Critical Material Attributes Research Articles

Event‐triggered data‐ and knowledge‐driven adaptive quality iterative learning control with uncertainty for a pharmaceutical cyber‐physical system

AbstractIn the context of Pharma 4.0, a cyber‐physical systems (CPSs)‐based pharmaceutical quality control (PQC) mode holds a critical position in ensuring the quality of drug products. This paper is concerned with a PQC problem with uncertainty embodied in ever‐changing critical material attributes, which present new challenges related to costs and efficiency during pharmaceutical development. So, an event‐triggered data‐ and knowledge‐driven adaptive PQC framework is proposed. First, a data‐ and knowledge‐driven adaptive iterative learning control‐based PQC scheme is developed with the assistance of process knowledge that also contains much additional information reflecting the laws and trends governing process operations. Second, an event‐triggering condition suitable for the PQC tasks is designed and embedded in the controller design to reduce some unnecessary computing and communication loads. Furthermore, the integration of process data and knowledge is used for the adaptive adjustment of control parameters and the determination of initial control directions. Finally, several data experiments illustrate the effectiveness of the proposed methods.

Quality by Design (QbD) Approach for a Nanoparticulate Imiquimod Formulation as an Investigational Medicinal Product

The present article exemplifies the application of the concept of quality by design (QbD) for the systematic development of a nanoparticulate imiquimod (IMQ) emulsion gel formulation as an investigational medicinal product (IMP) for evaluation in an academic phase-I/II clinical trial for the treatment of actinic keratosis (AK) against the comparator Aldara (EudraCT: 2015-002203-28). The design of the QbD elements of a quality target product profile (QTPP) enables the identification of the critical quality attributes (CQAs) of the drug product as the content of IMQ, the particle-size distribution, the pH, the rheological properties, the permeation rate and the chemical, physical and microbiological stability. Critical material attributes (CMAs) and critical process parameters (CPPs) are identified by using a risk-based approach in an Ishikawa diagram and in a risk-estimation matrix. In this study, the identified CPPs of the wet media ball-milling process's milling time and milling speed are evaluated in a central composite design of experiments (DoEs) approach, revealing criticality for both factors for the resulting mean particle size, while only the milling time is significantly affecting the polydispersity. To achieve a mean particle size in the range of 300-400 nm with a minimal PdI, the optimal process conditions are found to be 650 rpm for 135 min. Validating the model reveals a good correlation between the predicted and observed values. Adequate control strategies were implemented for intermediate products as in-process controls (IPCs) and quality control (QC) tests of the identified CQAs. The IPC and QC data from 13 "IMI-Gel" batches manufactured in adherence to good manufacturing practice (GMP) reveal consistent quality with minimal batch-to-batch variability.

Formulation development, optimization, and characterization of anti-fungal topical biopolymeric film using a niosomal approach

Background: Griseofulvin is an antifungal drug that is currently available in the market only in oral dosage forms. So, the development of topical treatment could be advantageous for the treatment of superficial fungal infections. Though for superficial fungal treatment, the skin acts as a major target as well as a principal barrier for drug delivery. To overcome this the colloidal carrier system niosome was used. Niosomes being in the nanometer size range would allow the delivery of the drug at the desired site. Niosomes being non-ionic surfactant-based vehicles would facilitate the passage of the drugs through as skin is composed of both lipid and aqua, which would create problems for any other delivery system. Methodology: Griseofulvin belonging to the BCS Class II was formulated in the form of niosomes to enhance the drug’s solubility. In this study, optimization of niosomal formulation was done using OVAT (one variable at a time) method. Here, the CMAs (critical material attributes) such as surfactant type, conc. of charge inducer and the ratio of surfactant: cholesterol and CPPs (critical processing parameters) such as rotational speed of evaporator flask, external phase temperature, hydration time, and external phase volume (both aqueous and organic), which are independent variables influencing factors at different levels. These are said to have a potential risk on the CQAs (critical quality attributes), which are dependent variables, such as vesicle size, vesicle shape, vesicle lamellarity, niosome aggregation, and drug entrapment efficiency, for the final selection of improved optimum batch. The films were prepared from the incorporation of griseofulvin-loaded optimized niosomes in chitosan film for topical drug delivery in superficial fungal infections. Characterization: The films properties were characterized by physical appearance, film thickness, weight variation, folding endurance, tensile strength, moisture, uptake, moisture content, drug content uniformity, In-vitro drug diffusion studies, ex-vivo studies, and antifungal efficacy against Candida albicans sp. Result and Discussion: Thus, chitosan film formulation integrating griseofulvin-loaded niosomes for topical delivery enhanced the solubility of the drug and avoided the side effects associated with the orally-administered marketed formulation. Conclusion: Biopolymer chitosan exhibited antifungal activity implying enhanced drug efficacy. Therefore, two concepts of using optimized vesicular carrier systems and biopolymeric films have been combined and this topical novel composite film having the potential for griseofulvin delivery to superficial fungal infections has been formulated.

