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1
Pebriani, Alifia Syifa, Sandra Megantara, and Rina Wijayanti. "Tinjauan Critical Quality Attributes (Cqa) dan Critical Process Parameter (Cpp) Sebagai Bagian dari Pendekatan Quality by Design dalam Proses Pengembangan Tablet Salut Selaput Film." Majalah Farmasetika 7, no. 4 (2022): 255. http://dx.doi.org/10.24198/mfarmasetika.v7i4.38841.
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Quality by Design (QbD) merupakan suatu pendekatan sistematis untuk pengembangan produk yang dimulai dengan penetapan tujuan dan menekankan pemahaman produk, proses serta kontrol proses, berdasarkan ilmu pengetahuan dan manajemen risiko mutu. Terdapat beberapa elemen yang termasuk ke dalam QbD, diantaranya adalah Critical Quality Attributes (CQA) dan Critical Parameter Process (CPP). Sebagian besar bentuk sediaan tablet di pasaran merupakan tablet salut film. Sehingga, tujuan dari review ini adalah untuk mengetahui CQA dan CPP pada proses pengembangan tablet salut film. Dalam membuat review ini digunakan jurnal dan artikel hasil penelusuran di internet melalui website NCBI (dengan kategori yang dipilih adalah PubMed), science direct, dan google scholar yang sudah dipublikasi dalam 10 tahun terakhir. Dari hasil pencarian, didapatkan bahwa atribut mutu yang berpotensi untuk menjadi CQA dapat diidentifikasi dari setiap ruahan granul, inti tablet serta tablet salut. Selain itu, setiap tahapan proses dari mulai pengadukan, granulasi basah, pengayakan, pengeringan, pencetakan tablet, pencampuran larutan salut, serta penyalutan memiliki CPP yang perlu dipantau agar dapat dihasilkan produk yang sesuai dengan yang diharapkan.
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Ramadhani, Anietta Indri Nur, Sri Yuliana, and Teuku Nanda Saifullah Sulaiman. "QUALITY ASSURANCE OF SMALL VOLUME PARENTERAL PRODUCT WITH QUALITY BY DESIGN APPROACH: A REVIEW." Journal of Pharmaceutical Science and Application 6, no. 2 (2025): 65. https://doi.org/10.24843/jpsa.2024.v06.i02.p02.
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Background: Nowadays, many small-volume injection products are circulating on the market. Small-volume parenteral (SVP) products are usually designed for treatment purposes that provide systemic effects. If it is not produced strictly, the product will be hazardous and even life-threatening. Quality assurance is one of the primary tools used to ensure the acceptable performance of SVP products. Quality by design (QbD) represents a systematic strategy for product development that starts with setting a target product quality and emphasizes product process control based on a scientific approach and quality risk assessment. The purpose is to ensure SVP product quality from design to production process. Objective: This review will determine generally Critical Quality Attributes (CQA), Critical Material Attributes (CMA), and Critical Process Parameters (CPP) in terms of explaining the quality assurance of SVP products with a quality-by-design approach. Methods: All articles were obtained by electronic search using ICH guidelines, Science Direct, and Google Scholar. Results: From the literature review, it was found that using a quality-by-design approach through integrated CQA, CMA, and CPP can produce SVP products that comply with QTPP (Quality Target Product Profile) and regulatory requirements. Conclusion: QbD has been established as a valuable scientific approach for ensuring quality assurance within the pharmaceutical industry. Pharmaceutical companies prioritize obtaining regulatory approval before introducing any product to the market. Keywords: Critical Process Parameter; Critical Quality Attributes; Quality by Design; Parenteral; Small Volume Parenteral.
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Manish Majumder, Ramesh B, and Minaketan Tripathy. "Development and Validation of a Ultra Flow Liquid Chromatography Method for the Assay of Boceprevir Using a Quality-by-Design Approach." International Journal of Research in Pharmaceutical Sciences 11, SPL4 (2020): 3023–32. http://dx.doi.org/10.26452/ijrps.v11ispl4.4599.
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Quality by design guided. The assay method of Boceprevir is developed in accordance with ICH Q8(R2) guideline with due validation. .In this process, the Target analytical profile (TAP) of the drug was set and critical method parameters (CMP) were investigated by systematic risk assessment experimentation to control critical Quality Attributes (CQA). In this, A Cause Effect Risk Assessment Matrix with Control-Noise-Experiment (CNX) is used for identifying the high-risk variables i.e Percentage of Organic Modifier (% methanol), pH of the Buffer and flow rate of the mobile phase. The surface response methodology was applied to optimize the critical method parameters (CMP) as well as Critical Quality Attributes (CQA) to find out the Design space of the method. The Optimum assay method condition was mobile phase Acetate Buffer (50mM) pH 5.4: Methanol (11:89), Flow rate: 0.9 ml/min, Lambda Max: 207. The separation was achieved in the Eclip Plus C-18 column (250 × 4.6 mm, 5μm) at ambient temperature. The retention time of Boceprevir was found to be 4.2 min. The method evaluation was performed according to the (Q2R1) ICH guideline.
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Daram Sushma Reddy, Vadla Pranay Kumar, Thalaari Shyam, Vadagam Chandana, Trunugu Sai Priya, and Vankunavath Sandeep. "Critical evaluation of quality by design software." International Journal of Science and Research Archive 14, no. 2 (2025): 1548–59. https://doi.org/10.30574/ijsra.2025.14.2.0343.
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Quality by design (QbD) represents the modern approach to ensuring pharmaceutical quality. This concept has significantly influenced the progress of pharmaceutical sciences, having been established and applied globally in accordance with the International Conference on Harmonization (ICH) Guidelines. The proposed ICH guidelines—Q8 for pharmaceutical development, Q9 for quality risk management, and Q10 for pharmaceutical quality systems—provide a foundation for integrating quality into products. In the QbD framework, it is crucial to define the desired product performance profile, known as the Target Product Profile (TPP), and the Target Product Quality Profile (TPQP), as well as to identify Critical Quality Attributes (CQA). Based on this, we can design both the product formulation and the process to meet these attributes. This leads to recognizing the impact of raw material Critical Material Attributes (CMA) and Critical Process Parameters (CPP) on the CQAs, and identifying sources of variability
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Obaid, Shaikh, Zaheer Zahid, Z. Ahmad Rana, and Shaikh Tazim. "QBD in Analytical Method Development and Validation: A Review." Journal of Pharmaceutical Quality Assurance and Quality Control 1, no. 2 (2019): 30–38. https://doi.org/10.5281/zenodo.3249784.
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<em>Quality advisedly is the current approach to the category of prescription drugs. The aim of the pharmaceutical development is to provide a prime quality factory-made product and its manufacturing technique to often deliver the approaching performance of the products. Quality can not be tested into product however quality ought to be inbuilt advisedly. It's a vital part of the trendy approach to pharmaceutical quality. During this construct of QBD, it's essential to stipulate need product expression profile [Target Product Profile &#40; TPP&#41, Object Product Quality Profile &#40;OPQP&#41;] and spot important quality attributed (CQA). On the bottom of this, we are able to style the merchandise formulation and method to fulfil the merchandise qualities. This lands up in recognizing the impact of raw materials [critical material attributes (CMA)], necessary technique parameters (CPP) on the CQA sand Identification and management sources of variability.</em>
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Soans, Deborose, R. Chandramouli, A. N. Kavitha, S. K. Roopesh, and Sangam Shrestha. "Application of Design of Experiments for Optimizing Critical Quality Attributes (CQA) in Routine Pharmaceutical Product Development." Journal of Pharmaceutical Research 15, no. 3 (2016): 96. http://dx.doi.org/10.18579/jpcrkc/2016/15/3/103041.
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Almakaiev, M. S., O. G. Bashura, and L. M. Sidenko. "The risk assessment of the combined medicine in the capsule dosage form at the pharmaceutical development stage." News of Pharmacy, no. 2(102) (October 19, 2021): 75–84. http://dx.doi.org/10.24959/nphj.21.54.
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Aim. To determine the potential risk factors associated with the critical quality indicators of the combined medicine “Neuronucleos” in the capsule dosage form for the treatment of polyneuropathies using the general risk assessment methodology while planning the drug quality at the stage of pharmaceutical development (PD). Materials and methods. The series of the combined medicine “Neuronucleos” in the capsule dosage form, critical indicators of the drug quality, the flowchart of the drug production, critical control points of the drug manufacturing process were developed. The method of causality was used. The quantitative assessment of risk factors was carriedout using the FMECA methodology. Results and discussion. The main objective of this study was to apply the Quality-by-Design (QbD) approach to PD of the combined medicine in the capsule dosage form based on uridine-5 monophosphate disodium salt (UMP), cytidine-5-monophosphate disodium salt (CMF), vitamin B6, thioctic acid and magnesium lactate dihydrate. For better patient compliance and the product quality, a target quality profile as a base for PD planning, as well as critical quality attributes (CQA) related to the product safety and efficacy were determined. The criticality of each CQA was assessed using a special scale. It was shown that “Quantitative content”, “Uniformity of dosage units”, “Dissolution”, “Impurities” were defined as the most CQA due to the minimum amount of UMF and CMF in the capsule and the possibility of their decomposition and increase in the quantity of impurities. The critical attributes of materials (CMA) were identified, and the characteristics required to control them were determined in order to ensure the expected product quality. The primary assessment of the quality indicator risks of the active ingredients was performed. It was found that the particle size affected the homogeneity, the quantitative content of API and dissolution in FPP, and it was shown that the solubility of active substances had a high risk when performing the “Dissolution” test. To determine the potential factors with a significant impact on the drug quality the maximum number of factors was found, and the Ishikawa diagram was constructed. The risk factors associated with the quality and compatibility of active substances and excipients, the quality of primary packaging, production conditions, the drug quality control and the technological process were identified. These factors are the causes of risk and can lead to a situation with negative consequences for the quality of a medicinal product. The FMECA process assessment allowed us to determine the impact of the manufacturing process on the CQA. Conclusions. At the stage of PD for the combined medicine in the capsule dosage form the potential critical indicators of the drug quality have been determined. The critical parameters of the quality of the initial components and the properties of the product have been assessed; the most probable risks for the drug quality have been identified, analyzed and assessed. Further research is advisable to focus on studying the effect of process parameters on critical parameters of the product quality and assessing risks for quality and creating a validation plan and its implementation.
