Critical Quality Attributes Research Articles

Quality by Design Perspectives for Designing Delivery System for Flavour and Fragrance: Current State‐of‐the‐Art and for Future Exploration

ABSTRACTQuality by design (QbD) is a systematic method for the development of product and process design to ensure quality and efficacy. In the fragrance and flavour industry, the design of delivery systems plays a crucial role in the overall product quality and consumer acceptance. This article analyses the current state‐of‐the‐art and future explorations from QbD perspective for designing appropriate delivery systems for flavour and fragrance applications. The QbD approach for delivery system design involves classifying critical quality attributes of the product and process, defining the critical process parameters and developing a design space to ensure product quality within the specified range. In addition, risk assessment and mitigation strategies are also a component of the QbD techniques, which ensure the robustness of the delivery system. Various delivery systems such as microencapsulation, nanoencapsulation, solid lipid nanoparticles and liposomes have been explored in the flavour and fragrance industry. These delivery systems provide controlled release, protection, and enhanced stability of the active ingredients. However, challenges such as scale‐up, reproducibility, and cost‐effectiveness need to be addressed to ensure their commercial viability. In conclusion, the QbD outlook provides a comprehensive framework for the design of carrier system for fragrance and flavour applications. The incorporation of risk assessment and mitigation strategies ensures the robustness of the delivery system, and the future exploration of advanced technologies may further enhance the efficiency and effectiveness of the QbD approach.

Development and Validation of 1H Nuclear Magnetic Resonance Quantitative Method for Efavirenz API Quality Control

Background: The pharmaceutical industry is constantly looking for a better way to ensure and improve its products' safety, quality, and effectiveness. Since there are many attributes of the drug substance and excipients that could potentially affect the Critical Quality Attributes (CQAs) of the intermediates and the final product, the evaluation of the raw material's physicochemical characteristics is crucial as they directly affect the quality, safety, efficacy, and lot-to-lot consistency. Scientists rely on methods, like HPLC, HPTLC, LC-MS, GC-MS, and NMR, to analyze these substances. The advantage of NMR is that it is considered a primary analytical method compared to other analytical techniques. Objective: This work aimed to present a simple, rapid, specific, and accurate method by proton Nuclear Magnetic Resonance spectroscopy (1H-NMR) developed to determine the activity of the antiretroviral Efavirenz’s (EFZ) Active Pharmaceutical Ingredient (API). The method was based on quantitative NMR spectroscopy (qNMR). Methods: A Bruker Avance spectrometer (11.7 Tesla, 500 MHz for 1H) with a 5mm probe was used. The 1H-NMR signal at 7.54 ppm corresponding to the analyte of interest was employed to quantify the drug. The method was validated for specificity, selectivity, intermediate precision, linearity, range of work, accuracy, and robustness. Results: The method developed was specific and linear (r2 = 0.9998) with a value between 4.30 mg/mL and 12.40 mg/mL. The relative standard deviation for accuracy and precision was 0.4% or less. The method's robustness was demonstrated by changing four different parameters, and the difference among each was 1.2% or less. The results of this work have been found to be in agreement with those obtained from High-performance Liquid Chromatography (HPLC) analysis. Conclusion: The proposed method has been found to be a valuable and practical tool for quality control. Its applicability to determining many APIs and saving solvent use and time is highlighted.

Quality risk management and data integrity in R&D laboratories supporting CMC lifecycle of biological products

The development of pharmaceutical products is the critical bridge that moves a potential new medicine from academic discovery to applied treatment of patients. It translates an idea for a new drug to bench-level research on how it can be manufactured, formulated, characterized and controlled for use in non-clinical and early clinical trials.From pre-clinical R&D discovery work through the commercial launch, substantial R&D CMC data is generated to develop and optimize cGMP manufacturing and testing operations, while also supporting product comparability, elucidating product / impurity structures, assessing critical quality attributes, developing the drug delivery mode, and developing the product formulation for long-term stability. Significant R&D CMC work continues post-approval to support continuous improvement and market expansion of the commercial product. These activities are crucial elements of Product Lifecycle Management, and taken together, they comprise Pharmaceutical Quality or Chemistry, Manufacturing and Controls (CMC). The objective of this paper is to mitigate the regulatory ambiguity of R&D quality systems with practical, risk-based examples and recommendations when conducting supportive CMC studies for biological products.Making sound strategic CMC decisions under any circumstances assumes data from R&D studies are reliable, traceable, and complete. While there are specific regulatory guidelines on phase-appropriate cGMP activities, none exist for quality practices in R&D CMC laboratories conducting non-cGMP studies. Hindsight is not the time to discover that R&D studies lack key elements that would otherwise have allowed the data to be directly presented to regulators, if needed. There is a strong prospective business interest in protecting considerable investments made for CMC R&D studies. Therefore, establishment of a robust and stage-appropriate R&D laboratory quality system is essential for companies seeking to capitalize on prior knowledge, protect investments, and be prepared for accelerated approval pathways.

