Formulation and process optimisation of ethionamide 250 MGtablets using quality by design principles

The traditional approach of Quality by Testing (QbT) limits the assurance of product quality to in-process and post-production testing. To overcome these limitations, a more proactive and systematic means to product development and optimisation is required. Quality by Design (QbD) is an example of such an approach which focuses on understanding the product and its manufacturing process and emphasises that quality should be built into the product and not merely tested. The study aims to optimise ethionamide tablets, an immediate release oral solid dosage form using QbD

Understanding Pharmaceutical Quality by Design

This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review

A BRIEF REVIEW ON PROCESS ANALYTICAL TECHNOLOGY (PAT)

Process analytical technology (PAT) has been defined as a mechanism to design, analyze and control pharmaceutical manufacturing processes through measurement of critical process parameters which affect critical quality attributes. PAT checks the quality of raw material attributes both physically and chemically (i.e. at off-line, on-line, in-line). PAT involves a shift from testing the quality of building to the quality of products by testing at several intermediate steps. PAT saves a huge amount of time and money required for sampling and analysis of products. The main goal of PAT is to provide successful tools such as multivariate data analysis and acquisition tools, modern process analyzers or analytical chemistry, endpoint process monitoring, controlling tools and continuous improvement and knowledge improvement tools. In this review attempt has been carried out to explore the concept of PAT, different tools of PAT, goals of PAT, How it Works and Its benefits

Understanding the Impact of Solvents in Oral Solid Dosage Formulation and Process Development

The successful delivery of chemical compounds for the purpose of therapeutic treatments and prophylactics is a substantial undertaking in modern drug development. Notably, the adoption of high throughput screening techniques has led to the proliferation of poorly water soluble and/or highly potent molecules which further complicate development activities. Spray dried amorphous solid dispersions are an increasingly important formulation strategy to overcome solubility issues while wet granulation approaches are the method of choice for the preparation of highly potent APIs in oral solid dosage forms. A common connection between these critical techniques is their reliance on solvent-based processing that can often result in unexpected outcomes on product quality and performance. Solvent choice has been shown to influence API form, habit, stabilizing interactions, and physical and chemical properties of drug product intermediates, which requires greater understanding. The objective of this dissertation is to provide a general overview and assessment of the role of solvents in the important methods of spray dried dispersions (SDDs) and highly potent compounds by wet shear granulations (HP-WSG) to address concerns related to poorly soluble and/or highly potent APIs. Light scattering (LS) and dilute solution viscometry (DSV) techniques have been utilized to assess critical drug-polymer-solvent interactions in the solution state and explore the mechanisms by which solvent choice may influence SDD physical stability. Next, solid-state characterization techniques were leveraged to understand how the interplay between wet granulation processing parameters, API physical form, and environmental moisture may dictate chemical stability issues of a highly potent API. Conclusions and future work are presented with next steps that can be pursued in expanding our knowledge of complex multi-component solutions which are frequently encountered in pharmaceutical development

A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing

Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight about the advances in tablet excipients, manufacturing, analytical techniques and deployment of Quality by Design (QbD). Various excipients offering novel functionalities such as solubility enhancement, super-disintegration, taste masking and drug release modifications have been developed. Furthermore, co-processed multifunctional ready-to-use excipients, particularly for tablet dosage forms, have benefitted manufacturing with shorter processing times. Advances in granulation methods, including moist, thermal adhesion, steam, melt, freeze, foam, reverse wet and pneumatic dry granulation, have been proposed to improve product and process performance. Furthermore, methods for particle engineering including hot melt extrusion, extrusion-spheronization, injection molding, spray drying / congealing, co-precipitation and nanotechnology-based approaches have been employed to produce robust tablet formulations. A wide range of tableting technologies including rapidly disintegrating, matrix, tablet-in-tablet, tablet-in-capsule, multilayer tablets and multiparticulate systems have been developed to achieve customized formulation performance. In addition to conventional invasive characterization methods, novel techniques based on laser, tomography, fluorescence, spectroscopy and acoustic approaches have been developed to assess the physical-mechanical attributes of tablet formulations in a non- or minimally invasive manner. Conventional UV-Visible spectroscopy method has been improved (e.g., fiber-optic probes and UV imaging-based approaches) to efficiently record the dissolution profile of tablet formulations. Numerous modifications in tableting presses have also been made to aid machine product changeover, cleaning, and enhance efficiency and productivity. Various process analytical technologies have been employed to track the formulation properties and critical process parameters. These advances will contribute to a strategy for robust tablet dosage forms with excellent performance attributes

Determination of the effect of different blade speeds and mixing times on the homogeneity of mixtures containing different ratios of two powders