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Swain, Suryakanta, Rabinarayan Parhi, Bikash Ranjan Jena, and Sitty Manohar Babu. "Quality by Design: Concept to Applications." Current Drug Discovery Technologies 16, no. 3 (2019): 240–50. http://dx.doi.org/10.2174/1570163815666180308142016.
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Background: Quality by Design (QbD) is associated with a modern, systematic, scientific and novel approach which is concerned with pre-distinct objectives that not only focus on product, process understanding but also lead to process control. It predominantly signifies the design and product improvement and the manufacturing process in order to fulfill the predefined manufactured goods or final products quality characteristics. It is quite essential to identify the desired and required product performance report, such as Target Product Profile, typical Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQA). Methods: This review highlighted the concepts of QbD design space, for critical material attributes (CMAs) as well as the critical process parameters that can totally affect the CQAs within which the process shall be unaffected thus, consistently manufacturing the required product. Risk assessment tools and design of experiments are its prime components. Results: This paper outlines the basic knowledge of QbD, the key elements; steps as well as various tools for QbD implementation in pharmaceutics field are presented briefly. In addition to this, quite a lot of applications of QbD in numerous pharmaceutical related unit operations are discussed and summarized. Conclusion: This article provides a complete data as well as the roadmap for universal implementation and application of QbD for pharmaceutical products.
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Bhise, Jayashri J., Omprakash G. Bhusnure, Shrikrishna T. Mule, Imran N. Mujewar, Sachin B. Gholve, and Pallavi U. Jadhav. "A Review on Quality by Design Approach (QBD) for Pharmaceuticals." Journal of Drug Delivery and Therapeutics 9, no. 3-s (2019): 1137–46. http://dx.doi.org/10.22270/jddt.v9i3-s.3014.
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Quality by Design is the modern approach for quality of pharmaceuticals. It describes use of Quality by Design to ensure quality of Pharmaceuticals. In this review, the Quality by Design is described and some of its elements identified. Process parameters and quality attributes are identified for each unit operation. Benefits, opportunities and steps involved in Quality by Design of Pharmaceutical products are described. It is based on the ICH Guidelines Q8 for pharmaceutical development, Q9 for quality risk management, Q10 for pharmaceutical quality systems. It also gives application of Quality by Design in pharmaceutical development and manufacturing of pharmaceuticals. It includes the Quality target product profile, critical quality attributes and key aspects of Quality by Design. It also gives comparison between product quality by end product testing and product quality by Quality by Design. The foundation of Quality by Design is ICH Guidelines. Keywords: QbD design, ICH, QTPP, CQA, PAT.
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Priani, Sani Ega, Taufik Muhammad Fakih, Gofarana Wilar, Anis Yohana Chaerunisaa, and Iyan Sopyan. "Quality by Design and In Silico Approach in SNEDDS Development: A Comprehensive Formulation Framework." Pharmaceutics 17, no. 6 (2025): 701. https://doi.org/10.3390/pharmaceutics17060701.
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Background/Objectives: The Self-Nanoemulsifying Drug Delivery System (SNEDDS) has been widely applied in oral drug delivery, particularly for poorly water-soluble compounds. The successful development of SNEDDS largely depends on the precise composition of its components. This narrative review provides an in-depth analysis of Quality by Design (QbD), Design of Experiment (DoE), and in silico approach applications in SNEDDS development. Methods: The review is based on publications from 2020 to 2025, sourced from reputable scientific databases (Pubmed, Science direct, Taylor and francis, and Scopus). Results: Quality by Design (QbD) is a systematic and scientific approach that enhances product quality while ensuring the robustness and reproducibility of SNEDDS, as outlined in the Quality Target Product Profile (QTPP). DoE was integrated into the QbD framework to systematically evaluate the effects of predefined factors, particularly Critical Material Attributes (CMAs) and Critical Process Parameters (CPPS), on the desired responses (Critical Quality Attributes/CQA), ultimately leading to the identification of the optimal SNEDDS formulation. Various DoEs, including the mixture design, response surface methodology, and factorial design, have been widely applied to SNEDDS formulations. The experimental design facilitates the analysis of the relationship between CQA and CMA/CPP, enabling the identification of optimized formulations with enhanced biopharmaceutical, pharmacokinetic, and pharmacodynamic profiles. As an essential addition to this review, in silico approach emerges as a valuable tool in the development of SNEDDS, offering deep insights into self-assembly dynamics, molecular interactions, and emulsification behaviour. By integrating molecular simulations with machine learning, this approach enables rational and efficient optimization. Conclusions: The integration of QbD, DoE, and in silico approaches holds significant potential in the development of SNEDDS. These strategies enable a more efficient, rational, and predictive formulation process.
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Borchert, Daniel, Thomas Zahel, Yvonne E. Thomassen, Christoph Herwig, and Diego A. Suarez-Zuluaga. "Quantitative CPP Evaluation from Risk Assessment Using Integrated Process Modeling." Bioengineering 6, no. 4 (2019): 114. http://dx.doi.org/10.3390/bioengineering6040114.
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Risk assessments (RAs) are frequently conducted to assess the potential effect of process parameters (PPs) on product quality attributes (e.g., a critical quality attribute (CQA)). To evaluate the PPs criticality the risk priority number (RPN) for each PP is often calculated. This number is generated by the multiplication of three factors: severity, occurrence, and detectability. This mathematical operation may result in some potential errors due to the multiplication of ordinal scaled values and the assumption that the factors contribute equally to the PPs criticality. To avoid these misinterpretations and to assess the out of specification (OOS) probability of the drug substance, we present a novel and straightforward mathematical algorithm. This algorithm quantitatively describes the PPs effect on each CQA assessed within the RA. The transcription of severity and occurrence to model effect sizes and parameters distribution are the key elements of the herein developed approach. This approach can be applied to any conventional RA within the biopharmaceutical industry. We demonstrate that severity and occurrence contribute differently to the PP criticality and compare these results with the RPN number. Detectability is used in a final step to precisely sort the contribution of each factor. To illustrate, we show the misinterpretation risk of the PP critically by using the conventional RPN approach.
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Sitre, Dnyaneshwar, and Ravindra Kamble. "Articulation of Quality By Design Elements for Product Development and its Unique Applications." Journal of Drug Delivery and Therapeutics 10, no. 3 (2020): 253–61. http://dx.doi.org/10.22270/jddt.v10i3.4080.
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Quality by Design (QbD) is a methodical approach to pharmaceutical product development that begins with predefined objectives and emphasizes product and process comprehension and process control based on sound science and quality risk management. Pharmaceutical development should lead to the design a quality product and its manufacturing process to meet the QTPP and CQA parameters. To arrive at the robust product development QbD articulation is important which is missing in most of the reviews. This review articulates the QbD elements in the product development. QbD process stars with identification of QTPP and source CQA from QTPP. CMAs and CPPs are derived with risk assessment from the product ingredients and process. Their impact on the CQAs can be studies with DoE tools. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the design space and control strategy. Product process follows life cycle management approach with continuous improvement. PAT tools are utilized for the online monitoring of the processes. This review paper is dedicated to provide QbD element articulation in product development and its unique applications in the various areas of the product development such as Biotechnology, Nanotechnology products, Nasal products, Inhalation, Injectable products, Targeted drug delivery, complex Solid oral, Transdermal and topical products, Bioavailability and dissolution enhancement, Analytical processes and API manufacturing etc. Current trends in the technical application of the PAT tools are discussed.
 Keywords: Quality by Design (QbD), Quality Target Product Profile (QTPP), Critical Quality Attributes (CQA) and Design of Experiment (DoE): Product development application of QbD
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Divyani, R. Patil, K. Patil Divyashree, and Sunila A. Patil Dr. "Enhancing Pharmaceutical Development: A Comprehensive Review on Quality by Design." Journal of Advancement in Immunology 1, no. 1 (2024): 29–34. https://doi.org/10.5281/zenodo.10958010.
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<em>The recent advancement in pharmaceutical quality, known as "quality by design" or "QbD," is crucial. Every regulatory authority for pharmaceutical products has placed a high priority on quality. In terms of services, goods, and procedures, quality means client satisfaction. All pharmaceutical items can be made with higher quality by using QbD. This essay discusses the use of Quality by Design (QbD) in the pharmaceutical industry and how it may be used to guarantee the accuracy of pharmaceutical analyses. It's critical to recognise your desired product performance report within this notion of being throughout product design and growth. the quality target product profile (QTPP), the objective item profile (TPP), and the recognizable proof of fundamental quality ascribes (CQA). Figuring out the impacts of basic cycle boundaries (CPP), basic material ascribes (CAM), and natural substance.</em>
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Dyck, Yan Felix Karl, Daniel Rehm, Jan Felix Joseph, et al. "Forced Degradation Testing as Complementary Tool for Biosimilarity Assessment." Bioengineering 6, no. 3 (2019): 62. http://dx.doi.org/10.3390/bioengineering6030062.
