Quality by Design

Glycation of immunoglobulin G (IgG) can result from incubation with a reducing sugar in vitro or during circulation in vivo. Upon injection of a recombinantly produced human therapeutic IgG into humans, changes in the glycation levels could be observed as a function of circulation time. Mass changes on the individual IgG polypeptide chains as the results of glycation were determined using reversed-phase liquid chromatography/mass spectrometry. Changes to the light and heavy chains were low but easily detectable at 0.00092 and 0.0021 glucose (Glc) additions per chain per day, respectively. Levels of glycation found on the Fc portion of IgG isolated from healthy subjects, using a similar analytical approach, were on average 0.045 Glc molecules per fragment. In vivo glycation rates could be approximated in vitro by modeling the physiological glycation reaction with a simplified incubation containing physiological Glc concentrations, pH and temperature but with a high concentration of a single purified IgG. To test the impact of glycation on IgG function, highly glycated IgG1 and IgG2 were prepared containing on average 42-49 Glc molecules per IgG. Binding to FcγIIIa receptors, neonatal Fc receptor or protein A was similar or identical to the non-glycated IgG controls. Although the modifications were well distributed throughout the protein sequence, and at high enough levels to affect the elution position by size-exclusion chromatography, no changes in the tested Fc functions were observed.

Glycation of immunoglobulin G (IgG) can result from incubation with a reducing sugar in vitro or during circulation in vivo. Upon injection of a recombinantly produced human therapeutic IgG into humans, changes in the glycation levels could be observed as a function of circulation time. Mass changes on the individual IgG polypeptide chains as the results of glycation were determined using reversed-phase liquid chromatography/mass spectrometry. Changes to the light and heavy chains were low but easily detectable at 0.00092 and 0.0021 glucose (Glc) additions per chain per day, respectively. Levels of glycation found on the Fc portion of IgG isolated from healthy subjects, using a similar analytical approach, were on average 0.045 Glc molecules per fragment. In vivo glycation rates could be approximated in vitro by modeling the physiological glycation reaction with a simplified incubation containing physiological Glc concentrations, pH and temperature but with a high concentration of a single purified IgG. To test the impact of glycation on IgG function, highly glycated IgG1 and IgG2 were prepared containing on average 42-49 Glc molecules per IgG. Binding to FcγIIIa receptors, neonatal Fc receptor or protein A was similar or identical to the non-glycated IgG controls. Although the modifications were well distributed throughout the protein sequence, and at high enough levels to affect the elution position by size-exclusion chromatography, no changes in the tested Fc functions were observed.

Single-use bioreactors (SUB) and stainless steel bioreactors (SSB) differ in their physical properties. This can have an effect on the performed processes. To be able to guarantee flexible planning in a facility, any kind of processes in SUB and SSB must be sufficiently similar. To date, assessments of SUB and SSB have been exclusively specific for one single product. This study shows a general nonproduct-specific comparison of the production of different types of monoclonal antibodies in different scales of SUBs and SSBs. The study is set up with 72 clinical manufacturing fermentation runs in total by comparing the cell culture performance and quality attributes of these two bioreactor systems. The outcome is that SUBs and SSBs can produce monoclonal antibodies with comparable cell culture performance and product quality. This general comparability paves the way for SUBs to produce new and existing products for (clinical) manufacturing.

Objective: Clinically relevant critical quality attributes (CQA's) were identified for the development of generic drug products containing fluconazole and potential design spaces relevant to the clinical application of the drug candidate was explored. Significance: A simplified scoring system for the biopharmaceutics risk assessment roadmap (BioRAM) is proposed to guide product development. Methods: Factorial design of experiments was employed to study the effect of formulation and process variables on CQA's. The in vivo model was developed for predicting the fraction of drug absorbed and to identify the effect of formulation components on drug absorption. Results: BioRAM yielded low scores for fluconazole absorption with respect to severity (risks of sub and supra-bioavailable drug products), probability of incidence of bioinequivalent results and capacity of detection. The results demonstrated that dissolution was highly influenced by the API (active pharmaceutical ingredient) polymorphism and the ratio of diluents. Process variables (mixing time, lubricant concentration, lubrication time, filling speed) did not impact the clinical outcome of the formulation with respect to dissolution and content uniformity. Conclusion: Understanding the clinical implications of the adopted formulation approach led to the construction of purposeful design space and control strategy.

Clinically relevant critical quality attributes (CQA's) were identified for the development of generic drug products containing fluconazole and potential design spaces relevant to the clinical application of the drug candidate was explored. A simplified scoring system for the biopharmaceutics risk assessment roadmap (BioRAM) is proposed to guide product development. Factorial design of experiments was employed to study the effect of formulation and process variables on CQA's. The in vivo model was developed for predicting the fraction of drug absorbed and to identify the effect of formulation components on drug absorption. BioRAM yielded low scores for fluconazole absorption with respect to severity (risks of sub and supra-bioavailable drug products), probability of incidence of bioinequivalent results and capacity of detection. The results demonstrated that dissolution was highly influenced by the API (active pharmaceutical ingredient) polymorphism and the ratio of diluents...