Quality risk assessment and DoE – Practiced validated stability-indicating chromatographic method for quantification of Rivaroxaban in bulk and tablet dosage form

AbstractA systematic DoE and Analytical Quality by Design (AQbD) approach was utilized for the development and validation of a novel stability indicating high-performance thin–layer chromatographic (HPTLC) method for Rivaroxaban (RBN) estimation in bulk and marketed formulation. A D-optimal design was used to screen the effect of solvents, volume of solvents, time from spotting to development and time for development to scanning. ANOVA results and Pareto chart revealed that toluene, methanol, water and saturation time had an impact on retention time. The critical method and material attributes were further screened by Box-Behnken design (BBD) to achieve optimal chromatographic condition. A stress degradation study was carried out and structure of major alkaline degradant was elaborated. According to the design space, a control strategy was used with toluene: methanol: water (6:2:2) and the saturation time was 15 min. A retention factor (RF) of 0.59 ± 0.05 was achieved for RBN using chromatographic plate precoated with silica gel at detection wavelength 282 nm with optimized conditions. The linear calibration curve was achieved in the concentration range of 200–1,200 ng/band with r2 > 0.998 suggesting good coordination between analyte concentration and peak areas. The quadratic model was demonstrated as the best fit model and no interaction was noted between CMAs. The optimized HPTLC method was validated critically as stated in International Conference on Harmonization (ICH) Q2 (R1) guideline and implemented successfully for stress degradation study of RBN. The developed HPTLC method obtained through AQbD application was potentially able to resolve all degradants of RBN achieved through forced degradation study. The obtained results demonstrate that a scientific AQbD approach implementation in HPTLC method development and stress degradation study drastically minimizes the number of trials in experiments, ultimately time and cost of analysis could be minimized.

Application of Quality-by-Design Approach to Justify the Composition and Technology of Two-component Suppositories

Introduction. One of the modern remedies used to treat vaginal infections are suppositories "Depantol", which have an antiseptic, regenerating effect due to the combination of chlorhexidine and dexpanthenol. The initial stage in the life cycle of any medicinal product (MP) is pharmaceutical development, a systematic approach to which implies the principle of Quality-by-Design (QbD), which is based on obtaining reliable scientific data and risk management for quality. With this approach, pharmaceutical development begins with a preliminary determination of significant factors in the creation of a drug.Aim. Aim of study was to design Quality Target Product Profile, Critical Quality Attributes, Critical Material Attributes – the initial data necessary for the development of composition and technology of a generic drug in accordance with the QbD methodology of ICH Guidance Q8 "Pharmaceutical Development".Materials and methods. Objects of study: chlorhexidine bigluconate, dexpanthenol, PEG-400 and PEG-1500, pharmaceutical development documents. Methods of study: content analysis, system analysis; FMECA method (Failure Modes, Effects and Criticality Analysis).Results and discussion. In order to implement the QbD for the production of a drug of good quality, initial data for the development of the composition and technology of two-component suppositories were obtained. Quality Target Product Profile (QTPP) was compiled taking into account the data of the original drug was used as reference. Based on the compiled QTPP, Critical Quality Attributes (CQAs) were identified. The determination of CQAs from QTPP parameters was based on the strength of the potential harm to the product. Due to the fact that we developed a well-known dosage form, quality indicators were chosen that are standard for hydrophilic suppositories. In order to determine the parameters of the drug components that affect the Critical Quality Attributes, for each of the active pharmaceutical ingredients (APIs) suppositories contain, the Critical Material Attributes (CMAs) were determined. For example, for liquid ingredients, according to the specification of the substance manufacturer, these are pH, viscosity, impurities, identification, assay, refraction index. For the initial risk assessment, risk assessment matrices of the influence of the Сritical Material Attributes of the components on the Critical Quality Attributes were compiled. When evaluating the effect of chlorhexidine bigluconate on the critical characteristics of the final product, attention was paid to all parameters from the manufacturer's specification, since any deviations in pH, density, presence of related substances and extraneous impurities, assay and identification of the substance may signal the chemical unsuitability of the component. The weight uniformity of suppositories is affected only by the parameters of the technological process. The influence of CMAs of dexpanthenol on the Critical Quality Attributes of the finished product is generally similar to the influence of the parameters of chlorhexidine bigluconate. The difference in the influence of pH and water content on the microbial limits: unlike chlorhexidine bigluconate, which has antiseptic properties, dexpanthenol is more susceptible to microbial contamination. The effect of base CMAs on identification, content uniformity, and assay is not critical. Whereas the pH, assay and identification of PEG-400 and PEG-1500 have a significant impact on the dissolution profile of the active ingredients from the finished dosage form.Conclusion. The data required for the pharmaceutical development of a generic drug, two-component suppositories, was obtained: Quality Target Product Profile, Critical Quality Attributes, Critical Material Parameters. The impact of the critical characteristics of the raw materials on the critical quality attributes of the developed suppositories was assessed.