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Oxidation of monoclonal antibodies (mAbs) can impact their efficacy and may therefore represent critical quality attributes (CQA) that require evaluation. To complement classical CQA, bevacizumab and infliximab were subjected to oxidative stress by H2O2 for 24, 48, or 72 h to probe their oxidation susceptibility. For investigation, a middle-up approach was used utilizing liquid chromatography hyphenated with mass spectrometry (LC-QTOF-MS). In both mAbs, the Fc/2 subunit was completely oxidized. Additional oxidations were found in the light chain (LC) and in the Fd’ subunit of infliximab, but not in bevacizumab. By direct comparison of methionine positions, the oxidized residues in infliximab were assigned to M55 in LC and M18 in Fd’. The forced oxidation approach was further exploited for comparison of respective biosimilar products. Both for bevacizumab and infliximab, comparison of posttranslational modification profiles demonstrated high similarity of the unstressed reference product (RP) and the biosimilar (BS). However, for bevacizumab, comparison after forced oxidation revealed a higher susceptibility of the BS compared to the RP. It may thus be considered a useful tool for biopharmaceutical engineering, biosimilarity assessment, as well as for quality control of protein drugs.
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Almuqbil, Rashed M., Nagaraja Sreeharsha, and Anroop B. Nair. "Formulation-by-Design of Efinaconazole Spanlastic Nanovesicles for Transungual Delivery Using Statistical Risk Management and Multivariate Analytical Techniques." Pharmaceutics 14, no. 7 (2022): 1419. http://dx.doi.org/10.3390/pharmaceutics14071419.
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As regulatory and technical landscapes for pharmaceutical formulation development are rapidly evolving, a risk-management approach using multivariate analysis is highly essential for designing a product with requisite critical quality attributes (CQA). Efinaconazole, a newly approved poorly water-soluble antifungal triazole drug has poor permeability. Spanlastics, new-generation surfactant nanovesicles, being fluidic, help improve the permeability of drugs. Therefore, we optimized efinaconazole spanlastics using the concepts of Formulation-by-Design (FbD) and explored the feasibility of transungual delivery for the management of onychomycosis. Using the Ishikawa fishbone diagram, the risk factors that may have an impact on the CQA of efinaconazole spanlastic vesicles were identified. Application of the Plackett–Burman experimental design facilitated the screening of eight different formulation and process parameters influencing particle size, transmittance, relative deformability, zeta potential, entrapment efficiency, and dissolution efficiency. With the help of Pareto charts, the three most significant factors were identified, viz., vesicle builder (Span), edge activator (Tween), and mixing time. The levels of these three critical variables were optimized by FbD to reduce the particle size and maximize the transparency, relative deformability, encapsulation efficiency, and dissolution efficiency of efinaconazole spanlastic nanovesicles. Bayesian and Lenth’s analysis and mathematical modeling of the experimental data helped to quantify the critical formulation attributes required for getting the formulation with optimum quality features. The optimized efinaconazole-loaded spanlastic vesicles had a particle size of 197 nm, transparency of 91%, relative deformability of 12.5 min, and dissolution efficiency of 81.23%. The spanlastic formulation was incorporated into a gel and explored ex vivo for transungual delivery. This explorative study provides an example of the application of principles of risk management, statistical multivariate analysis, and the FbD approach in developing efinaconazole spanlastic nanovesicles.
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Özakın, Süleyman. "pH effect on paraben stability for parenteral drug formulation." Journal of Research in Pharmacy 29, no. 1 (2025): 280–86. https://doi.org/10.12991/jrespharm.1643757.
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The pH optimization and EDTA are widely used in pharmaceutical formulations. The aim of the research work was to evaluate the pH effect and develop a including stable paraben pharmaceutical product. pH of final product is most important critical quality attributes (CQA). Variability pH of formulation is affecting paraben stability. Therefore, chemical stability may affect paraben assay, so this CQA was be evaluated throughout parenteral formulation. A total of four formulations were designed to the stability study. To improve the stability of paraben formulations (T1-T4) were evaluated with different pH ranges and EDTA during stability period. Stability studies were performed to assay analysis of methyl paraben and propyl paraben. The rate of assay results was compared to T1-T4 formulations. As a result of paraben assay analysis for T2 formulation was found to be within in specification limit. The one of them were determined to the best formulations for paraben stability during stability periods. The research proposes a novel stable formulation and proper storage conditions for paraben parenteral solutions. The instability problem of paraben formulation was optimized with targeted pH modification.
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Saliy, O., O. Los, T. Palchevska, and K. Nebylytsia. "Implementation of the Quality by Design approach for developing the composition and the manufacturing technology of an injectable drug for intra-articular introduction." News of Pharmacy, no. 1(101) (February 1, 2021): 28–37. http://dx.doi.org/10.24959/nphj.21.44.
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Aim. To implement the Quality by Design (QbD) approach in order to develop the composition and the manufacturing technology of injectable hyaluronate sodium (HS) in combination with chondroitin sulfate (CS) for intra-articularintroduction. Materials and methods. The composition of the solution for injection was developed using samples of the active pharmaceutical ingredient (API) of HS and CS. The approaches of the ICH international guidelines were used to create the QbD protocol. The quality target product profile (QTPP) was developed based on the literature review, analysis of similar drugs and the previous in-house experimental studies. Determination of critical quality assessment (CQA) product indicators was performed by risk analysis for all quality indicators listed in QTPP. The risk assessment of quality indicators was performed by assessing them according to the Risk Priority Number system (hereinafter – RPN) by a 9-point scale. When studying the composition and the manufacturing technology of the injectable solution the quality risk management (QRM) was developed according to the Ishikawa diagram. Results and discussion. It has been found that the QbD concept is a systematic approach to the drug development. At the first stage QTPP was developed. Based on the QTPP data the CQA indicators were determined, and quality risks were assessed. The critical process parameters (CPP) of the solution for injection based on HS and CS, their control methods, as well as the critical material attributes (CMA) were determined. Based on the data obtained the drug control strategy was proposed taking into account the need to minimize the repetition of control experiments. Using the Isikawa diagram the variability of the material and the process with the environmental factors affecting the qualityof the solution for injection with HS and CS was shown.Conclusions. Using the basic QbD approaches when developing the composition and the manufacturing technology of an injectable drug for intra-articular introduction it has been found that the route of administration, dose, potency, and consumer properties of the product are important aspects of QTPP. It has been proven that the quality indicators, such as transparency, viscosity, sterility and the quantitative content of API are determined as CQA to achieve the objectives defined in QTPP. The study shows that almost all stages of production are critical, therefore, they need to be constantly monitored and checked to obtain a quality product. In further experimental studies to confirm the composition developed and the manufacturing technology according to QRM it is necessary to focus on such indicators as the solution temperature, stabilization time, degassing mode and filtration conditions.
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Witika, Bwalya A., Kokoette E. Bassey, Patrick H. Demana, Xavier Siwe-Noundou, and Madan S. Poka. "Current Advances in Specialised Niosomal Drug Delivery: Manufacture, Characterization and Drug Delivery Applications." International Journal of Molecular Sciences 23, no. 17 (2022): 9668. http://dx.doi.org/10.3390/ijms23179668.
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Development of nanomaterials for drug delivery has received considerable attention due to their potential for achieving on-target delivery to the diseased area while the surrounding healthy tissue is spared. Safe and efficiently delivered payloads have always been a challenge in pharmaceutics. Niosomes are self-assembled vesicular nanocarriers formed by hydration of a non-ionic surfactant, cholesterol or other molecules that combine to form a versatile drug delivery system with a variety of applications ranging from topical delivery to targeted delivery. Niosomes have advantages similar to those of liposomes with regards to their ability to incorporate both hydrophilic and hydrophobic payloads. Moreover, niosomes have simple manufacturing methods, low production cost and exhibit extended stability, consequently overcoming the major drawbacks associated with liposomes. This review provides a comprehensive summary of niosomal research to date, including the types of niosomes and critical material attributes (CMA) and critical process parameters (CPP) of niosomes and their effects on the critical quality attributes (CQA) of the technology. Furthermore, physical characterisation techniques of niosomes are provided. The review then highlights recent applications of specialised niosomes in drug delivery. Finally, limitations and prospects for this technology are discussed.
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Kim, Sun Ho, Su Hyeon Han, Dong-Wan Seo, and Myung Joo Kang. "Evaluation of Prediction Models for the Capping and Breaking Force of Tablets Using Machine Learning Tools in Wet Granulation Commercial-Scale Pharmaceutical Manufacturing." Pharmaceuticals 18, no. 1 (2024): 23. https://doi.org/10.3390/ph18010023.
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Background/Objectives: This study aimed to establish a predictive model for critical quality attributes (CQAs) related to tablet integrity, including tablet breaking force (TBF), friability, and capping occurrence, using machine learning-based models and nondestructive experimental data. Methods: The machine learning-based models were trained on data to predict the CQAs of metformin HCl (MF)-containing tablets using a commercial-scale wet granulation process, and five models were each compared for regression and classification. We identified eight input variables associated with the process and material parameters that control the tableting outcome using feature importance analysis. Results: Among the models, the Gaussian Process regression model provided the most successful results, with R2 values of 0.959 and 0.949 for TBF and friability, respectively. Capping occurrence was accurately predicted by all models, with the Boosted Trees model achieving a 97.80% accuracy. Feature importance analysis revealed that the compression force and magnesium stearate fraction were the most influential parameters in CQA prediction and are input variables that could be used in CQA prediction. Conclusions: These findings indicate that TBF, friability, and capping occurrence were successfully modeled using machine learning with a large dataset by constructing regression and classification models. Applying these models before tablet manufacturing can enhance product quality during wet granulation scale-up, particularly by preventing capping during the manufacturing process without damaging the tablets.
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Nandi, Uttom, Vivek Trivedi, Steven A. Ross, and Dennis Douroumis. "Advances in Twin-Screw Granulation Processing." Pharmaceutics 13, no. 5 (2021): 624. http://dx.doi.org/10.3390/pharmaceutics13050624.
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Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding.