Purpose The FDA's process validation guidance 2011 has rightly resulted in discontinuing the Bone size fits all^practice. The guidance aligns process validation with quality by design and quality risk management guidelines. However, the process validation guidance has thrown a challenge with respect to determining the statistically appropriate number of batches for process performance qualification (PPQ) stage. This study reviews various approaches for estimating the number of PPQ batches, and their merits and limitations. Additionally, a knowledge factor-based method in which residual risk level is related to the knowledge factor by a probability scale is proposed. The risk-based methods assign a confidence level to unit processes based on the risk posed to critical quality attributes of the product. The level of product understanding and residual risk would determine the number of PPQ batches required for process validation. The knowledge factor-based method like other Bayesian methods provides an opportunity to incorporate knowledge gained during product/process development and scale up studies for estimating PPQ batch numbers. The number of batches required using this method are 6, 12, and 15, respectively, for low-, moderate-, and high-risk processes with corresponding knowledge factors of 0.1, 0.5, and 0.9. Conclusions Greater understanding and knowledge of product would reduce the requirement of PPQ batches remarkably. On the other hand, the higher residual risk level indicates knowledge gaps in product understanding; consequently, higher number of PPQ batches would be required to gain confidence in the product and the process before commercialization.

Background: To accurately quantify orlistat, an anti-obesity drug that is a pancreatic lipase inhibitor thus Depending on the assay system, orlistat illustrates studies at intestines receptors by temporarily blocking the intestines' pancreatic and stomach lipases. High-performance liquid chromatography in the reverse phase was employed. The method's primary goal is to keep the analysis's sensitivity, accuracy, and stability Methods: A stationary phase XBridge C8 Column, 130 Å, 5 µm, 4.6 mm × 250 mm column and a mobile phase was acetonitrile used in the separation procedure. Orlistat was detected at a wavelength of 202 nm at a flow rate of 1 ml/min with an injection volume of 10 µl. HPLC data acquisition and analysis were performed using Empower 3 software. Results: An exact correlation between concentration and response was established by constructing a calibration curve with an r 2 value of 0.9991 of API Orlistat and 0.9994 of Market formulation of orlistat in the concentration range of 50-300 ppm and other parameters were also in the range of ICH guidelines (RSD Less than 2 %) Conclusion: The anti-obesity drug Orlistat is identified and quantified using a novel RP-HPLC technology. According to ICH norms, the method has been verified using criteria such as the system given in ICH guidelines for both API and Market formulations of Orlistat.

Mucuna prureins extract (MPE) is useful in reducing depression symptoms. However, MPE's transit through biological membranes is restricted due to its large molecular weight and hydrophilic nature. Phytosomes could be promising carriers for improving the oral absorption of such encapsulated extracts. One of the major challenges was to get the desired EE and that was achieved by using soya phosphatidylcholine. In this work optimized batch of Mucuna prureins phytosomes (MPP) was subjected to accelerated stability studies and evaluated at regular time intervals for entrapment efficiency, particle size, polydispersity index, and zeta potential. Further, capsules of MPE and MPP were formulated and evaluated for quality control evaluation tests like weight variation, in vitro disintegration time, and in vitro dissolution testing. The accelerated stability studies revealed that the optimized phytosomeformulation was stable under the stability conditions of temperature and relative humidity. Moreover, MPE and MPP had weight variation, and in vitro disintegration time within permissible limits according to IP. The dissolution profile of MPP was found superior to MPE capsules. The findings demonstrated the ability of Mucuna prureins phytosomes to maintain quality control features under accelerated stability conditions. Furthermore, phytosomes could be given in a capsule dosage form, allowing for a prolonged release of encapsulated extracts with long-term health benefits.

Along with the fast developments in the drug production and control technologies, it has been easier to comment on the drug and its production, as well as observing/seeing the defects. These developments have brought within new arrangements in the regulations. Recently added ICH Q8, Q9, Q10 and Q11 guidelines have aimed to make the drug industry to develop rather an information based understanding towards the drug. Within this frame, especially during the drug formulation and active substance development studies, all factors that may affect the quality of the drug should be examined with scientific/statistical methods. For drug development that is compliant with the regulations, proper understanding and interpretation of new concepts explained in the guidelines are initially necessary. Some of these new concepts are Quality by Design (QbD), Critical Quality Attributes (CQA) and Critical Process Parameters (CPP). Each dosage form has its specific Design Space, Critical Quality Attrib...