Ensuring Pharmaceutical Product Success through Excipient QbD Efforts

It isessential to understand excipients’ critical material attributes. A QbDstrategy that includes historical data analysis and experimental work has beenused in functional excipients such as Hypromellose (HPMC) to develop thisunderstanding. The use of multivariate analysis helped to identify excipientvariability and the support it could provide to improve the final product robustness.

Impact of Critical Material Attributes of HPMC on the Release of Gliclazide from Hydrophilic Matrix Tablets

The influence of HPMCviscosity and the degree of substitution hydroxypropyl level (DSHP) on therelease rate of gliclazide was examined. The increase in the HPMC viscosity ledto a significant decrease in the release rate. The second parameter, DSHP,showed a surprisingly high impact on the release rate with higher hydroxypropyllevels leading to a faster drug release. The results demonstrated the need forcontrol on both parameters for formulators of gliclazide tablets in order toensure a consistent drug release performance.

3D-Powder-Bed-Printed Pharmaceutical Drug Product Tablets for Use in Clinical Studies.

Printing of phase 1 and 2a clinical trial formulations represents an interesting industrial application of powder bed printing. Formulations for clinical trials are challenging because they should enable flexible changes in the strength of the dosage form by varying the active pharmaceutical ingredient (API) percentage and tablet mass. The aim of this study was to investigate how powder bed 3D printing can be used for development of flexible platforms for clinical trials, suitable for both hydrophilic and hydrophobic APIs, using only conventional tableting excipients. A series of pre-formulation and formulation studies were performed to develop two platform formulations for clinical trials using acetaminophen and diclofenac sodium as model compounds and lactose and starch as excipients. The results showed that the type of starch used as the formulation binder must be optimized based on the type of API. Moreover, powder blend flow and liquid penetration ability proved to be critical material attributes (CMAs) that need to be controlled, particularly at high drug loading. Optimization of these CMAs was performed by selecting the appropriate particle size of the API or by addition of silica. A critical process parameter that had to be controlled for production of tablets of good quality was the quantity of the printing ink. After optimization of both the formulation and process parameters, two platform formulations, that is, one for each API, were successfully developed. Within each platform, drug loading from 5 up to 50% w/w and tablet mass from 50 to 500 mg were achieved. All 3D-printed tablets could be produced at tensile strength above 0.2 MPa, and most tablets could enable immediate release (i.e., >80% w/w within 30 min).

Emerging Artificial Intelligence (AI) Technologies Used in the Development of Solid Dosage Forms.

Artificial Intelligence (AI)-based formulation development is a promising approach for facilitating the drug product development process. AI is a versatile tool that contains multiple algorithms that can be applied in various circumstances. Solid dosage forms, represented by tablets, capsules, powder, granules, etc., are among the most widely used administration methods. During the product development process, multiple factors including critical material attributes (CMAs) and processing parameters can affect product properties, such as dissolution rates, physical and chemical stabilities, particle size distribution, and the aerosol performance of the dry powder. However, the conventional trial-and-error approach for product development is inefficient, laborious, and time-consuming. AI has been recently recognized as an emerging and cutting-edge tool for pharmaceutical formulation development which has gained much attention. This review provides the following insights: (1) a general introduction of AI in the pharmaceutical sciences and principal guidance from the regulatory agencies, (2) approaches to generating a database for solid dosage formulations, (3) insight on data preparation and processing, (4) a brief introduction to and comparisons of AI algorithms, and (5) information on applications and case studies of AI as applied to solid dosage forms. In addition, the powerful technique known as deep learning-based image analytics will be discussed along with its pharmaceutical applications. By applying emerging AI technology, scientists and researchers can better understand and predict the properties of drug formulations to facilitate more efficient drug product development processes.