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Gupta, Ashutosh, Jatin Kumar, Surajpal Verma, and Harmanpreet Singh. "APPLICATION OF QUALITY BY DESIGN APPROACH FOR THE OPTIMIZATION OF ORODISPERSIBLE FILM FORMULATION." Asian Journal of Pharmaceutical and Clinical Research 11, no. 14 (2018): 8. http://dx.doi.org/10.22159/ajpcr.2018.v11s2.28508.
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Objective: The present study was done to understand the effect of formulation variables on the quality of orodispersible films using quality by design (QbD) approach as mentioned in ICH Q8 (R2) guideline.Methods: A definitive screening design of experiments (DoE) was used to identify and classify the critical formulation variables affecting critical quality attributes (CQA) using 2×2 factorial design. Based on prescreening study, the critical formulation variables, i.e. concentration of film-forming polymer and plasticizers (propylene glycol and polyethylene glycol 400 [PEG 400]) were kept in the range of 1.5–2.5% w/w and 0.5–1% v/v, respectively. A total of eight laboratory-scale formulations were prepared which were provided by DoE using solvent casting method. These batches were evaluated for CQA’s, i.e. mechanical properties such as folding endurance (FD) and disintegration time (DT). Data were analyzed for elucidating interactions between two variables and for providing a predictive model for the process. Finally, the drug was incorporated into optimized batches, and these were evaluated for in vitro dissolution study in simulated saliva (pH 6.8) as well as their mechanical properties.Results: The results suggested that the concentration of film-forming polymer and plasticizer was critical to manufacture orodispersible film with desired CQA, i.e. mechanical property (FD [>150 folds]) and DT (<60 s). The percent drug release, FD, and DT of optimized Formulation I (hydroxypropyl methylcellulose [HPMC] E5 (2%) and propylene glycol [0.15 mL]) were found to be 82.13%±0.260 (in 15 min), 164±2, and 49±1.5 s, respectively, and for optimized Formulation II (HPMC E5 [2%] and PEG 400 [0.15 mL]) was found to be 64.26%±2.026 (in 15 min) and 218±6 and 55±4 s, respectively.Conclusion: From the results, it has been found that the percentage drug release of naratriptan hydrochloride containing propylene glycol as a plasticizer was greater than the formulation containing PEG 400 as plasticizer. From this, we concluded that QbD is very much useful approach to get an optimized formulation in an economic and faster way in comparison to traditional method (hit and trail methods). The futuristic application of the film will involve the management of an acute migraine.
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Nitta, Carolina Franco, Aiyana Parker, Sopaul Hem, et al. "Cell identity, count, and viability for critical quality attributes using the Cellaca PLX image cytometer." Journal of Immunology 210, no. 1_Supplement (2023): 250.05. http://dx.doi.org/10.4049/jimmunol.210.supp.250.05.
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Abstract Cell and gene therapy is one of the fastest growing fields for cancer therapeutics that heavily relies on robust and consistent instrumentations and technologies to verify and validate the fit-for-purpose critical quality attributes (CQA). Some of the key parameters required for satisfying CMC (Chemistry Manufacturing and Controls) criteria standards for cellular therapeutic products are routinely performed using flow cytometry. In the past decade, image cytometry was developed for cell characterization and cell-based assays but had not yet demonstrated the sensitivity required for surface marker detection. We demonstrate the capability of the Cellaca PLX image cytometry system for surface marker population analysis, GFP and RFP cell viability, and cell health in comparison to flow cytometry. For immunophenotyping, PBMCs were stained with Hoechst/CD3/CD4/CD8, and viability detection of GFP and RFP-containing cell lines was performed by staining with Hoechst/RubyDead. Additionally, apoptosis was induced in Jurkat cells with staurosporine and cells stained with Hoechst/Caspase 3-488/RubyDead. All assays were analyzed on the Cellaca PLX and compared directly to the CytoFLEX. Results show similar surface marker populations: CD3 (76% and 81%, PLX and CytoFLEX, respectively), CD4 (43% and 42%), and CD8 (15% and 17%). Viabilities of RFP and GFP cells were equivalent on both platforms, and population percentages of Hoechst/Caspase 3/RubyDead positive cells were within 5% of each other. Our experiments demonstrate that the Cellaca PLX image cytometer can be of significant value to the Cell and Gene Therapy communities to satisfy several CMC criteria including high-throughput, high sensitivity, and low maintenance.
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Aziz, Kaiser Jay. "Gene Therapy: Development, Design of Studies, and Approval Process." Journal of Biotechnology & Bioinformatics Research 3, no. 3 (2021): 1–4. http://dx.doi.org/10.47363/jbbr/2021(3)134.
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Genome editing can be applied to various areas of medical diagnosis and treatments. Gene therapy pre-market applications comprise of systematically assessing a product’s design controls, manufacturing process controls, and proposed protocols for post-marketing surveillance. Quality risk management principles have been described in various FDA regulatory guidances for several aspects of good manufacturing practices (GMPs) such as several stages of process validation and verification in the genome product’s life cycle including critical quality attributes (CQAs) and monitoring critical process parameters (CPPs). A CPP is defined as a process parameter whose variability has an impact on a CQA of genome product and, therefore, should be monitored or controlled to ensure that the manufacturing process produces an end product of the desired quality. FDA’s mission is to facilitate the premarket review and evaluation of new genomic products for clinical use. The FDA guidances emphasize a quality management approach to the design of studies by providing oversight and objective review based on risk-benefit analysis of new genomic products. FDA reviews, evaluates, verifies and validates the implementation of the regulatory design-control requirements which are applied to the control genomic product’s quality throughout the total product life cycle (TPLC) [1-5].
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Jena, Tapan Kumar, and Rakesh Kumar Jat. "Formulation and Optimization of Immediate Release Tablet of Sapropterin Dihydrochloride by Dry Granulation Process." Journal of Drug Delivery and Therapeutics 14, no. 6 (2024): 105–8. http://dx.doi.org/10.22270/jddt.v14i6.6583.
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The research aims to develop and evaluate an immediate-release dosage form of sapropterin dihydrochloride to improve efficacy, stability, and patient acceptance in treating hyperphenylalaninemia (HPA), ensuring rapid therapeutic action upon administration. Formulation development began with a pre-formulation study to evaluate drug-excipient compatibility, solubility, and compressibility, followed by feasibility trials to create a prototype formulation. Dissolution tests and optimization methods, including DoE and OFAT, were employed to refine the formulation based on critical quality attributes. Process optimization involved identifying and fine-tuning critical parameters through sequential unit operations and risk assessments, ensuring uniformity and quality during scale-up for commercial production. The prototype formulation development for a tablet product based on the reference product Kuvan involved strategic excipient selection to meet critical quality attributes (CQA) and mitigate concerns like mottling. The formulation deviates from the reference by using LH 21 as a binder, colloidal silicon dioxide as a glidant, and omitting anhydrous dibasic calcium phosphate, with Mannitol SD (Pearlitol 200) chosen for its flowability and compressibility. The feasibility trial aimed at achieving pharmaceutical equivalence to Kuvan tablets, focusing on bioequivalence, stability, and API distribution, and involved top spray fluid bed granulation with roller compaction and blending identified as high-risk steps. Optimization of tablet formulation considered drug substance particle size, blend ratios, and excipient selection, with adjustments in intra and extra-granular ratios significantly impacting tablet characteristics. Keywords: Immediate Release, Sapropterin Dihydrochloride, Dry Granulation Process
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Emerson, Rachel M., Nepu Saha, Pralhad H. Burli, Jordan L. Klinger, Tiasha Bhattacharjee, and Lorenzo Vega-Montoto. "Analyzing Potential Failures and Effects in a Pilot-Scale Biomass Preprocessing Facility for Improved Reliability." Energies 17, no. 11 (2024): 2516. http://dx.doi.org/10.3390/en17112516.
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This study demonstrates a failure identification methodology applied to a preprocessing facility generating conversion-ready feedstocks from biomass meeting conversion process critical quality attribute (CQA) specifications. Failure Modes and Effects Analysis (FMEA) was used as an industrially relevant risk analysis approach to evaluate a logging residue preprocessing system to prepare feedstock for pyrolysis conversion. Risk evaluations considered both system-level and operation unit-level assessments considering process efficiency, product quality, cost, sustainability, and safety. Key outputs included estimations of semi-quantitative risk scores for each failure, identification of the failure impacts, identification of failure causes associated with material attributes and process parameters, ranking success rates of failure detection methods, and speculation of potential mitigation strategies for decreasing failure risk scores. Results showed that deviations from moisture specifications had cascading consequences for other CQAs along with process safety implications. Failures linked to fixed carbon specifications carried the highest risk scores for product quality and process efficiency impacts. As increased throughput can be inversely related to meeting product quality specifications; achieving throughput and other material-based CQAs simultaneously will likely require system optimization or prioritization based on system economics. Ultimately, this work successfully demonstrates FMEA as a risk analysis approach for other bioenergy process systems.
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Butré, Claire I., Valentina D’Atri, Hélène Diemer, et al. "Interlaboratory Evaluation of a User-Friendly Benchtop Mass Spectrometer for Multiple-Attribute Monitoring Studies of a Monoclonal Antibody." Molecules 28, no. 6 (2023): 2855. http://dx.doi.org/10.3390/molecules28062855.
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In the quest to market increasingly safer and more potent biotherapeutic proteins, the concept of the multi-attribute method (MAM) has emerged from biopharmaceutical companies to boost the quality-by-design process development. MAM strategies rely on state-of-the-art analytical workflows based on liquid chromatography coupled to mass spectrometry (LC–MS) to identify and quantify a selected series of critical quality attributes (CQA) in a single assay. Here, we aimed at evaluating the repeatability and robustness of a benchtop LC–MS platform along with bioinformatics data treatment pipelines for peptide mapping-based MAM studies using standardized LC–MS methods, with the objective to benchmark MAM methods across laboratories, taking nivolumab as a case study. Our results evidence strong interlaboratory consistency across LC–MS platforms for all CQAs (i.e., deamidation, oxidation, lysine clipping and glycosylation). In addition, our work uniquely highlights the crucial role of bioinformatics postprocessing in MAM studies, especially for low-abundant species quantification. Altogether, we believe that MAM has fostered the development of routine, robust, easy-to-use LC–MS platforms for high-throughput determination of major CQAs in a regulated environment.