Quality by Design (QbD) studies areused in the pharmaceutical industry since 2004. The first step started with the Process Analytical Technologies guideline, which was followed by the International Conference on Harmonisation Q8, Q9, Q10 and Q11 guidelines. During the multi-parameter processes of pharmaceutical production, it is necessary to make different variations in either the formulation or the process. However, these variations cannot be performed without permission of Authorities. Design space is a production space provided by the control of critical parameters that are determined by the formulation and manufacturing process. In addition, working within this Design space is not considered a change. This study is based on the fact that Regulatory authorities do not have to be informed of changes as long as the Quality by Design studies remain within the Design space of the Quality by Design formulations. The objective of this study was to demonstrate the flexibility of post-ap...

This research attempts to bring together the positive aspects of lipid nanoparticles and Quality by Design (QbD) approach for developing a novel drug delivery system for skin cancers and aktinic keratosis. Lipid nanoparticles which is one of the most efficacious options for topical treatment of skin diseases were prepared due to their ability to overcome the complex structure of skin barrier and to enhance the skin penetration. Since the formulation development contains complex variables of active ingredients, raw materials or production method; all the variables of the product should be elaborated. QbD approach which refers to design and develop formulations and manufacturing processes to maintain the prescribed product quality was also successfully adopted to achieve a time-and cost-saving process ensuring a high-quality product. 5-Fluorouracil (5-FU) loaded lipid nanoparticles, both solid lipid nanoparticles and nanostructured lipid carriers, were developed and characterized by following QbD steps. Optimal lipid nanoparticle formulation with guaranteed quality which was within the design space has been reached through the artificial neural networks. The optimal lipid nanoparticle formulation which is a NLC formulation with a mean particle size of 205,8 ± 9,34 nm, narrow size distribution (0.279 ± 0.01) and negative zeta potantial -30,20±0,92 was produced by high pressure homogenization method. Cytotoxicity profiles of the optimal NLC was determined by cell culture studies on epidermoid carcinoma cells and human keratinocyte cells. Optimal NLC showed significantly higher anticancer effect on epidermoid carcinoma cells than free 5-FU and also less cytotoxicity towards human keratinocyte cells. Optimal NLC was formulated in hydrogel formulation for ease of application which has suitable occlusive and mechanical properties, viscocity and pH for patient complience. The cumulative amount of 5-FU in dermal tissues of rat skin was found 20.11 ± 2.14 μg/cm2 and 9.73 ± 0.87 μg/cm2 after application of NLC enriched hydrogel and 5-FU hydrogel respectively. In conclusion, this study showed that a time and cost saving process ensuring a high-quality product can be obtained by QbD guided formulation development study with the help of artificial neural networks. A novel semisolid dosage form enriched by NLC which is promising for topical treatment of skin cancers was developed.

In this study, within the framework of Quality by Design which is a systematically scientific approach which enables to understand and control the production and formulation variables during the process design and development, different parameters in the formulation and production process were detected and critical process parameters and critical material attributes were determined via risk evaluation methods. Then, different oral disintegrating tablet formulations were prepared and tested by changing the usage of co-formulated disintegrating excipient and other disintegrant combined with sodium starch glycolate and mannitol. Powder flow characteristics were examined. Suitable formulations compressed via direct compression method at two different pressure levels. Compressed tablets were tested physically and chemically. The results thus obtained were evaluated in the Artificial Neural Network and Gene Expression Programming modules.

Purpose: To investigate the impact of critical quality attributes (CQAs) and critical process parameters (CPPs) on quality target product profile (QTPP) attributes of orally disintegrating tablet (ODT) containing ondansetron (OND) using two artificial neural network (ANN) programs. Methods: Different amounts of two different commercial superdisintegrants commonly used in ODT formulations (Ludiflash® and Parteck®) were examined as CQAs, while three different tablet-pressing forces were evaluated as CPPs for an orally disintegrating tablet (ODT) formulation. The impact of CQAs, and CPPs on the target product profile (tablet hardness, friability and disintegration time) were analysed using gene expression programming (GEP) and neuro-fuzzy logic (NFL) models. Results: NFL model defined the relations between CQAs, CPPs and QTPP, while GEP model favoured the use of an ODT formulation with suitable QTPP features which contained 4 mg ondansetron, 21.30 mg Parteck®, and 119 mg Avicel, fabricated with a compression force of 515 psi. In this regard, the tablet formulation demonstrated the required specifications. Conclusion: ANN programs are a useful tool for research and development (R&D) studies in the pharmaceutical industry and the use of ANNs can be beneficial in terms of raw materials, time and cost, as demonstrated for ondansetron ODT tablets.