Consideration of quality by design principles in the use of sterilizing grade filters for clarification and final sterile filtration in adeno-associated virus applications

The development of gene therapy applications using recombinant adeno-associated viruses (AAV) as a gene delivery vector has gained significant momentum in recent years. Although there are numerous applications for potential therapies to treat unmet medical needs, the ability to implement robust AAV manufacturing processes continues to be a bottleneck to fully realizing the potential of AAV based therapeutics. This includes the requirement to understand the characteristics (quality attributes) that are critical to product quality and patient safety, and to define these in appropriate detail for regulatory submissions such as chemistry, manufacturing and controls (CMC) information. Sterilizing grade filtration plays an important role in AAV manufacturing, both for drug substance (DS) as well as final drug product (DP). However, to fulfill regulatory expectations for provision of CMC information, it is recommended that the principles of quality by design (QbD) are considered during the early product development stages of the AAV manufacturing process. Both prior knowledge and experimental data should be used to identify potential critical quality attributes (CQAs). Enhanced knowledge should result from increased experience, and ultimately the critical process parameters (CPPs) and critical material attributes (CMAs) that can impact the CQAs can then be defined. The objective is to define a manufacturing control strategy that includes appropriate control of CPPs and CMAs to assure the CQAs of the drug product. Here, the application of QbD principles for sterilizing grade filtration in both DS clarification and DP final fill steps of a typical AAV manufacturing process is described. Both experimental and data review approaches are included to help understand what a typical design space could look like, from which appropriate controls can be implemented. Ultimately, the expectations from regulatory agencies for assurance of product quality and patient safety are aligned with the requirement for a robust manufacturing control strategy to ensure consistent product quality is achieved.

Current Advances in Specialised Niosomal Drug Delivery: Manufacture, Characterization and Drug Delivery Applications.

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.

Real-time droplet size analysis using laser micrometer as a process analytical technology tool for continuous dripping process.

Process analysis and monitoring during the manufacturing of the dripping pills are essential. However, research on developing sensor‐based technology or process analytical technology (PAT) tools to analyze and monitor the dripping process is minimal. The purpose of this work is to develop a fast and non‐destructive laser detection system for quantitative visualization of droplets, which involves detecting the size of the droplet and calculating the weight of the dripping pills during the dripping process. Several factors influencing the detection performance of the detection system and the detection system capability for quantitation of the pill weight were explored. The laser detection system accurately detects the weight of the dripping pills with the coefficients of determination (R2) higher than 0.99. It was also robust concerning the variation in critical process parameters and critical material attributes. Furthermore, the laser detection system was successfully applied to the production line of Ginkgo biloba leaf dripping pills to monitor the dripping pills weight. The proposed laser detection system can analyze and monitor the dripping process in dripping pill manufacturing with stable performance, high accuracy, and high efficiency.

Control strategy definition for a drug product continuous wet granulation process: Industrial case study

This paper describes the specific control strategy of the commercial manufacturing process of an immediate release tablet formulation based on continuous twin-screw wet granulation. This control strategy has been defined by a multidisciplinary team using an enhanced approach, in alignment with the quality by design principles. During process development, experiments have been performed according to multivariate designs first to identify critical material attributes and critical process parameters and then, to define process conditions generating a product having the required quality. Hence, controls have been applied on critical quality attributes and on related critical process parameters and critical material attributes. Due to the specificity of the process that combines batch and continuous unit operations, a specific control strategy has been designed to ensure intermediate and end product quality. Therefore, controls including soft sensor model and in process controls have been developed to continuously monitor granules residual moisture content, assay and dissolution as granules and tablets critical attributes. In addition, process analytical technology implementation enabled increased process understanding and provided support for the development of the control strategy. This study is therefore considered as a real industrial case study of control strategy definition and implementation for an intended commercial continuous manufacturing process.

