributes which can impact cell culture performance and associated therapeutic protein product quality profiles. Metals such as copper and manganese act as cofactors and reagents for numerous metabolic pathways which govern cell growth, protein expression, and glycosylation, thus mandating elemental monitoring. The growing complexity of modern cell culture media formulations adds additional opportunities for elemental variance and its associated impact risks. This article describes an analytical technique applying inductively coupled plasma mass spectrometry to characterize a list of common raw materials and media powders used in mammalian cell culture and therapeutic protein production. We aim to describe a method qualification approach suitable for biopharmaceutical raw materials. Furthermore, we present detailed profiles of many common raw materials and discuss trends in raw material subtypes. Finally, a case study demonstrating the impact of an unexpected source of raw material variation is presented along with recommendations for raw material elemental risk profiling and control.

Quality by Design: A new practice for production of pharmaceutical products

This is the advanced approach for development of pharmaceutical product with full range and specified limits of variables during procurements, storage and manufacturing process with a qualification, at desired level of quality within the limits of low and higher values of variables to ensures the Pharmaceutical product Quality by design (QbD) of manufacturing a finished product. The Quality by Design is depicted and a portion of its components recognized and process parameters with quality characteristics are identified for every unit activity. Advantages, openings and steps engaged with Quality by Design of Pharmaceutical items are depicted. The point of the pharmaceutical advancement is to plan a quality item and it’s assembling procedure to reliably convey the proposed execution of the item. Quality can't be tried into items however quality ought to be worked in by outline. It incorporates the Quality target item profile, basic quality traits and key parts of Quality by Design. It likewise gives correlation between item quality by end item testing and item quality by Quality by Design. The establishment of Quality by Design is ICH Guidelines. It depends on the ICH Guidelines Q8 for pharmaceutical improvement, Q9 for quality hazard administration, Q10 for pharmaceutical quality frameworks. It moreover gives utilization of Quality by Design in pharmaceutical improvement and assembling of pharmaceuticals.
 Keywords: Quality by Design, Design Space, Target Product Quality Profile, Critical Quality Attributes

Human platelet lysate current standards and future developments.

A state-of-the-art workshop focused on the use of human platelet lysate (HPL) for cell therapy. The meeting established that HPL is used mainly as an adjunct material for ex vivo expansion of mesenchymal stem/progenitor cells (MSCs), where it is successfully used as a substitute for fetal bovine serum. HPL manufacturing as a cell expansion supplement is currently not yet uniformly standardized with regard to platelet source and production methodology. There are very few reports of HPL preparations manufactured specifically for direct clinical use. There exists an urgent need for controlled clinical studies for HPL and for standardization of product definition. Workshop participants also stated a need for consensus minimum release criteria to allow for better product definition and to limit variability in performance. The increasing use of cell-based therapies including MSCs has led to an increasing demand for HPL, either produced in blood establishments or large-scale manufacture by biopharmaceutical companies. The use of pooled donor platelets for HPL production may require the implementation of pathogen inactivation procedures and/or removal steps to improve the safety of advanced cell therapy products. There should also be a requirement for thorough risk assessments and risk mitigation steps, including the qualification of suppliers and identification of ingredients as well as meticulous monitoring of product quality and safety profiles. State-of-the-art regulatory approaches for HPL used for human cell propagation and PRP in direct clinical applications were reviewed.

Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles.

L-Asparaginase (ASNase) is a vital component of the first line treatment of acute lymphoblastic leukemia (ALL), an aggressive type of blood cancer expected to afflict over 53,000 people worldwide by 2020. More recently, ASNase has also been shown to have potential for preventing metastasis from solid tumors. The ASNase treatment is, however, characterized by a plethora of potential side effects, ranging from immune reactions to severe toxicity. Consequently, in accordance with Quality-by-Design (QbD) principles, ingenious new products tailored to minimize adverse reactions while increasing patient survival have been devised. In the following pages, the reader is invited for a brief discussion on the most recent developments in this field. Firstly, the review presents an outline of the recent improvements on the manufacturing and formulation processes, which can severely influence important aspects of the product quality profile, such as contamination, aggregation and enzymatic activity. Following, the most recent advances in protein engineering applied to the development of biobetter ASNases (i.e., with reduced glutaminase activity, proteolysis resistant and less immunogenic) using techniques such as site-directed mutagenesis, molecular dynamics, PEGylation, PASylation and bioconjugation are discussed. Afterwards, the attention is shifted toward nanomedicine including technologies such as encapsulation and immobilization, which aim at improving ASNase pharmacokinetics. Besides discussing the results of the most innovative and representative academic research, the review provides an overview of the products already available on the market or in the latest stages of development. With this, the review is intended to provide a solid background for the current product development and underpin the discussions on the target quality profile of future ASNase-based pharmaceuticals.

Analysis and model-based optimization of a pectin extraction process

Raw material quality disparity is an unavoidable and systemic variability in the solid-liquid extraction process of pectin manufacturing. A mathematical model is considered for a robust optimization of the process, taking into the account raw material quality uncertainty, for two different scenarios of pectin product quality profiles. Before application, the model is evaluated through local sensitivity analysis. Raw material-specific parameters and non-significant parameters are removed from the parameter set targeted for identification. Furthermore, it is shown that the model outputs are highly sensitive to the peel specific parameters, which inherently vary from peel-to-peel. This impact was further assessed through an uncertainty analysis, which quantified the variability of model predictions due to the raw material parameter uncertainty for three different types of fruit. The model exhibits a good general depiction of the extraction phenomena. Major operating variables, i.e., temperature, pH and batch time, are optimized in a deterministic manner for each fruit to maximize the final pectin concentration while satisfying given requirements. Based on this, a robust optimization strategy is examined to design an optimal operation strategy in consideration of the inherent uncertainty of feedstock and the desired product quality.

Application of near-infrared spectroscopy combined with design of experiments for process development of the pulsed spray fluid bed granulation process

The boundaries of a target product quality profile of certain failure modes can be exploited to construct the operation window, a process design space (PDS), for the granulation process. The purpose of this study is to implement process design and development for the pulsed spray fluid bed granulation (PSFBG) on a laboratory-scale granulator. This work consists of three parts: (1) implementation of Process Analytical Technology (PAT) combined with multivariate data analysis to monitor the formulation characteristics including moisture content, particle size and granule yield; (2) adoption of a new design of experiments (DoE) method Definitive Screening Design (DSD), with the well-established PAT monitoring tools, to investigate the process response to the intended changes in the critical process parameters (CPPs); and finally, (3) the definition of a PDS for the PSFBG, within which the acceptable performance of the process is guaranteed. The effects of the process parameters (i.e., the inlet air temperature, inlet air relative humidity, binder spray rate, atomization pressure, pulse cycle and pulse width) on granule size were evaluated. Two different failure modes were identified based on the measured target product quality (granule size) profile: risk of bed collapse due to over-wetting and low granulating efficiency. Using the constructed PDS for desired granulation, the expected final granule attributes can be obtained through properly controlling the process trajectory by adjusting the process parameters.