The use of orthogonal analytical approaches to profile lipid nanoparticle physicochemical attributes

Abstract Lipid nanoparticles have become a major disruptor within the drug delivery field of complex RNA molecules. The wide applicability of prototype nanomedicines have the potential to fill clinical requirements against current untreatable diseases. The uptake and implementation of analytical technologies to evaluate these prototype nanomedicines have not experienced similar growth rates hindering the translation of LNPs. Here, we evaluate a model RNA-LNP formulation with a selection of routine, and high-resolution orthogonal analytical techniques across studies on manufacturing process parameter impact and formulation stability evaluation under refrigerated and ultra-low temperatures. We analysed model cationic RNA complexed lipid nanoparticle formulation through process impact on formulation critical quality attributes, short term refrigerated stability evaluation, and frozen storage stability using zetasizer dynamic light scattering and nanoparticle tracking analysis. We also evaluated freeze/thaw induced stress on LNP formulation using high resolution field-flow fractionation. Statistical analysis and correlations between techniques were drawn to further enhance our understanding of LNP formulation design, and physiochemical attributes to facilitate LNP formulation clinical translation.

Can We Simplify Liposome Manufacturing Using a Complex DoE Approach?

Microfluidic liposome production presents a streamlined pathway for expediting the translation of liposomal formulations from the laboratory setting to clinical applications. Using this production method, resultant liposome characteristics can be tuned through the control of both the formulation parameters (including the lipids and solvents used) and production parameters (including the production speed and mixing ratio). Therefore, the aim of this study was to investigate the relationship between not only total flow rate (TFR), the fraction of the aqueous flow rate over the organic flow rate (flow rate ratio (FRR)), and the lipid concentration, but also the solvent selection, aqueous buffer, and production temperature. To achieve this, we used temperature, applying a design of experiment (DoE) combined with machine learning. This study demonstrated that liposome size and polydispersity were influenced by manipulation of not only the total flow rate and flow rate ratio but also through the lipids, lipid concentration, and solvent selection, such that liposome attributes can be in-process controlled, and all factors should be considered within a manufacturing process as impacting on liposome critical quality attributes.

Mitigating In-Column Artificial Modifications in High-Temperature LC-MS for Bottom-Up Proteomics and Quality Control of Protein Biopharmaceuticals.

Elevating the column temperature is an effective strategy for improving the chromatographic separation of peptides. However, high temperatures induce artificial modifications that compromise the quality of the peptide analysis. Here, we present a novel high-temperature LC-MS method that retains the benefits of a high column temperature while significantly reducing peptide modification and degradation during reversed-phase liquid chromatography. Our approach leverages a short inline trap column maintained at a near-ambient temperature installed upstream of a separation column. The retentivity and dimensions of the trap column were optimized to shorten the residence time of peptides in the heated separation column without compromising the separation performance. This easy-to-implement approach increased peak capacity by 1.4-fold within a 110 min peptide mapping of trastuzumab and provided 10% more peptide identifications in exploratory LC-MS proteomic analyses compared with analyses conducted at 30 °C while maintaining the extent of modifications close to the background level. In the peptide mapping of biopharmaceuticals, where in-column modifications can falsely elevate the levels of some critical quality attributes, the method reduced temperature-related artifacts by 66% for N-terminal pyroGlu and 63% for oxidized Met compared to direct injection at 60 °C, thus improving reliability in quality control of protein drugs. Our findings represent a promising advancement in LC-MS methodology, providing researchers and industry professionals with a valuable tool for improving the chromatographic separation of peptides while significantly reducing the unwanted modifications.