Systematic Formulation Approach for Development and Evaluation of Cefixime G ranules for Pediatric Application

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

Flowability of Crumbler Rotary Shear Size-Reduced Granular Biomass: An Experiment-Informed Modeling Study on the Angle of Repose

Biomass has potential as a carbon-neutral alternative to petroleum for chemical and energy products. However, complete replacement of fossil fuel is contingent upon efficient processes to eliminate undesirable characteristics of biomass, e.g., low bulk density, variability, and storage-induced quality problems. Mechanical size reduction via comminution is a processing operation to engineer favorable biomass flowability in handling. Crumbler rotary shear mill has been empirically demonstrated to produce more uniformly shaped particles with higher flowability than hammermilled biomass. This study combines modeling and experimentation to unveil fundamental understandings of the relation between granular particle characteristics and biomass flow behavior, which elucidate underlying mechanisms and guide selection of critical processing parameters. For this purpose, the impact of critical material attributes, including particle size (2–6 mm), particle shape (briquette, chip, clumped-sphere, cube, etc.), and surface roughness, on the angle of repose (AOR) of milled pine chips were investigated using discrete element method (DEM) simulations. Forest Concepts Crumbler rotary shear system is used to produce milled pine particles within the same size range considered in DEM simulations. AOR of different sets of these particles were measured experimentally to benchmark DEM results against experimental data. Specific energy consumption for the comminution of biomass with different particle size and moisture content are measured for technoeconomic analysis. Our results show that the smaller size (2 mm) of pine particle achieves better followability (i.e., smaller AOR) while the energy cost of comminution is significantly higher and bulk density is almost the same as the 6-mm pine particles. For the 2-mm particle size, Crumbles from veneer have better flow properties than Crumbles from chips. Contrarily, no significant difference was observed between the AOR of the two materials for the 6-mm particle size. Furthermore, from DEM simulations, mechanical interlocking between particles was found as a dominant factor in determining AOR of complex-shaped particles such as milled pine, which cannot be accurately captured by using simple particle shapes (e.g., mono-sphere) with a rolling resistance model. Conversely, clumped-sphere model alleviates this limitation without increasing computational cost significantly and can be used for accurate representation of biomass granular particles when simulating free-flow behavior.

Evaluation and Characterization of Stabilized Drug, Formulated as Oro Dispersible Tablet Using Advanced Method

In a challenge to prepare a stable Oro-dispersible tablet (ODT) of Desloratadine, using dry resin was incorporated into a fast-disintegrating matrix to prepare an optimized ODT that achieved the desired criteria of stabilization and patient acceptance. In this study, the critical process parameters (CPPs) and critical material attributes (CMAs) were determined via risk assessment methods within the framework of Quality by Design (QbD). The results showed that resin (Amberlite IRP64®) can be used as a dry stabilizer and the selected variables in the optimization phase have a strong influence on the blend flowability, disintegration time, and wetting time of the ODTs. Furthermore, by comparing the optimized formula with the marketed one, the optimized formula showed a significantly lower disintegration, lower wetting time, and an almost similar dissolution profile.

Impact of critical process parameters and critical material attributes on the critical quality attributes of liposomal formulations prepared using continuous processing

Liposomes were one of the earliest drug delivery vehicles used for anti-cancer therapeutics and similarly, lipid-based nanoparticles have been used for abundance of applications as gene therapies. The methods to produce these particles have remained relatively unchanged until the recent emergence of continuous manufacturing. Continuous processing enables accelerated development of nanoparticle formulations while providing a scalable manufacturing solution. For this work a continuous processing platform for the production of lipid and polymeric-based nanoparticle formulations has been developed at the University of Connecticut. This research focuses on the formation of liposomes encompassing multiple design of experiments (DoEs) to identify functional relationships between critical process parameters (CPPs), critical material attributes (CMAs), and critical quality attributes (CQAs) for liposomal formulations produced using this continuous processing platform. Liposomes of various sizes and of low polydispersity index (PDI) were produced with different material attributes under various processing conditions. In general, lower mole percentages of cholesterol produced larger particles whereas the mole percent of phosphatidylglycerol did not seem to have a s impact on the size of the liposomes that were produced. The results showed that similarly sized liposomes could be produced with different processing conditions allowing for the flexibility to operate in regions most suitable for formulation components that may be sensitive to certain processing conditions. For example, if the target size of a formulation is 100 nm but the active pharmaceutical ingredient is sensitive to temperature, then the formulation can be manufactured at high (55 °C) or low (30 °C) depending on its characteristics. Additionally, the relationships between CMAs and CPPs were different from conventional liposomal manufacturing methods, allowing for more flexibility when using a continuous processing system. Models that can effectively predict the hydrodynamic diameter of monodispersed liposomes produced using continuous processing were developed. The models developed from the DoEs in this study may be useful for accelerated development of new lipid formulations as well as facilitate the translation from traditional manufacturing methods to continuous manufacturing for products already on the market.