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Limarkar, Nirmala, Dipika Chavda, Vaishali Thakkar, and Tejal Gandhi. "Systematic Formulation Approach for Development and Evaluation of Cefixime G ranules for Pediatric Application." Journal of Pharmaceutical Research 21, no. 1 (2022): 13–22. http://dx.doi.org/10.18579/jopcr/v21i1.ms21.78.
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The present study was aimed to apply quality by design to develop stable and flexible pediatric granules of BCS class II drug Cefiximeto improve dissolution profile using Soluplus®. Thegranules were prepared by employing the wet granulation technique. The concentration of Soluplus®(X1), Croscarmellose sodium(X2), Sodium bicarbonate(X3) were identified as critical material attributes(CMA). The critical quality attribute (CQA) are percentage drug release in 20 minutes (Y1) and dispersion time (Y2). All 17 batches were evaluated for micromeritics properties, drug content, particle size distribution, dispersion time, granules' strength/friability, In vitro drug release, comparison with marketed product and stability study. All 17 batches from the Box Behnken showed all the test results values within limits, indicating that the prepared granules were of standard quality. The optimized batch of granules showed 94.45±0.26% drug release in 20min, while the dispersion time was 90.85±0.04 sec and the similarity factor (f2) was 56.39 to marketed product (ZIPRAX). In addition, the optimized batch exhibited no significant change in drug content, dispersion time, in vitro drug release after storage at 40°C ±2°C and 75% RH ± 5% RH for one month. The formulated granules showed better drug release and dispersion time. The granules can be reconstituted with water to prepare dispersion of the drug just before use to improve compliance of paediatric patients. Keywords: Cefixime, granules, Quality by design, Box Behnken design, Soluplus®, Design space
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Vachan Y, Y Anand Kumar, Srikanth N, and Pavan Kumar. "Quality by design approach for optimizing the formulation properties of escitalopram oxalate Oro-dispersible tablets." Open Access Research Journal of Engineering and Technology 7, no. 2 (2024): 126–41. https://doi.org/10.53022/oarjet.2024.7.2.0062.
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The quality by design (QbD) approach was applied for optimizing the formulation of Escitalopram oxalate (ES) orodispersible tablets (ODTs) using Design-Expert Software. To Optimize ES-ODTs a quality target product profile was established in which critical quality attributes (CQAs) such as wetting time, dispersion time, disintegration time and drug release rates were defined and quantified. As critical formulation parameters (CFP) that were evaluated for their effect on the CQA. Percentage of Crospovidone (CP) and Croscaramellose (CCS) were choosen. Response surface methodology (RSM) such as Central Composite Design (CCD) was used to evaluate the effects of the CFPs on the CQAs of the final product. The main factor affecting disintegration, wetting time, dispersion time and release rate was the combination of CP and CCS. Disintegration time, wetting time and dispersion time were found to be sensitive to the percentage of CP and CCS. From the results a design space could be created. The results suggest QbD appears to be a useful approach for the rational design of ES-ODTs. The chosen model helps to visualize the different effects of the CFPs on the CQAs.
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Witika, Bwalya A., Vincent J. Smith, and Roderick B. Walker. "A Comparative Study of the Effect of Different Stabilizers on the Critical Quality Attributes of Self-Assembling Nano Co-Crystals." Pharmaceutics 12, no. 2 (2020): 182. http://dx.doi.org/10.3390/pharmaceutics12020182.
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Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol were rapidly injected into a pre-cooled vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer. The particle size, polydispersity index and Zeta potential were elucidated. Further characterization was undertaken using powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and energy dispersive X-ray spectroscopy scanning electron microscopy. Different surfactants were assessed for their ability to stabilize the nano co-crystals and for their ability to produce nano co-crystals with specific and desirable critical quality attributes (CQA) including particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < −30 mV. All surfactants produced co-crystals in the nanometer range. The PDI and PS are concentration-dependent for all nano co-crystals manufactured while only ZP was within specification when sodium dodecyl sulfate was used in the process.
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Bezerra, Mariana, Juan Almeida, Matheus de Castro, Martin Grootveld, and Walkiria Schlindwein. "Enhancing Process Control and Quality in Amorphous Solid Dispersions Using In-Line UV–Vis Monitoring of L* as a Real-Time Response." Pharmaceutics 17, no. 2 (2025): 151. https://doi.org/10.3390/pharmaceutics17020151.
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Background: This study demonstrates the application of the sequential design of experiments (DoE) approach within the quality by design (QbD) framework to optimize extrusion processes through screening, optimization, and robustness testing. Methods: An in-line UV–Vis process analytical technology (PAT) system was successfully employed to monitor critical quality attributes (CQAs) of piroxicam amorphous solid dispersion (ASD) extrusion products, specifically lightness (L*). Results: L* measurement proved highly effective for ensuring the quality and uniformity of ASDs, offering real-time insights into their physical appearance and process stability. Small variations in L* acted as early indicators of processing issues, such as phase separation or bubble formation, enabling timely intervention. This straightforward and rapid technique supports real-time process monitoring and control, allowing automated adjustments to maintain product consistency and quality. By adopting this strategy, manufacturers can minimize variability, reduce waste, and ensure adherence to quality target product profiles (QTPPs). Conclusions: Overall, this study highlights the value of in-line UV–Vis spectroscopy as a PAT tool in hot melt extrusion, enhancing CQA assessment and advancing the efficiency and reliability of ASD manufacturing.
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Witika, Bwalya A., Vincent J. Smith, and Roderick B. Walker. "Top-Down Synthesis of a Lamivudine-Zidovudine Nano Co-Crystal." Crystals 11, no. 1 (2020): 33. http://dx.doi.org/10.3390/cryst11010033.
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Lamivudine (3TC) and zidovudine (AZT) are antiretroviral agents used to manage HIV/AIDS infection. A wet media milling top-down approach was used to develop and produce nano co-crystals of 3TC and AZT. Micro co-crystals were prepared by solvent evaporation and subsequently milled in the presence of two surfactants, viz., sodium lauryl sulfate (SLS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000). Optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) to establish and identify parameters that may affect the manufacturing of nano co-crystals. The impact of SLS and TPGS 1000 concentration, milling time, and number of units of milling medium on the manufacturing of nano co-crystals, was investigated. The critical quality attributes (CQA) monitored were particle size (PS), Zeta potential (ZP), and polydispersity index (PDI). Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, transmission electron microscopy, energy dispersive X-ray spectroscopy scanning electron microscopy, and cytotoxicity assays were used for additional characterization of the optimised nano co-crystal. The mean PS, PDI, and ZP of the optimised top-down nanocrystal were 271.0 ± 92.0 nm, 0.467 ± 0.073, and −41.9 ± 3.94 mV, respectively. In conclusion, a simple, inexpensive, rapid, and precise method of nano co-crystal manufacturing was developed, validated, and optimised using DoE and RSM, and the final product exhibited the target CQA.
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Aziz, Kaiser Jay. "Genome Editing: New, Emerging, and Interesting Developments for Clinical Applications." Journal of Biotechnology & Bioinformatics Research 3, no. 1 (2021): 1–4. http://dx.doi.org/10.47363/jbbr/2021(3)127.
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Principles of Genome Editing can be applied in the various areas of medical diagnosis and treatments ---from early process design/development through maintenance of the validated state during commercial manufacturing and post-marketing surveillance. Gene editing and clinical applications comprises of systematically assessing, monitoring, and reviewing manufacturing processes and subsequently monitoring measures to control output risks. Quality risk management (QRM) principles have been described in various FDA’s regulatory guidances for several aspects of good manufacturing practices (GMPs) such as several stages of process validation and verification in the drug product lifecycle including critical quality attributes (CQA’s) and monitoring critical process parameters (CPPs). A CPP is defined as a process parameter whose variability has an impact on a CQA and, therefore, should be monitored or controlled to ensure that manufacturing process produces end product of the desired quality. FDA’s mission is to facilitate the premarket review and evaluation of new genomic products for clinical use. The FDA guidances emphasize quality management approach to design of studies by providing oversight and objective review based on risk-benefit analysis and guides the use of new medical products by providing patients organized data and appropriate labeling information in support of the new product’s intended clinical use [1-3].
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Shah, Akashkumar, and Khushbu Patel. "Development and Evaluation of Therapeutically Beneficial Fast Dissolving Tablet Containing Herbal Extracts: A Quality by Design Approach." Indian Journal Of Science And Technology 18, no. 9 (2025): 682–95. https://doi.org/10.17485/ijst/v18i9.3480.