The publication of the International Conference of Harmonization (ICH) Q8, Q9, and Q10 guidelines paved the way for the standardization of quality after the Food and Drug Administration issued current Good Manufacturing Practices guidelines in 2003. "Quality by Design", mentioned in the ICH Q8 guideline, offers a better scientific understanding of critical process and product qualities using knowledge obtained during the life cycle of a product. In this scope, the "knowledge space" is a summary of all process knowledge obtained during product development, and the "design space" is the area in which a product can be manufactured within acceptable limits. To create the spaces, artificial neural networks (ANNs) can be used to emphasize the multidimensional interactions of input variables and to closely bind these variables to a design space. This helps guide the experimental design process to include interactions among the input variables, along with modeling and optimization of pharmaceutical formulations. The objective of this study was to develop an integrated multivariate approach to obtain a quality product based on an understanding of the cause-effect relationships between formulation ingredients and product properties with ANNs and genetic programming on the ramipril tablets prepared by the direct compression method. In this study, the data are generated through the systematic application of the design of experiments (DoE) principles and optimization studies using artificial neural networks and neurofuzzy logic programs.

Background: Respiratory syncytial virus (RSV) is a major cause of severe acute lower respiratory tract infections in infants and there is no vaccine available. In early life, the most important contributors to protection against infectious diseases are the innate immune system and maternal antibodies. However, the mechanisms by which antibodies can protect against severe RSV disease are incompletely understood, as both antibody levels and neutralization capacity correlate poorly with protection. Methods: We performed an observational case-control study including infants hospitalized for RSV infection (n=43), hernia surgery (n=16), or RSV-negative viral respiratory tract infections (n=18). First, we determined RSV antigen-specific antibody levels in infant plasma using a multiplex immunoassay. Subsequently, we measured the capacity of these antibodies to activate natural killer (NK) cells. Finally, we assessed Fc-glycosylation of the RSV-specific antibodies by mass spectrometry. Resu...

A novel Quality by Design methodology was used to develop and validate a rapid, accurate, precise, simple, efficient and reproducible isocratic Reversed Phase-High Performance Liquid Chromatographic (RP-HPLC) method for the estimation of Luliconazole in bulk and pharmaceutical dosage form. Luliconazole was separated using Kromasil C18 column (250mm×4.6 mm, 5µm particle size), Shimadzu LC2030 HPLC system having UV detector and the mobile phase contained a mixture of 0.01M Ammonium acetate buffer and Acetonitrile (35:65). The flow rate was set to 1.2 ml/min with the responses measured at 294nm. The retention time of Luliconazole was found to be 3.092 min. Central composite design employed for design of experiment and optimization. Desirability value was found to be 0.723 and overall model was found to significant. Linearity was established for Luliconazole in the range of 20-120 µg/ml with correlation coefficient (r2=0.9995). Limit of detection (LOD) and limit of quantitation (LOQ) were evaluated and found to be 1.1700 and 3.5455 respectively. The accuracy values were found to be in the range of 98 -102% and every parameter found with in limit. Validation parameters were evaluated for the method according to the International Conference on Harmonization (ICH) Q2 R1 guidelines. This method can be used for the estimation and analysis of Luliconazole drug in active pharmaceutical ingredients and pharmaceuticals.

A simple, rapid and accurate RP-HPLC method was developed for the determination of levosalbutamol in pure and tablet dosage form by RP-HPLC method using C 18 BDS column (Phenomenex, 250 x 4.6 mm, 5 μm) in isocratic mode. The mobile phase consisted of Acetonitrile and buffer in the ratio of 20:80 (v/v) was used and maintain the pH 3. The flow rate was maintained at 1 mL/min and the injection volume was 20 μL . Detection wavelength with UV detector at 276 nm and run time was kept 10 min. The retention time of levosalbutamol was 5.4 min. The method was linear over the concentration range 7-12 μg/ml. The recovery was found to be 100.44± 0.27%. The validation of method was carried out utilizing ICH-guidelines. The described HPLC method was successfully employed for the analysis of pharmaceutical formulations.

Acne vulgaris is a common inflammatory skin disorder. It affects the pilosebaceous units followed by an overgrowth by Propionibacterium acne bacteria. Dapsone is a sulfone antibiotic with an antiinflammatory effect, which is considered to be accountable for its effectiveness in the treatment of acne vulgaris. The present study aims to prepare and evaluate the effectiveness of dapsone niosomes for topical application with an objective to control and prolong the release of the drug with improved skin penetration as a novel formulation for healing of mild to moderate acne vulgaris. Niosomes were formulated by thin film hydration method using different ratios of surfactants (various spans 20, 40, 60 and 80) and cholesterol and were investigated with respect to its shape, size, entrapment efficiency, Fourier transform infrared spectroscopy (FTIR) and in vitro release. Fifteen patients with mild to moderate acne vulgaris were selected and treated with dapsone niosomes as a single topical treatment for their acne lesions. Clinical assessment was done before and after 2 and 8 weeks of treatment. Niosomes containing span 60 showed a higher percentage of drug release after 24 h and greater entrapment efficiency as compared to other formulations. The clinical improvement was noticeable after 2 weeks of treatment with highly significant improvement of acne lesions after 8 weeks of treatment (P < 0.001). Dapsone niosomes is a promising topical formulation for safe, tolerable and effective drug delivery system with minimal side effects apart from mild erythema and postinflammatory hyperpigmentation.