A two-stage mechanistic reduced-order model of pharmaceutical tablet dissolution: Population balance modeling and tablet wetting functions

We propose a two-stage reduced-order model (ROM) of pharmaceutical tablet dissolution that is comprised of (i) a mechanistic dissolution function of the active pharmaceutical ingredient (API) and (ii) a tablet wetting function. The former is derived from a population balance model, using a high-resolution finite volume algorithm for a given API crystal size distribution and dissolution rate coefficient. The latter is obtained from the mechanistic understanding of water penetration inside a porous tablet, and it estimates the rate at which the API is exposed to the buffer solution for a given formulation and the dimensions of the tablet, contact angle, and surface tension between the solid and liquid phases, liquid viscosity, and mean effective capillary radius of the pore solid structure. In turn, the two-stage model is mechanistic in nature and one-way coupled by means of convolution in time to capture the start time of the API dissolution process as water uptake, swelling, and disintegration take place. The two-stage model correlates dissolution profiles with critical process parameters (CPPs), critical material attributes (CMAs), and other crucial critical quality attributes (CQAs). We demonstrate the model’s versatility and effectiveness in predicting the dissolution profiles of diverse pharmaceutical formulations. Specifically, we formulate and fabricate acetaminophen and lomustine solid tablets using different API content and size distributions, characterize their dissolution behavior, and estimate capillary radius as a function of tablet porosity. The estimations generated by the proposed models consistently match the experimental data across all cases investigated in this study.

From microchips to microneedles: semiconductor shear testers as a universal solution for transverse load analysis of microneedle mechanical performance

Abstract Microneedles are a promising technology for pain-free and efficient pharmaceutical delivery. However, their clinical translation is currently limited by the absence of standardized testing methods for critical quality attributes (CQAs), such as mechanical robustness, which are essential for demonstrating safety and efficacy during regulatory review. A key aspect of mechanical robustness is transverse load capacity, which is currently assessed using diverse, non-standardized methods, which have limited capability to measure transverse failure forces at different heights along a microneedle. This is critical for understanding mechanics of potential failure modes during insertion after skin penetration. In this work we utilize a wire bond shear tester, a piece of test equipment widely used in the semiconductor industry, to measure the transverse load capacities of various microneedle designs. This approach is compatible with diverse microneedle types, geometries, and materials, and offers high-throughput and automated testing capabilities with high precision. We measure transverse failure loads with micron-scale control over the test height and have established comprehensive profiles of mechanical robustness along the length of different microneedle designs, which is a capability not previously demonstrated in literature for polymeric and metal microneedles. Transverse failure forces were 10±0.3 gf to 128±12 gf for wire bonded gold and silver microneedles, 11±0.7 gf to 480±69 gf for conical and pyramidal polymeric microneedles, and 206±80 gf to 381±1 gf for 3D printed conical stainless steel microneedles. Additionally, we present standardized definitions for microneedle structural failure modes resulting from transverse loads, which can facilitate root cause failure analysis and defect detection during design and manufacturing, and aid in risk assessment of microneedle products. This work establishes a standardized approach to evaluating a significant CQA of microneedle products, which is a critical step towards expediting their clinical adoption.

Comparison of Four Rapid N-Glycan Analytical Methods and Great Application Potential in Cell Line Development

N-glycan, a critical quality attribute (CQA) of monoclonal antibodies, profoundly impacts potency, immunogenicity, safety, and clinical efficiency. Therefore, N-glycan should be monitored and controlled during development. The conventional 2-AB method is considered the gold standard for N-glycan analysis, which is labor intensive and time consuming. Moreover, its sample requirement is relatively high and cannot be met in early-stage development, including cell line development. In this study, we compared the performance of four rapid analytical methods in N-glycan analysis of mAbs, including the rapid 2-AB method, reduction method, off-line IdeS digestion method, and two-dimensional liquid chromatography-mass spectrometry (2D-LC-MS) method. Our results showed that these four rapid analytical methods could provide comparable N-glycan data. Moreover, these four rapid methods shortened the testing time for the conventional 2-AB method from days to just minutes. They also reduced the sample requirement for the conventional 2-AB method from milligrams to micrograms. Among these four rapid methods, the 2D-LC-MS method demonstrated great potential for applications in time-consuming cell line development because it required less testing time and a lower sample requirement.

Assessing a single-cell multi-omic analytic platform to characterize ex vivo-engineered T-cell therapy products.