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Objectives: The QbD approach validates the formulation during development, ensuring therapeutic benefits through the careful selection of herbal extracts. Methods: Oral dosage forms, especially fast dissolving tablets with different herbal extracts (curcumin, saffron, and gingerol) were developed to get their desired therapeutic actions immediately. Quality by Design (QbD) emphasizes a science-based approach to product development. Design of Experiments (DOE) and ANOVA are used to analyze high-risk Critical Quality Attributes (CQAs). Design Expert software helps determine the optimal quantities of variables in the formulation by analyzing the effects of independent variables to establish design space. Findings: The effect of identified independent variables croscarmellose sodium (CCS) and polyvinyl pyrrolidone K30 (PVP K30) were investigated. The impact of independent variables on critical responses Disintegration Time and Friability were analyzed. Both variables were found to have a sizeable impact on both the responses. The optimized formulation with 5mg/tablet of CCS and 0.5mg/tablet of PVP K30 meets the desired QTPP and Pharmacopoeial standards of fast dissolving tablet. ANOVA indicates the p-values of respective variables were 0.0168 and 0.0374 which indicates that the model was significant. The optimized FDT (fast dissolving tablet) formulation with three herbal combinations was found to have a DT of 22.02±0.83 seconds and hardness of 3.34±0.18 kg/cm² which was highly desired as per formulation perspectives. Novelty: The successful development of a fast-dissolving tablet with curcumin, saffron, and gingerol using a QbD approach highlights the unique challenges of formulation compared to other potent APIs. Moreover, achieving both the desired DT and hardness in a formulation with herbal extracts at 23.5% potency is a novel accomplishment. There is no existing QbD approach for a product that combines three different herbal extracts into a fast-dissolving tablet dosage form. Therefore, applying QbD to develop and optimize the formulation and achieve the desired results is an accomplishment. Keywords: Herbal Extracts, QbD - Quality By Design, Fast Dissolving Tablets, QTPP-Quality Target Product Profile, DOE-Design Of Experiments, CQA-Critical Quality Attributes
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Powar, Trupti, Ashok Hajare, Ravindra Jarag, and Sopan Nangare. "Development and Evaluation of Lyophilized Methotrexate Nanosuspension using Quality by Design Approach." Acta Chimica Slovenica 68, no. 4 (2021): 861–81. http://dx.doi.org/10.17344/acsi.2021.6858.
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With the application of the quality by design (QbD) approach, a high-pressure homogenizer (HPH) methodology was employed to develop methotrexate nanosuspension (MTX-NS) to boost bioavailability. The Ishikawa diagram was used to analyze potential risk factors in formulation development. To screen and study the impact of various formulation and process factors on the critical quality attributes (CQA), the Placket–Burman design and central composite design were utilized. The number of HPH cycles, poloxamer 188 concentration, and tween 80 concentration were shown to be significant parameters (P<0.05), that were further optimized using Central Composite Design. The zeta potential of optimized lyophilized MTX-NS was determined to be –11.6 ± 7.52 mV and the average particle size was 260 ± 0.25 nm. In vitro cytotoxicity experiments revealed a greater than 80% inhibition, with apoptotic cells shrinking, fragmentation, and cell death. Furthermore, the Cmax and AUC0-t were increased by 2.53 and 8.83 folds, respectively. The relative bioavailability of MTX-NS was found to be 8.83 times higher than that of MTX-aqueous dispersion. As a result, the QbD method resulted in the development of a lyophilized MTX-NS with process understanding and control based on quality risk management.
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Raman, N. V. V. S. S., Useni Reddy Mallu, and Hanimi Reddy Bapatu. "Analytical Quality by Design Approach to Test Method Development and Validation in Drug Substance Manufacturing." Journal of Chemistry 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/435129.
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Pharmaceutical industry has been emerging rapidly for the last decade by focusing on product Quality, Safety, and Efficacy. Pharmaceutical firms increased the number of product development by using scientific tools such as QbD (Quality by Design) and PAT (Process Analytical Technology). ICH guidelines Q8 to Q11 have discussed QbD implementation in API synthetic process and formulation development. ICH Q11 guidelines clearly discussed QbD approach for API synthesis with examples. Generic companies are implementing QbD approach in formulation development and even it is mandatory for USFDA perspective. As of now there is no specific requirements for AQbD (Analytical Quality by Design) and PAT in analytical development from all regulatory agencies. In this review, authors have discussed the implementation of QbD and AQbD simultaneously for API synthetic process and analytical methods development. AQbD key tools are identification of ATP (Analytical Target Profile), CQA (Critical Quality Attributes) with risk assessment, Method Optimization and Development with DoE, MODR (method operable design region), Control Strategy, AQbD Method Validation, and Continuous Method Monitoring (CMM). Simultaneous implementation of QbD activities in synthetic and analytical development will provide the highest quality product by minimizing the risks and even it is very good input for PAT approach.
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Grau-Vorster, Marta, Luciano Rodríguez, Anna del Mazo-Barbara, et al. "Compliance with Good Manufacturing Practice in the Assessment of Immunomodulation Potential of Clinical Grade Multipotent Mesenchymal Stromal Cells Derived from Wharton’s Jelly." Cells 8, no. 5 (2019): 484. http://dx.doi.org/10.3390/cells8050484.
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Background: The selection of assays suitable for testing the potency of clinical grade multipotent mesenchymal stromal cell (MSC)-based products and its interpretation is a challenge for both developers and regulators. Here, we present a bioprocess design for the production of Wharton’s jelly (WJ)-derived MSCs and a validated immunopotency assay approved by the competent regulatory authority for batch release together with the study of failure modes in the bioprocess with potential impact on critical quality attributes (CQA) of the final product. Methods: The lymphocyte proliferation assay was used for determining the immunopotency of WJ-MSCs and validated under good manufacturing practices (GMP). Moreover, failure mode effects analysis (FMEA) was used to identify and quantify the potential impact of different unexpected situations on the CQA. Results: A production process based on a two-tiered cell banking strategy resulted in batches with sufficient numbers of cells for clinical use in compliance with approved specifications including MSC identity (expressing CD73, CD90, CD105, but not CD31, CD45, or HLA-DR). Remarkably, all batches showed high capacity to inhibit the proliferation of activated lymphocytes. Moreover, implementation of risk management tools led to an in-depth understanding of the manufacturing process as well as the identification of weak points to be reinforced. Conclusions: The bioprocess design showed here together with detailed risk management and the use of a robust method for immunomodulation potency testing allowed for the robust production of clinical-grade WJ-MSCs under pharmaceutical standards.
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Iglesias, Cristovão Freitas, Milica Ristovski, Miodrag Bolic, and Miroslava Cuperlovic-Culf. "rAAV Manufacturing: The Challenges of Soft Sensing during Upstream Processing." Bioengineering 10, no. 2 (2023): 229. http://dx.doi.org/10.3390/bioengineering10020229.
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Recombinant adeno-associated virus (rAAV) is the most effective viral vector technology for directly translating the genomic revolution into medicinal therapies. However, the manufacturing of rAAV viral vectors remains challenging in the upstream processing with low rAAV yield in large-scale production and high cost, limiting the generalization of rAAV-based treatments. This situation can be improved by real-time monitoring of critical process parameters (CPP) that affect critical quality attributes (CQA). To achieve this aim, soft sensing combined with predictive modeling is an important strategy that can be used for optimizing the upstream process of rAAV production by monitoring critical process variables in real time. However, the development of soft sensors for rAAV production as a fast and low-cost monitoring approach is not an easy task. This review article describes four challenges and critically discusses the possible solutions that can enable the application of soft sensors for rAAV production monitoring. The challenges from a data scientist’s perspective are (i) a predictor variable (soft-sensor inputs) set without AAV viral titer, (ii) multi-step forecasting, (iii) multiple process phases, and (iv) soft-sensor development composed of the mechanistic model.
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Mohseni-Motlagh, S. Farid, Roshanak Dolatabadi, Majid Baniassadi, and Mostafa Baghani. "Application of the Quality by Design Concept (QbD) in the Development of Hydrogel-Based Drug Delivery Systems." Polymers 15, no. 22 (2023): 4407. http://dx.doi.org/10.3390/polym15224407.
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Hydrogel-based drug delivery systems are of interest to researchers for many reasons, such as biocompatibility, high diversity, and the possibility of administration from different routes. Despite these advantages, there are challenges, such as controlling the drug release rate and their mechanical properties during the manufacturing of these systems. For this reason, there is a need for the production and development of such drug delivery systems with a scientific strategy. For this reason, the quality by design (QbD) approach is used for the development of drug delivery systems. This approach, by identifying the most effective factors in the manufacturing of pharmaceutical products and controlling them, results in a product with the desired quality with the least number of errors. In this review article, an attempt is made to discuss the application and method of applying this approach in the development of hydrogel-based drug delivery systems. So that for the development and production of these systems, according to the type of drug delivery system, what target characteristics should be considered (QTPP) and what factors, such as material properties (CMA) or process parameters (CPP), should be taken into account to reach the critical quality attributes of the product (CQA).
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Shete, Nikhil Arun, Vishwajeet Swami, Vaibhav Kulkarni, Gajanan Paratkar, and Rahul Mohan. "Optimization of Process Parameters for Formulation of Fluvastatin Tablet by Using Dry Granulation Method." Journal of Drug Delivery and Therapeutics 10, no. 5-s (2020): 97–107. http://dx.doi.org/10.22270/jddt.v10i5-s.4347.
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The manufacturing process of the tablet is a very complex process; it can be affected by the several process parameters or variables. The aim of this study was to understand and optimize the process parameters such as mixing, granulation, lubrication and tablets compression processes using quality by design (QbD) approach for a model Anti- Hyperlipidemic drug Fluvastatin sodium. During the processes there are several parameters which may influence or affect product quality. So the main objective of present work was to identify various process parameters and optimize this parameter, for the formulation of good quality product which needs to optimize Blending time, Roller force, Compression force and machine speed. A scale up batch was taken to evaluate and optimize the parameters. Critical quality attributes (CQA) such as flow behavior, granules parameters, Blend uniformity, tablet appearance, effect on tablet quality like physical appearance (surface, weight etc.) and tablet dissolution time as well as drug release. The test results of following parameters at various in-process phases are complies with the specified limits and finished product sample results were found to be within specified limits. This study results assures the manufacturing process is reproducible, robust and will yield consistent product, which meets specification.
 Keywords: Process Parameters, Quality by Design, Fluvastatin, Granulation, Blending, Compression etc,.