On the cutting edge of freeze-drying processes / Barresi, A. A.; Fissore, D.; Pisano, R.; Oddone, I.; Capozzi, L.; Colucci, D.; Mussini, P.; Demichela, M.. ELETTRONICO. (2016), p. paper 137. ((Intervento presentato al convegno Convegno GRICU 2016: &quot;Gli Orizzonti 2020 dell’Ingegneria Chimica&quot; tenutosi a Anacapri (ITA) nel 12-14 Settembre 2014. Original On the cutting edge of freeze-drying processes

Liquid formulations are mostly used in the paediatric population. However, with certain active pharmaceutical ingredients (APIs), it is very difficult to guarantee quality and stability; this is the case, for example, with omeprazole. Omeprazole is used as a model drug due to the lack of a paediatric formulation meeting gastro-resistance requirements, which remains a challenge today. In this experimental study, the development of enteric polymer-coated pellets is proposed. It is proposed to use aqueous coating dispersions without the use of organic solvents, which are commonly used in fluidised bed coatings. To do this, the design of experiments method is used as a statistical tool for experiment creation and the subsequent analysis of the responses. In particular, this study uses a randomised full factorial design. The mean weight increases of the protective layer and the enteric coating are chosen as factors. Each factor is assigned two levels. Therefore, the design of the used ex...

QbD (Quality by Design) is the recent systematic, scientific, risk-based, holistic, proactive approach & regulatory requirement for designing and developing the product and the manufacturing process to achieve the predefined product quality objectives and to reduce rejection or reprocessing of the batch, with increased cost and regulatory burden. New Castle Disease is one of the most common causing factors which can affect the high demand of the poultry eggs and meats. Although vaccines are commercially available to have protection against the New Castle Disease infection in poultry, there is need for the sero monitoring and quick detection of the developed antibody in the poultry. QbD concept is to be adopted for the development and manufacturing of the New Castle Disease (NDV) antibody detection test kit to have the detection kit with identified and required target profile. The results of the adaptation is to be evaluated on the products manufactured after the QbD concept is built...

Stability of eberconazole nitrate (EBZ) was investigated using a stability indicating HPLC method. Quality by Design (QbD) approach was used to facilitate method development. EBZ was exposed to different stress conditions, including hydrolytic (acid, base, neutral), oxidative, thermal and photolytic. Relevant degradation was found to take place in all the conditions. The degradation of EBZ followed (pseudo) first-order kinetics under experimental conditions. The kinetic parameters (rate constant, t 1/2 , and t 90 ) of the degradation of EBZ were calculated.

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patientfocused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increasing the detectability of CQA failures.

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increas...

Artificial intelligence (AI) has emerged as a powerful tool that harnesses anthropomorphic knowledge and provides
expedited solutions to complex challenges. Remarkable advancements in AI technology and machine learning
present a transformative opportunity in the drug discovery, formulation, and testing of pharmaceutical dosage
forms. By utilizing AI algorithms that analyze extensive biological data, including genomics and proteomics,
researchers can identify disease associated targets and predict their interactions with potential drug candidates. This
enables a more efficient and targeted approach to drug discovery, thereby increasing the likelihood of successful
drug approvals. Furthermore, AI can contribute to reducing development costs by optimizing research and
development processes. This comprehensive review explores the wide-ranging applications of AI in drug
discovery, drug delivery dosage form designs, process optimization, testing, and
pharmacokinetics/pharmacodynamics (PK/PD) studies. This review provides an overview of various AI-based
approaches utilized in pharmaceutical technology, highlighting their benefits and drawbacks. Nevertheless, the
continued investment in and exploration of AI in the pharmaceutical industry offer exciting prospects for
enhancing drug development processes and patient care.

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Artificial intelligence (AI) has emerged as a powerful tool that harnesses anthropomorphic knowledge and provides
expedited solutions to complex challenges. Remarkable advancements in AI technology and machine learning
present a transformative opportunity in the drug discovery, formulation, and testing of pharmaceutical dosage
forms. By utilizing AI algorithms that analyze extensive biological data, including genomics and proteomics,
researchers can identify disease associated targets and predict their interactions with potential drug candidates. This
enables a more efficient and targeted approach to drug discovery, thereby increasing the likelihood of successful
drug approvals. Furthermore, AI can contribute to reducing development costs by optimizing research and
development processes. This comprehensive review explores the wide-ranging applications of AI in drug
discovery, drug delivery dosage form designs, process optimization, testing, and
pharmacokinetics/pharmacodynamics (PK/PD) studies. This review provides an overview of various AI-based
approaches utilized in pharmaceutical technology, highlighting their benefits and drawbacks. Nevertheless, the
continued investment in and exploration of AI in the pharmaceutical industry offer exciting prospects for
enhancing drug development processes and patient care.