Optimization of the lyophilisation process for esomeprazole 40 mg powder for solution for injection/infusion using quality by design concept

The aim of this work was to apply the of Quality by Design concept in optimization of lyophilisation process in production of esomeprazole 40 mg powder for solution for injection/infusion. Optimization has been triggered by the product solution's sensitivity to oxygen, which leads to a fast decrease in pH value and limits allowable duration of air exposure. Lyophilizer capacity and number of ‘’good’’ vials of finished product are thereby significantly reduced, presenting serious obstacle for scale-up from 17,000 vials to 33,000 vials. With goal to maintain pH stable during production of an almost twice as big batch, a pre-freezing phase after filling, and before lyophilisation was introduced. Starting from the Quality Target Product Profile, Failure mode and effects analysis (FMEA) was applied for the purpose of defining Critical Process Parameters (CPPs), Critical Material Attributes (CMAs), Critical Quality Attributes (CQAs) and control strategy for the production. It was confirmed that temperature of shelfs of −30 °C, as opposed to 20 °C, significantly extends the time for which esomeprazole solution remains stable. Finally, an artificial neural network model was built and trained in order to define the design space for the lyophilisation process. It was demonstrated that the pH of esomeprazole solution remains stable and in specification within the lyophilizer's shelf temperature range of −10 °C to −30 °C for 5–26 h.

Investigation of the effect of polymers on dermal foam properties using the QbD approach

Dermal foams are promising drug delivery systems due to their many advantages and ease of application. Foams are also considered a novelty in the field of dermatology. In particular, they are beneficial for the treatment of skin conditions where patients have highly inflamed, swollen, infected and sensitive skin, as the application of the foam to the skin surface to be treated minimizes the need for skin contact. In order to formulate foams, it is necessary to know which material and process parameters influence the quality characteristics of foams and which methods can be used to study foams; this part of the research is assisted by the QbD approach. By using the QbD concept, it contributed during the development process to ensure quality-based development. With initial risk assessment, the critical material attributes (CMAs) and the critical process parameters (CPPs) were identified to ensure the required critical quality attributes (CQAs). During the initial risk assessment, five high-risk CQAs, namely foam volume stability, foam expansion, cross point, the initial values of the number and size of bubbles, and three medium-risk CQAs, namely spreadability, relative foam density and viscosity of the liquid system were identified and investigated. In this research, different types of polymers (xanthan gum, hydroxyethylcellulose, different types of hyaluronic acids) were used to improve the properties of foam formulations. The formulations containing xanthan gum and high molecular weight hyaluronic acid had good foam properties and will be appropriate delivery systems for an active pharmaceutical ingredient. Overall, the polymer content had a great effect on the properties of the foams. Different polymers affect the properties of foams in different ways. When used in combination, the methods reinforce each other and help to select a formula for dermal application.

QbD Consideration for Developing a Double-Layered Tablet into a Single-Layered Tablet with Telmisartan and Amlodipine.

The aim of this study was to develop a single-layered version of commercially available Twynstar® (Telmisartan + Amlodipine) double-layered tablets to improve the dosing convenience. A quality-by-design approach was applied to develop the single-layered version. To evaluate the range and cause of risks for a single-layered tablet in the formulation design research, we used the tools of the risk assessment, initial risk assessment of preliminary hazard analysis and main risk assessment of failure mode and effect analysis to determine the parameters affecting formulation, drug dissolution, and impurities. The critical material attributes were the stabilizer and disintegrant, and the critical process parameters were the wet granulation and tableting process. The optimal range of the design space was determined using the central composite design in the wet granulation and tablet compression processes. The stabilizer, kneading time, and disintegrant of the wet granulation were identified as X values affecting Y values. The compression force and turret speed in the tablet compression were identified as X values affecting Y values. After deciding on the design space with the deduced Y values, the single-layered tablets were formulated, and their dissolution patterns were compared with that of the double-layered tablet. The selected quality-by-design (QbD) approach single-layered tablet formulated using design space were found to be bioequivalent to the Twynstar® double-layered tablets. Hence, the development of single-layered tablets with two API using the QbD approach could improve the medication compliance of patients and could be used as a platform to overcome time-consuming and excessive costs and the technical and commercial limitations related to various multi-layered tablets.