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Thombre, Nilima A., Pradeep S. Ahire, and Sanjay J. Kshirsagar. "Formulation Development and Evaluation of Mouth Dissolving Tablet of Aspirin by Using QbD Approach." Dhaka University Journal of Pharmaceutical Sciences 20, no. 1 (2021): 19–29. http://dx.doi.org/10.3329/dujps.v19i2.50854.
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In the current investigations, mouth dissolving tablets (MDT) were developed by applying quality by design (QbD) approach. Direct compression method was applied for the preparation of MDT containing aspirin using 32 factorial design with quantity of drug, microcrystalline cellulose (MCC) and crosscarmellose sodium (CCS) as dependant variables. MCC and CCS were used as superdisintegrants. Sodium stearyl fumarate was used as lubricant. Developed MDT were evaluated for characteristics like hardness, friability, disintegration time (DT) and in vitro drug release . Design Expert 11.0 described adequately impact of selected variables (MCC and CCS) at various levels for response under study (DT and friability). The optimized batch showed disintegration time of 15-28 secs, friability within 1% and in vitro drug release of 75-98% after 30 mins, respectively. The present study of experimental design revealed that MCC and CCS are fruitful at low concentration to develop the optimized formulation. As per the results obtained from the experiments, it can be concluded that QbD is an effective and efficient approach for the development of quality into MDT with the application of QTPP, risk assessment and critical quality attributes (CQA).
 Dhaka Univ. J. Pharm. Sci. 20(1): 19-29, 2021 (June)
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Mohammad, Tarikul Islam Bossunia, Farjana Urmi Khandokar, and Chironjit Kumar Shaha. "Quality-By-Design Approach to Stability Indicating RP-HPLC Analytical Method Development for Estimation of Canagliflozin API and Its Validation." Pharmaceutical Methods 8, no. 2 (2017): 01–10. https://doi.org/10.5281/zenodo.14856243.
Full textAbstract:
Context: Stability Indicating RP-HPLC analytical method validation for estimation of Canagliflozin API have been reported, but there are not studies related to the application of Analytical Quality by Design (AQbD) concepts to the development of a comprehensive science and risk based stability indicating RP-HPLC Analytical method for the analysis of Canagliflozin Active Pharmaceutical Ingredient (API). Aim: Development of a comprehensive science and risk based stability indicating RP-HPLC Analytical method for the analysis of Canagliflozin Active Pharmaceutical Ingredient (API) according to Analytical Quality by Design (AQbD) concept. Methods: AQbD key tools - identification of ATP (Analytical Target Profile), CQA (Critical Quality Attributes) with risk assessment, Method Optimization and Development with DoE, MODR (method operable design region), Control Strategy, AQbD Method Validation, and Continuous Method Monitoring (CMM) ware studied. An efficient experimental design based on systematic scouting of all key components of the RP-HPLC Analytical method (e.g. Diluents, λmax, Column and mobile phase composition) ware presented. The final method was validated according to ICH validation guideline. Results: The method was linear. (r2=0.999). The accuracy was 99% to 101%. The precision, ruggedness and robustness values were also within the prescribed limits (<1%). Conclusion: This result indicated that a consistent, reliable and cost effective method is developed for the routine analysis of Canagliflozin in quality control laboratories.
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Kis, Zoltán. "Stability Modelling of mRNA Vaccine Quality Based on Temperature Monitoring throughout the Distribution Chain." Pharmaceutics 14, no. 2 (2022): 430. http://dx.doi.org/10.3390/pharmaceutics14020430.
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The vaccine distribution chains in several low- and middle-income countries are not adequate to facilitate the rapid delivery of high volumes of thermosensitive COVID-19 mRNA vaccines at the required low and ultra-low temperatures. COVID-19 mRNA vaccines are currently distributed along with temperature monitoring devices to track and identify deviations from predefined conditions throughout the distribution chain. These temperature readings can feed into computational models to quantify mRNA vaccine critical quality attributes (CQAs) and the remaining vaccine shelf life more accurately. Here, a kinetic modelling approach is proposed to quantify the stability-related CQAs and the remaining shelf life of mRNA vaccines. The CQA and shelf-life values can be computed based on the conditions under which the vaccines have been distributed from the manufacturing facilities via the distribution network to the vaccination centres. This approach helps to quantify the degree to which temperature excursions impact vaccine quality and can also reduce vaccine wastage. In addition, vaccine stock management can be improved due to the information obtained on the remaining shelf life of mRNA vaccines. This model-based quantification of mRNA vaccine quality and remaining shelf life can improve the deployment of COVID-19 mRNA vaccines to low- and middle-income countries.
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Koyanagi, Keita, Akinori Ueno, Tetsuo Sasaki, and Makoto Otsuka. "Real-Time Monitoring of Critical Quality Attributes during High-Shear Wet Granulation Process by Near-Infrared Spectroscopy Effect of Water Addition and Stirring Speed on Pharmaceutical Properties of the Granules." Pharmaceuticals 15, no. 7 (2022): 822. http://dx.doi.org/10.3390/ph15070822.
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To produce high-quality pharmaceuticals, a real-time monitoring method for the high-shear wet granulation process (HSWG) was developed based on near-infrared spectroscopy (NIRS). Samples consisting of lactose, potato starch, and hydroxypropyl cellulose were prepared using HSWG with varying amounts of purified water (80, 90, and 100 mL) and impeller speed (200, 400, and 600 rpm), which produces granules of different characteristics. Twelve batches of samples were used for the calibration and nine batches were used for validation. After drying, the median particle size (D50), tapped density (TD), and Hauser ratio (HR) were measured. The best calibration models to predict moisture content (MC), D50, TD, and HR were determined based on pretreated NIR spectra using partial least squares regression analysis (PLSR). The temporal changes in the pharmaceutical properties under different amounts of water added and stirring speed were monitored in real time using NIRS/PLSR. Because the most important critical quality attribute (CQA) in the process was MC, granule characteristics such as D50, TD, and HR were analyzed with respect to MC. They might be used as robust and simple monitoring methods based on MC to evaluate the pharmaceutical properties of HSWG granules.
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Nitta, Carolina Franco, Mackenzie Pierce, Aiyana Parker, et al. "Abstract 5330: Cell identity, count, and viability for critical quality attributes using the Cellaca PLX image cytometer." Cancer Research 83, no. 7_Supplement (2023): 5330. http://dx.doi.org/10.1158/1538-7445.am2023-5330.
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Abstract Cell and Gene therapy is one of the fastest growing fields for cancer therapeutics that heavily relies on robust and consistent instrumentations and technologies to verify and validate the critical quality attributes (CQA) that are fit-for-purpose. Some of the key parameters required for satisfying CMC (Chemistry Manufacturing and Controls) criteria standards for cellular therapeutic products are cell identity, count, viability, purity, potency, stability, and microbiological quality, which may be routinely performed using flow cytometry. Some of these critical attributes can be exceedingly trivial for flow cytometric analysis, which can be complex, requires a dedicated user, and may carry a high maintenance cost. In the past decade, affordable image cytometry has been developed for cell characterization and cell-based assays but has not demonstrated the sensitivity required for visualization and analysis of surface markers, cell health, and viability. In this work, we demonstrate the capability of the newly developed Cellaca PLX image cytometry system for population analysis of surface markers, viability of fluorescent protein expressing cells, and cell health in comparison to flow cytometry. For immunophenotyping assays, PBMCs were stained with anti-human CD3/CD4/CD8 antibodies with Hoechst. Additionally, viability detection of GFP and RFP-containing cell lines was performed by staining with RubyDead and Hoechst. Finally, apoptosis was induced in Jurkat cells with staurosporine and stained with Caspase 3-488, RubyDead, and Hoechst. All assays were imaged and analyzed using the Cellaca PLX image cytometer, and the data generated were compared directly to the CytoFlex flow cytometer. Results show similar percentages of surface marker populations: CD3 (76% and 81%, PLX and CytoFlex, respectively), CD4 (43% and 42%), and CD8 (15% and 17%). RFP and GFP-containing cells showed comparable viabilities on Cellaca PLX and CytoFlex, and the population percentages of Hoechst positive cells stained with Caspase 3 and RubyDead were within 5% of each other. Our experiments demonstrate that the Cellaca PLX can be of significant value to the Cell and Gene Therapy communities providing novel image cytometry methods which may satisfy several CMC criteria including high-throughput, high sensitivity, and low maintenance. Citation Format: Carolina Franco Nitta, Mackenzie Pierce, Aiyana Parker, Sopaul Hem, Timothy Smith, Surbhi Ratnani, Marek Dobrowolski, Srinivas Gundimeda, Bo Lin, Dmitry Kuksin, Leo L. Chan. Cell identity, count, and viability for critical quality attributes using the Cellaca PLX image cytometer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5330.
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Al-Hakim, Ali. "General Considerations for Diversifying Heparin Drug Products by Improving the Current Heparin Manufacturing Process and Reintroducing Bovine Sourced Heparin to the US Market." Clinical and Applied Thrombosis/Hemostasis 27 (January 2021): 107602962110522. http://dx.doi.org/10.1177/10760296211052293.
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Heparin is one of the most widely used drugs in the world. It has been described as a lifesaving drug due to its roles in treating many serious diseases and illnesses including kidney dialysis, surgery, cardiac-invasive, heart attack, cardiac arrhythmia, acute coronary syndrome, pulmonary embolism, stroke, deep vein thrombosis, blood clot prevention, and many other related uses. Heparin drug products currently approved in the United States are obtained from porcine intestinal mucosa sourced from pigs, the majority of which is imported from China. However, due to the heparin contamination crisis (2008) and potential shortage and to safeguard the quality of current and future heparin supply chains including raw material, Food and Drug administration (FDA) posted a notification on its website titled “FDA Encourages Reintroduction of Bovine-Sourced Heparin”. This perspective is intended to address the history of regulatory and scientific background of heparin drug products obtained from bovine and porcine sources and general recommendations for improving the quality of current heparin manufacturing process including Critical Quality Attributes (CQA), control management, process control, related tests, limits, etc. Additionally, a general plan with systematic steps is proposed for diversifying heparin supply chains by reintroduction of bovine sourced heparin to the US market.