The top objective of any pharmaceutical industry is to produce products of necessary characteristic and quality reliably, in a cost-effective manner. Development of a method is essential for discovery, development, and evaluation of medicines in the pharmaceutical formulation. The main aim of this review article was to check the development and validation of the procedure employed for the medication from the starting of the formulation to the complete commercial batch of product. At the point when an analytical technique is applied to produce outcomes for the quality of medicine associated samples, it is necessary that the outcomes are reliable. In the pharma industry, validation policy is documented for how to perform validation, types of validation and validation policy are complied with the necessities of good manufacturing practice (GMP) regulations. Validation is very important for the effective running of the pharmaceutical firms. At every stage from raw material to the finish...

The goal of PAT (Process Analytical Technology) is to build quality into products through better understanding and control of manufacturing processes, rather than merely testing the quality of the end product. Pharmaceutical manufacturers are trying to develop and implement new technologies in pharmaceutical production and quality control for real-time measurements of critical product and process parameters. Characterization of manufacturing process through experimental design, for evaluation of the effect of product and process variables, represents an integral part of the PAT framework. However, the publications regarding real PAT application to pharmaceutical process are very limited and the technologies are confidential as well. In this review, the case studies related to PAT are shown with real applications from a pharmaceutical company. Additionally, various applications of PAT on the developing stage are introduced with high analytical technologies for the improvement of quality control on manufacturing process.

Analytical method validation is critical for reliability and accuracy in pharmaceutical chemistry laboratories. Ensuring that analytical methods consistently produce valid results is vital for drug development, quality control, and regulatory compliance. This article presents a critical review and thematic synthesis of recent studies on analytical method validation, focusing on parameters such as accuracy, precision, specificity, linearity, and robustness. Drawing on peer-reviewed articles published over the past decade, this review categorizes validation approaches and statistical tools employed in different pharmaceutical laboratory settings. Inclusion criteria were based on relevance to pharmaceutical analysis, use of validated protocols (e.g., ICH Q2(R1)), and publication within the past 10 years. Key findings reveal a convergence in method validation practices across laboratories worldwide, but also highlight persistent challenges such as matrix effects, instrument sensitivity, and a lack of harmonized protocols in emerging regions. This article further analyzes methodological gaps and proposes a thematic framework for validating methods with increased reproducibility and regulatory alignment. The synthesis seeks to support both educational and professional laboratories in adopting rigorous validation standards. Ultimately, this article contributes to the scholarly debate by connecting practical laboratory applications with theoretical validation models and encourages future studies to focus on cost-effective and sustainable validation practices.

The top objective of any pharmaceutical industry is to produce products of necessary characteristic and quality reliably, in a cost-effective manner. Development of a method is essential for discovery, development, and evaluation of medicines in the pharmaceutical formulation. The main aim of this review article was to check the development and validation of the procedure employed for the medication from the starting of the formulation to the complete commercial batch of product. At the point when an analytical technique is applied to produce outcomes for the quality of medicine associated samples, it is necessary that the outcomes are reliable. In the pharma industry, validation policy is documented for how to perform validation, types of validation and validation policy are complied with the necessities of good manufacturing practice (GMP) regulations. Validation is very important for the effective running of the pharmaceutical firms. At every stage from raw material to the finish...

Osteomyelitis continues to be a major concern when orthopedic surgery is performed. Orthopedic infections have an incidence of 5% to 10% but their management proves to be quite difficult due to both biofilm formation and limited access of the drug to the infected area when systemic treatment is employed. The aim of the study was to optimize the synthesis process of a gentamicin loaded poly(-lactic-co-glycolic) acid (PLGA) based biodegradable composite by varying parameters that affect both efficiency encapsulation and nanoparticle size. Furthermore, a kinetic study was conducted to study the biodegradation process of the polymer. Gentamicin loaded PLGA nanoparticles were obtained using the double emulsion technique which allows the variation of several factors such as gentamycin concentration, PLGA concentration, buffer concentration and stirring speed. Out of the four factors evaluated, gentamicin concentration had the highest impact on both encapsulation efficiency and nanoparticl...