Genetically engineered CD8+ T cells are being explored for the treatment of various cancers. Analytical characterization represents a major challenge in the development of genetically engineered cell therapies, especially assessing the potential off-target editing and product heterogeneity. As conventional sequencing techniques only provide information at the bulk level, they are unable to detect off-target CRISPR translocation or editing events occurring in minor cell subpopulations. In this study, we report the analytical development of a single-cell multi-omics DNA and protein assay to characterize genetically engineered cell products for safety and genotoxicity assessment. We were able to quantify on-target edits, off-target events, and potential translocations at the targeting loci with per-cell granularity, providing important characterization data of the final cell product. Conclusion: A single-cell multi-omics approach provides the resolution required to understand the composition of cellular products and identify critical quality attributes (CQAs).

Quality by design steered approach for co-encapsulation of timolol maleate and dorzolamide hydrochloride in injectable liposomes

Glaucoma is caused by high intraocular pressure, which can causes blindness. Combinations of timolol and dorzolamide are used for its treatment with a requirement of multiple dosing with dosing being twice or four times a day. Conventional eye drops have poor pre-corneal retention and is thus less available for action. This study utilizes principles of Quality by Design for formulation of injectable liposomes coloaded with timolol maleate and dorzolamide HCl, which overcomes limitations of conventional eye drops. For implementation of Quality by Design principles a systematic approach involving defining Quality Target Product Profile, identification of Critical Quality Attributes, mapping Critical Quality Attributes to Critical Process Parameters and Critical Material Attributes, Failure Mode and Effect Analysis based risk assessment, Taguchi screening, and 32 full factorial Design of Experiments design were utilized. A robust model for formulation of coloaded liposomes was successfully developed. Design of Experiments approach allowed to obtain optimized batch having particle size of 116.1 nm, encapsulation efficiency of dorzolamide HCl of 72.12 % and encapsulation efficiency of timolol maleate of 71.94 %. In-vitro drug release showed a sustained release for 4 days. The prepared formulation was in the desired osmolarity range. Biosafety was proved using histopathological characterization. In-vivo studies for assessing the Intra Ocular Pressure reduction showed that there was no significant difference in Intra Ocular Pressure reduction between prepared liposomes and marketed formulation but were superior than marketed formulation because of less fluctuations in Intra Ocular Pressure. Prepared coloaded injectable liposomes lays the foundation for further research in the area and can be translated from to bench side for commercial clinical use.

Exploration of moisture activated dry granulation for the development of gastroretentive tablets aided by SeDeM diagram

Moisture activated dry granulation (MADG) is an attractive granulation process. However, only a few works have explored modified drug release achieved by MADG, and to the best of the authors knowledge, none of them have explored gastroretention. The aim of this study was to explore the applicability of MADG process for developing gastroretentive placebo tablets, aided by SeDeM diagram. Floating and swelling capacities have been identified as critical quality attributes (CQAs). After a formulation screening step, the type and concentration of floating matrix formers and of binders were identified as the most relevant critical material attributes (CMAs) to investigate in ten formulations. A multiple linear regression analysis (MLRA) was applied against the factors that were varied to find the design space. An optimized product based on principal component analysis (PCA) results and MLRA was prepared and characterized. The granulate was also assessed by SeDeM.In conclusion, granulates lead to floating tablets with short floating lag time (<2 min), long floating duration (>4 h), and showing good swelling characteristics. The results obtained so far are promising enough to consider MADG as an advantageous granulation method to obtain gastroretentive tablets or even other controlled delivery systems requiring a relatively high content of absorbent materials in their composition.

Integration of Quality by Design (QbD) Principles in the Engineering of an Oral Delivery Nanosystem Loaded with Fenofibrate

Background: Fenofibrate (FEN) is the FDA-approved drug used in the treatment of hyperlipidemia. FEN possesses limited bioavailability orally due to its low solubility. As a result, more frequent and larger doses are needed, which increases the likelihood of adverse effects. Objectives: This study aimed to develop and optimize polymeric nanoparticles loaded with Fenofibrate (FEN) using the solvent evaporation method. Method: A Quality by Design (QbD) approach was used to ensure the quality of the finished product by evaluating the impact of critical material attributes (CMAs) and critical process parameters (CPPs) on the critical quality attributes (CQAs) of nanoparticles. The impact of CMAs (quantity of polycaprolactone, % polyvinyl alcohol, and % sodium lauryl sulphate) on particle size and Drug Entrapment Efficiency (DEE) was studied using Box-Behnken Design. Results: The optimized nanoparticles have 246.5 ± 4.38 nm particle size and 77.53 ± 0.9% DEE. SEM and TEM were used to analyze the surface morphology of nanoparticles. Furthermore, In-Vitro drug release study of optimized formulation was performed to confirm the efficacy of the polymeric nanoparticles. Conclusion: The solvent evaporation method was utilized to effectively formulate FEN-loaded polymeric nanoparticles and optimized through QbD principles to achieve minimum particle size and maximum % DEE