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Netra, Adhav Rishikesh Bachhav Shubhangi Bhalerao. "Quality By Design: A Concise Review In Pharmaceutical Sciences." International Journal of Pharmaceutical Sciences 2, no. 7 (2024): 103–10. https://doi.org/10.5281/zenodo.12607157.
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The current pharmaceutical quality assurance approach is no longer enough due to recent changes and limited resources for medication development and manufacturing, which has led to new study in these areas. In 2002, the FDA updated and modernised the regulations controlling pharmaceutical production and product quality in response to these research endeavours, resulting in a paradigm shift in the current Good Manufacturing Practices (cGMP). After the ICH Q8 was approved in 2005, the Quality by Design (QbD) methodology made its way into the pharmaceutical business in the previous ten years. Determining the critical quality ascribed (CQA) and defining the desired product performance profile (Target Product Profile (TPP), Target Product Quality Profile (TPQP)) are crucial steps in the design and development of a product under the QbD concept. We can then design the product formulation and procedure to meet the desired product qualities based on this. This results in the recognition of the influence of key process parameters (CPP) and raw materials [critical material attributes (CMA)] on the CQAs, as well as the identification and management of sources of variability. This paper discusses pharmaceutical QbD and explains how it can be used to develop pharmaceutical products well within the specified period of time. QbD is an emerging idea that offers pharmaceutical manufacturers increased self-regulated flexibility while maintaining tight quality standards and real-time drug product release. When designing and developing pharmaceutical dosage forms, quality-based drug development (QbD) is predicated on an awareness of the target product's quality profile (QTPP) and an evaluation of its hazards. QbD also discusses its tools, which include process analytical technologies, quality risk management, and DoE. The significance of QbD in fostering a science-based methodology in pharmaceutical product development is highlighted by these evaluations.
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Akashkumar, Shah, and Patel Khushbu. "Development and Evaluation of Therapeutically Beneficial Fast Dissolving Tablet Containing Herbal Extracts: A Quality by Design Approach." Indian Journal of Science and Technology 18, no. 9 (2025): 682–95. https://doi.org/10.17485/IJST/v18i9.3480.
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<strong>Objectives:</strong> The QbD approach validates the formulation during development, ensuring therapeutic benefits through the careful selection of herbal extracts. <strong>Methods:</strong> Oral dosage forms, especially fast dissolving tablets with different herbal extracts (curcumin, saffron, and gingerol) were developed to get their desired therapeutic actions immediately. Quality by Design (QbD) emphasizes a science-based approach to product development. Design of Experiments (DOE) and ANOVA are used to analyze high-risk Critical Quality Attributes (CQAs). Design Expert software helps determine the optimal quantities of variables in the formulation by analyzing the effects of independent variables to establish design space. <strong>Findings:</strong> The effect of identified independent variables croscarmellose sodium (CCS) and polyvinyl pyrrolidone K30 (PVP K30) were investigated. The impact of independent variables on critical responses Disintegration Time and Friability were analyzed. Both variables were found to have a sizeable impact on both the responses. The optimized formulation with 5mg/tablet of CCS and 0.5mg/tablet of PVP K30 meets the desired QTPP and Pharmacopoeial standards of fast dissolving tablet. ANOVA indicates the p-values of respective variables were 0.0168 and 0.0374 which indicates that the model was significant. The optimized FDT (fast dissolving tablet) formulation with three herbal combinations was found to have a DT of 22.02±0.83 seconds and hardness of 3.34±0.18 kg/cm² which was highly desired as per formulation perspectives. <strong>Novelty:</strong> The successful development of a fast-dissolving tablet with curcumin, saffron, and gingerol using a QbD approach highlights the unique challenges of formulation compared to other potent APIs. Moreover, achieving both the desired DT and hardness in a formulation with herbal extracts at 23.5% potency is a novel accomplishment. There is no existing QbD approach for a product that combines three different herbal extracts into a fast-dissolving tablet dosage form. Therefore, applying QbD to develop and optimize the formulation and achieve the desired results is an accomplishment. <strong>Keywords:</strong> Herbal Extracts, QbD - Quality By Design, Fast Dissolving Tablets, QTPP-Quality Target Product Profile, DOE-Design Of Experiments, CQA-Critical Quality Attributes
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Bentley, Elizabeth R., Stacia Subick, Michael Pezzillo, Stephen C. Balmert, Aidan Herbert, and Steven R. Little. "Identification and Characterization of Critical Processing Parameters in the Fabrication of Double-Emulsion Poly(lactic-co-glycolic) Acid Microparticles." Pharmaceutics 16, no. 6 (2024): 796. http://dx.doi.org/10.3390/pharmaceutics16060796.
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In the past several decades, polymeric microparticles (MPs) have emerged as viable solutions to address the limitations of standard pharmaceuticals and their corresponding delivery methods. While there are many preclinical studies that utilize polymeric MPs as a delivery vehicle, there are limited FDA-approved products. One potential barrier to the clinical translation of these technologies is a lack of understanding with regard to the manufacturing process, hindering batch scale-up. To address this knowledge gap, we sought to first identify critical processing parameters in the manufacturing process of blank (no therapeutic drug) and protein-loaded double-emulsion poly(lactic-co-glycolic) acid MPs through a quality by design approach. We then utilized the design of experiments as a tool to systematically investigate the impact of these parameters on critical quality attributes (e.g., size, surface morphology, release kinetics, inner occlusion size, etc.) of blank and protein-loaded MPs. Our results elucidate that some of the most significant CPPs impacting many CQAs of double-emulsion MPs are those within the primary or single-emulsion process (e.g., inner aqueous phase volume, solvent volume, etc.) and their interactions. Furthermore, our results indicate that microparticle internal structure (e.g., inner occlusion size, interconnectivity, etc.) can heavily influence protein release kinetics from double-emulsion MPs, suggesting it is a crucial CQA to understand. Altogether, this study identifies several important considerations in the manufacturing and characterization of double-emulsion MPs, potentially enhancing their translation.
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Krishnamanjari, A. Pawar, Ch Srujani, K. Roshini, and K. S. Nataraj. "Implementing Quality by Design approach in Analytical Reverse Phase High Performance Liquid Chromatography Method Development and Validation for the Determination of Fedratinib." International Journal of Pharmaceutical Sciences and Drug Research 13, no. 03 (2020): 253–62. http://dx.doi.org/10.25004/ijpsdr.2021.130303.
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A novel, accurate, precise, specific, sensitive, and robust reverse phase high performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of Fedratinib using the analytical quality by design (AQbD) approach mentioned in International Council for Harmonisation (ICH) Q8 (R2) guidelines. By implementing QbD in HPLC methods, ruggedness and robustness will be verified early in the stage of method development to ensure the method's performance over the product's lifetime. Design Expert® (12.0.12.0) modeling software (Stat-Ease Inc., Minneapolis, MN, USA) was used for response surface methodology (RSM). Plackett-Burman design was employed for the factor screening studies to identify the critical method parameters (CMP) affecting the critical quality attributes (CQA). The selected CMP's were systematically optimized using Central-composite design (CCD). Statistical analysis of the responses was done by applying analysis of variance. Chromatographic separation was accomplished on Agilent C18 (150×4.6 mm, 5 µm) column and PDA-UV detection was set at 268 nm. The optimized and predicted data from Design Expert software consisted of mobile phase Acetonitrile: 0.1% OPA buffer pH 4.18 (43: 57% v/v), pumped at a flow rate of 0.967 mL/min gave the highest desirability of 1. The developed chromatographic method was validated as per ICH Q2 (R1) guidelines and found to be linear over a concentration range of 15–90 µg/mL with a correlation coefficient of 0.999. Degradation studies were performed by exposing the drug to various stress conditions as per ICH Q1A (R2) guidelines, and significant degradation was found in acidic conditions.
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Dev, Asish, Jayesh Dwivedi, and Munira Momin. "Quality by Design based formulation and evaluation of acyclovir microsponges." Journal of Drug Delivery and Therapeutics 9, no. 1 (2019): 54–60. http://dx.doi.org/10.22270/jddt.v9i1.2159.
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Objective: The proposed study is focussed at developing acyclovir microsponges for oral drug delivery systems. QbD was applied for better understanding of the process and to generate design space, using quality target product profile, critical quality attributes, and risk assessment. The aim of the experiment is to prepare a safe, efficacious, stable and patient compliant microsponge dosage form of Acyclovir. Materials and methods: Pre-formulation studies were carried out which helped in developing a suitable dosage form. UV, FTIR, DSC, and SEM studies were done for pre-formulation and post-formulation evaluations. QbD was applied to generate design space, using QTPP, CQA, and risk assessment. Microsponges of acyclovir were developed by 23 factorial designs. Three variables Drug: Polymer ratio (X1), Concentration of surfactant (X2) and Stirring speed (RPM) (X3) at two levels low and high were selected and response surface plots were generated. The microsponges were prepared by Quassi-emulsion solvent diffusion method. Various characterizations that were carried out include entrapment efficiency, percentage yield, particle size determination, in-vitro drug release studies and kinetic modelling of drug release. Statistical analyses of batches and surface response studies were done to understand the effect of various independent variables on the dependent variables. Results and Discussions: The λmax was confirmed at 251 nm by UV spectroscopy. The melting point was determined experimentally to be 2460C which confirms the drug to be Acyclovir. FTIR and DSC studies confirmed that the drug is Acyclovir. Eight trials were taken as per the by 23 factorial designs. Conclusion: The study indicates that microsponges of Acyclovir by QbD approach were successfully developed.
 Keywords: Microsponge, Acyclovir, DoE, QbD