The use of biotech medicines is increasing, with consequent mounting expenses for National Health Systems (NHSs). Biosimilars should be considered an opportunity to improve access to care. On the other side, the general public might suspect to receive low-quality medicines to save money. Actually, no drugs with a lesser degree of pharmaceutical quality with respect to existing alternatives can be authorized on the ground of a lower price. Biosimilars can be authorized only if their quality is of the same level as that of the originator. There is no chemical identity between biosimilars and the originators: any differences in quality attributes must be justified and shown not to impact on the safety and efficacy of the biosimilar by scientific investigations including pre-approval nonclinical and/or clinical studies. The biosimilar safety profile may be different from the originator or change over time for the same product. Hence caveats limiting the widespread use of biosimilars yet exist and should be solved by education on the main biological issues of biotech medicines, and on continuous update of the rules set up by the Regulatory Authorities to assess biosimilarity and to monitor post-approval safety.

A robust and simplified high-performance liquid chromatography (HPLC) method was developed for the estimation of Pyrazinamide and its related substance. A systematic approach, one of the parts of QbD (quality by design) was used in suitable analytical method development. The HPLC segregation method was carried out with C-18 Column (3.9x300 mm, I. D. 10 µm), a mobile phase of phosphate buffer: acetonitrile (pH 3.0) 90:10 v/v, detected at 270 nm. Optimization to this method was done by response surface methodology by applying a three-level Box Behnken design with three center points.

A rapid and sensitive reverse phase HPLC method is depicted for the qualitative and quantitative assay of Terbinafine hydrochloride in pharmaceutical dosage form. Terbinafine hydrochloride was chromatographed on a reverse phase C18 column with a mobile phase consisting of methanol: water in the ratio of 80:20% v/v. The mobile phase was pumped at a flow rate of 1ml/min. The detection is carried out at 282 nm. The retenti on time of the drug was 5.84 min. The linearity curved showed a correlation coefficient (r 2 ) of 0.9974 with concentration range of 80-160 �g/ml. The method was validated with respect to line arity, precision, accuracy and Sensivity (LOQ and LOD).

Immune adjuvants are important components of current and prospective cancer vaccines. In this study, we aimed at evaluating the use of a synthetic lipid A derivative, pentaerythritol lipid A (PET lipid A), loaded into poly(lactic-co-glycolic acid) particles, as a potential cancer vaccine adjuvant. Poly(lactic-coglycolic acid) particles (size range: 250-600 nm) were successfully formulated to include PET lipid A and/ or the model tumor antigen, chicken ovalbumin (OVA). It was shown that particulated PET lipid A had a distinct advantage at promoting secretion of the immune potentiating cytokine, IL-12p70, and upregulating key costimulatory surface proteins, CD86 and CD40 in murine dendritic cells in vitro. In a murine tumor model, involving prophylactic vaccination with various permutations of soluble versus particulated formulations of OVA with or without PET lipid A, modest benefit was observed in terms of OVA-specific cell-mediated immune responses when PET lipid A was delivered in particles. These findings translated into a corresponding trend toward increased survival of mice challenged with OVAexpressing tumor cells (E.G7). In terms of translation of safe adjuvants into the clinic, these results promote the concept of delivering toll-like receptor-4 agonists in particles because doing so improves their adjuvant properties, while decreasing the chances of adverse effects due to off-target uptake by nonphagocytic cells.

A rapid and sensitive RP-HPLC method with UV detection (242 nm) for routine analysis of famciclovir in pharmaceutical formulations was developed. Chromatography was performed with mobile phase containing a mixture of methanol and phosphate buffer (50:50, v/v) with flow rate 1.0 mL min -1 . Quantitation was accomplished with internal standard method. The procedure was validated for linearity (correlation coefficient =0.9999), accuracy, robustness and intermediate precision. Experimental design was used for validation of robustness and intermediate precision. To test robustness, three factors were considered; percentage v/v of methanol in mobile phase, flow rate and pH; flow rate, the percentage of organic modifier and pH have considerable important effect on the response. For intermediate precision measure the variables considered were: analyst, equipment and number of days. The RSD value (0.86%, n=24) indicated an acceptable precision of the analytical method. The proposed method was simple, sensitive, precise, accurate and quick and useful for routine quality control.

The problem of process design for the freeze-drying of pharmaceutical products is here addressed. A comparative analysis between the various optimization tools so far proposed is given. The above analysis aims to give some guidelines to lyophilization professionals in the choice of the best design strategy compatible with their objectives and the technology available. In particular, this study examines the strengths and weaknesses of design space and of the different model-based control techniques so far proposed with a view to a better understanding of factors which still limits the use of these techniques at the manufacturing scale. With this regard, the above methods are compared in terms of robustness and scalability of the recipe, number and type of input parameters, management of product and equipment constraints, as well as batch unevenness. The first part of the study is carried out by means of mathematical simulations, as this approach makes it possible to better investigate the controller performance eliminating the uncertainty due to the experiment reproducibility. This study shows that although design space can provide a detailed view of the impact of processing conditions on product quality, its use for recipe development cannot lead to a real process optimization. By contrast, this objective can be achieved if model-based control is used. Experiments obtained for mannitol and sucrose-based formulations confirmed this result.