Rapid and simple dual extraction for the analysis of lipids and autoantigenic peptides within phosphatidylserine-liposomes

Autoimmune diseases are a major health concern in developed countries. Currently, only palliative treatments based on anti-inflammatories and immunosuppressors are available. A novel antigen-specific therapy that uses a physiological process of tolerance generation is being developed. This is plausible by using phosphatidylserine rich liposomes (PS-liposomes), which bio-mimic apoptotic cells, encapsulated with the autoantigen responsible of generating the autoimmunity. In this way, tolerance against the own cells or tissues that were considered hostile can be achieved. In addition, only by changing the encapsulated peptide, different autoimmune diseases can be treated. Efficacy of this approach was demonstrated in type I diabetes, rheumatoid arthritis, multiple sclerosis, and myasthenia gravis.In the regulatory pre-clinical phase, analytical methodologies to evaluate the quality of the product need to be developed. In this regard, identification and quantification of the encapsulated peptide and lipids are considered critical quality attributes. In this study, a rapid and simple liquid–liquid extraction procedure, based on Bligh-Dyer method, is described for dual extraction of peptides and lipids within PS-liposomes formulation. This single step allows the separation of lipids and the encapsulated peptide in two different phases. For the subsequent analysis, two different HPLC methods were developed. The organic phase, which contains the lipids was analysed by HPLC-ELSD, while the aqueous phase, containing the encapsulated peptide, was analysed by HPLC-UV. Both methods were also validated in terms of accuracy, precision, linearity, LOD and LOQ. The extraction procedure has demonstrated highly efficient separation of lipids and peptides, avoiding interferences between them in the quantification.

Novel identification of mAbs by Raman spectroscopy

AbstractThe identification of the critical quality attributes (CQAs) of monoclonal antibodies (mAbs) is a key component of quality by design. Traditional detection methods for the identification of mAbs, such as peptide mapping and weak cation‐exchange chromatography (WCX‐HPLC), require sophisticated equipment, experienced staff, and a considerable amount of time. In this study, the novel identification of mAbs was performed using Raman spectroscopy, combined with the evaluation of other CQAs, such as the appearance and purity of size‐exclusion high‐performance liquid chromatography(SEC‐HPLC), charge heterogeneity of WCX‐HPLC, and bioassay. Raman spectroscopy achieved comparable results to the conventional, but complex, approach to identifying anti‐vascular endothelial growth factor antibodies. Raman spectroscopy was used to identify and distinguish between different antibody types. Additionally, the Raman technique with principal component analysis of multivariate algorithms is rapid, efficient, and accurate for mAb identification; this technique has great potential to support biopharmaceutical development and counterfeiters.

Statistical analysis of the critical quality attributes of 1,2- dihydroxypropane as a pharmaceutical excipient

Statistical analysis of the critical quality attributes of 1,2- dihydroxypropane as a pharmaceutical excipient

Size-exclusion LC-UV/HRMS based method for the analysis of aggregates in synthetic GLP-1 analog liraglutide and evaluation of excipient impact on aggregation.

Peptide aggregation is one of the key challenges associated with the development of therapeutic peptides. Peptide and protein aggregates are considered as one of the most important critical quality attributes (CQA). Therapeutic liraglutide (LGT) is proteinaceous in nature, and aggregation can be triggered by various environmental stress condition. Therefore, it is essential to separate and identify aggregation states of such drugs. In this study, we have established size exclusion chromatography-liquid chromatography-ultraviolet/high resolution mass spectrometry (SEC-LC-UV/HRMS) method to separate and identify the stress induced LGT aggregates. LGT samples were subjected to photolytic, thermal, freeze thaw and shaking stress conditions. Additionally, LGT solution was incubated with surfactant and excipient that are commonly used in peptide formulation, to evaluate their impact on aggregation level and physicochemical stability over time. The developed SEC method was also validated for specificity, accuracy, precision and linearity. The results of this study will be useful for investigators to monitor LGT aggregates during product development.