This paper is focused on the secondary drying step of a freeze-drying process, where the bound water is desorbed from the (partially) dried product, with the goal to achieve the target value of residual moisture in the final product. Mathematical modeling is used to get a deep understanding of the process, i.e. to study the effect of the operating variables (mainly the temperature of the heating shelf and the duration of the operation) on the state of the product (temperature and residual moisture). An innovative tool is used to provide an effective support to get quality by design: it is based on the measurement of the desorption rate, through the test of pressure rise, and on a mathematical model of the process. It allows to monitor in-line the process, as well as to determine the kinetic parameters of water desorption, and their dependence on the operating conditions. The mathematical model of the process is used to build the design space of the secondary drying process, i.e. to identify those operating conditions that allow to fulfill product quality requirements, and then to minimize the duration of the secondary drying. The case study used to test the proposed methodology is the drying of 5% w/w aqueous solutions of sucrose: a linear dependence of the desorption rate on the residual moisture is evidenced by the experimental investigation, and the Arrhenius equation appears to adequately describe the dependence of the kinetic constant on the temperature, with a frequency factor equal to 277 s -1 , and an activation energy equal to 37,714 J mol -1 . The model is then used to calculate the design space, as well as to optimize the operating conditions: in case the target value of residual moisture is 2% the duration of secondary drying can be decreased from 16 h in case of constant shelf temperature to 7.35 h in case the recipe is optimized.

Arrhythmia follows chronobiology, thus necessitating the development of a time-dependent formulation for its treatment. The aim of the current work was to develop a solubility-enhanced chronotherapeutic system of felodipine, a widely prescribed antiarrhythmic. Systematically optimize hot-melt extrusion process was employed to formulate solubility-enhanced extrudates. The film casting method was adopted for the selection of polymers. Drug released at 5, 15, 30min was taken as response variables in 3 2 face-centered cube design. Nearly 10-fold increase was observed in the solubility of the optimized extrudates in comparison to pure drug. Physical characterization of the extrudates depicted complete amorphization of the drug. The sequential coating was performed onto the extrudates to enable a time-dependent release. In-vitro studies clearly demonstrated that 25% of the drug was available rapidly within 10 min of administration. The remaining 75% of the drug was available over a period of 4, 8 and 12h. Stability studies performed for 6 months at accelerated conditions depicted no significant change in the physicochemical characteristics of the optimized formulation. In-vivo pharmacokinetic studies conducted in beagle dogs ratified the results of in-vitro studies where a sequential time-dependent absorption of felodipine was observed over a period of 12h. Concisely, the studies demonstrated successful development of a solubility-enhanced chronotherapeutic system of felodipine.

The present research work was aimed to develop a validated UPLC method for simultaneous quantification of Ombitasvir, Paritaprevir and Ritonavir in bulk and pharmaceutical dosage forms. The analytes were successfully separated within 3 mins on waters SB C8 column using pH 4.0 phosphate buffer and acetonitrile in the ratio of 50:50v/v as mobile phase at a flow rate of 0.5ml/min with an injection volume of 0.5µl. The eluted analytes at 0.908, 1.190 and 1.739 min were detected at 250nm by PDA detector. The developed method was validated in compliance with ICH guidelines. The analytes under study obeyed beers law in the concentration range of 3.125-18.75µg/ml, 18.75-112.5µg/ml and 12.5-75µg/ml for Ombitasvir, Paritaprevir and Ritonavir respectively. The percentage recovery of analytes was found to be within 99-101% for the three analytes. The percentage RSD values of precision and robustness were within acceptable limits. The analytes were subjected to various stress conditions such as hydrolysis by acid, alkali and water, oxidation by hydrogen peroxide, exposure to High temperature and UV light, which enables analytes to degrade under these conditions. The proposed method was successful in separating and quantifying the compounds in the presence of degradants. Thus a specific, accurate and robust stability indicating method has been developed for simultaneous quantification of Ombitasvir, Paritaprevir and Ritonavir in their combined dosage form.

A simple, accurate, precise and sensitive UV-Vis method has been developed for simultaneous estimation of Saxagliptin HCL and Metformin HCL in active pharmaceutical ingredient form by using quality by design (QbD) approach. A UV spectroscopic method was validated in terms of input variable effects on characteristics of UV spectrum were selected for critical parameters selection and parameters like linearity, accuracy, precision, robustness, ruggedness. The ICH guidelines Q8 to Q11 have discussed QbD implementation in API synthetic process and formulation development. Analytical QbD key tools are identification of critical quality attributes (CQA) with risk assessment, control strategy and Risk assessment, Analytical QbD method validation, continuous method monitoring (CMM) and continual improvement. The wavelength of 204.5nm and 232.5 nm are selected as absorbance maxima for Saxagliptin HCL and Metformin HCL respectively.