Advancement and Innovations in Drying of Biopharmaceuticals, Nutraceuticals, and Functional Foods

AbstractDrying is a crucial unit operation within the functional foods and biopharmaceutical industries, acting as a fundamental preservation technique and a mechanism to maintain these products' bioactive components and nutritional values. The heat-sensitive bioactive components, which carry critical quality attributes, necessitate a meticulous selection of drying methods and conditions backed by robust research. In this review, we investigate challenges associated with drying these heat-sensitive materials and examine the impact of various drying methods. Our thorough research extensively covers ten notable drying methods: heat pump drying, freeze-drying, spray drying, vacuum drying, fluidized bed drying, superheated steam drying, infrared drying, microwave drying, osmotic drying, vacuum drying, and supercritical fluid drying. Each method is tailored to address the requirements of specific functional foods and biopharmaceuticals and provides a comprehensive account of each technique's inherent advantages and potential limitations. Further, the review ventures into the exploration of combined hybrid drying techniques and smart drying technologies with industry 4.0 tools such as automation, AI, machine learning, IoT, and cyber-physical systems. These innovative methods are designed to enhance product performance and elevate the quality of the final product in the drying of functional foods and biopharmaceuticals. Through a thorough survey of the drying landscape, this review illuminates the intricacies of these operations and underscores their pivotal role in functional foods and biopharmaceutical production.

Hybrid Modeling for On-Line Fermentation Optimization and Scale-Up: A Review

Modeling is a crucial tool in the biomanufacturing industry, namely in fermentation processes. This work discusses both mechanistic and data-driven models, each with unique benefits and application potential. It discusses semi-parametric hybrid modeling, a growing field that combines these two types of models for more accurate and easy result extrapolation. The characteristics and structure of such hybrid models will be examined. Moreover, its versatility will be highlighted, showing its usefulness in various stages of process development, including real-time monitoring and optimization. Scale-up remains one of the most relevant topics in fermentation processes, as it is important to have reproducible critical quality attributes, such as titer and yield, on larger scales. Furthermore, the process still relies on empirical correlations and iterative optimization. For these reasons, it is important to improve scale-up predictions, through e.g., the use of digital tools. Perspectives will be presented on the potential that hybrid modeling has by predicting performance across different process scales. This could provide more efficient and reliable biomanufacturing processes that require less resource consumption through experimentation.

Intelligent industry-oriented oro-solid formulation of famotidine: Advanced statistical optimization and Ex-Vivo characterization

BackgroundSol-Gel is the conventional approach for in-situ formulation having several limitations, including instability, stringent storage conditions, dose inaccuracy, inconsistent drug release, and patient inconvenience. ObjectivesThe aim of the present investigation was to design and characterize an intelligent oro-solid in-situ targeted dosage form of Famotidine (FTD) incorporating the cross-linked chitosan-vanillin (CrL-CSV) which instantly converted into a gel upon contact with acidic media. Material and MethodsCrL-CSV was designed using microwave-assisted method inculcating FTD and vanillin (VNL). Interaction was observed using FTIR and DSC. QbD was applied to develop intelligent formulation. Taguchi design was accomplished to screen significant critical material attributes (CMAs) and process parameters (CPPs). Box-Behnken design (BBD) was used to correlate the CMAs/CPPs: the amount of CS, VNL, microwave time, and critical quality attributes (CQAs): % FTD release, mucoadhesive strength, and viscosity. CrL-CSV were evaluated using various in-vitro, ex-vivo characterization and stability. Results and DiscussionFTIR and DSC revealed no interaction between the FTD and excipients. The amount of CS, VNL, and microwave time were screened as significant variables due to the high S/N ratio and delta value from the Taguchi design. A significant effect of CMA/CPP on the CQAs was observed in BBD. The optimum CrL-CSV was designed accomplishing 8.74 % chitosan (CS), 0.94 % VNL exposing 80sec in microwave. Immediate gelling (<1min.), desired viscosity (51432.6cps), optimal mucoadhesion strength (0.40 N), better control on drug release (91.5 % in 8 h) and high stability were achieved in the optimum batch of CrL-CSV. ConclusionAn intelligent formulation inculcating the CrL-CSV was developed, which has instant gelling time, high mucoadhesion time, and strength, and controlled release with desired physical properties. Progressive tools like Taguchi and BBD was explored. The formulation can be helpful at industry as it increases patient compliance, processing and stability.