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Pharmaceutical Affairs Johannesburg, 2014Aim The first step in a wet granulation process is dry mixing. This step has the objective of ensuring that all the raw materials are mixed such that the end product is homogeneous. Dry mixing in a high shear mixer instead of a blender saves cost. However, the mixing parameters have not been well researched. Dry mixing parameters that are currently used, have been established through experience, trial and error and in-process testing. Alexander and Muzzio (2006) confirms this by stating that there are currently no mathematical techniques to predict blending behaviour of granular components without prior experimental work; therefore, blending studies start with a small-scale, try-itand- see approach. Even though they are referring to blending, the same is also true for dry mixing. Both processes are the mixing of powders. Therefore the aim of this research was to develop parameters for dry mixing, based on experimental work. Methods Using a Saral rapid mixer and wet granulator (Saral Engineering Company, India), experiments were performed according to a 24 two-level Plackett-Burman Design method, to determine the effects of different blades (mixer/impeller and chopper) speeds and mixing times on the homogeneity of the mixtures containing different ratios of two powders that have different densities and particle sizes. One of the powders mixed, was enalapril maleate. This was chosen as it can be assayed. Samples were taken from the bowl and tested for assay. The mix for a specific experiment is homogeneous if the results of all 7 assayed samples are within 10 % of the target % w/w value and the % Relative Standard Deviation (% RSD) of the 7 results is less than or equal to 5,0 %. The outcome was being measured in % RSD. A lower % RSD indicates a more homogeneous mix. The parameters developed, will be beneficial to pharmaceutical companies as it can assist them to improve accuracy, consistency and quality of granular mixes. The experimental method used can serve as an example for future experiments. Results The results indicated that impeller blade mixing speed and mixing time are the two factors that have the biggest impact on the homogeneity of a mix in a high shear mixer. Chopper blade speed was also found to be significant, but less than the above two parameters mentioned. Optimal parameters were predicted. Conclusion As there are many parameters to be controlled during dry mixing in a high shear mixer, a statistical design method is suitable to establish the parameters that would have the most impact on the end result. Statistically it was found that mixing speed of the main impeller and chopper blades and overall mixing time are the three factors that have the biggest impact on the homogeneity of a mixture. The mixing time and impeller blade speed have proven to be more significant than the chopper blade speed. Concentration was found to be insignificant. For our experiments and for the specific granulator used the following optimal parameters could be deduced: Impeller blade set at 191 rpm, chopper blade set at 2002 rpm and mixing time set at 3.01 minutes

Emerging trends in pharmaceutical manufacturing technology

Dissertação de mestrado em Biotecnologia Farmacêutica, apresentada à Faculdade de Farmácia da Universidade de CoimbraWith the extremely high average development costs of innovative medicines, the pharmaceutical industry faces unprecedented challenges and is under constant pressure to optimize the drug development process, as consequence of increased competition and healthcare costs. Rapid development of the emerging markets, progress in drug research, the rise in generics production, the availability of high-potency drugs and innovation in manufacturing process will sustainably modify the global pharmaceutical landscape. Thus, the global process of pharmaceutical innovation is not only focused on developing new drug entities but also in new manufacturing processes, that can optimize this stage of drug development, making it more efficient and cost-effective, responding to felt needs in the pharmaceutical sector. Improvements in process product development approaches and streamlining of manufacturing operations can have a profound impact on the bottomline. To keep pace with advances of new formulations and the increasing number of highly potent drugs, and so on, engineering expertise is required to design equipment that can manufacture, and package such medicines according to the required specifications while ensuring the safety of the workers. The aim of this study is to describe new manufacturing processes used in the pharmaceutical industry with particular interest in the following techniques: Fluidized Hot Melt Granulation, Hot Melt Extrusion, Spray Drying Technology, Liquid Dispensing Technology and DiffCORE Technology. For each one of these manufacturing techniques, a description of the state of the art is given and the pharmaceutical applications, the equipment, the excipients and the advantages and limitations are describe

Optimisation of a legacy product with a history of tablet friability failures utilising quality by design

The concept of Quality by Design (QbD) was introduced as a method of building quality into the product during the initial stages of manufacturing. This study explores the suitability of utilising QbD to optimise a legacy product. With the aid of QbD, a higher level of quality assurance and product knowledge was achieved. Sound scientific and risk-based decisions allowed for a robust manufacturing process with inherent operational quality and flexibility. By the establishment a quality target product profile (QTPP) and determining the influence of the critical processing parameters (CPP's) on the product's critical quality attributes (cQA's) the process understanding of Product X can be more accurately defined. The relationships between several explanatory variables will be explored by using a sequence of Design of Experiments (DoE) to obtain an optimal response. The DoE were performed and analysed using Minitab® statistical software version 17.0 (Minitab Inc., United Kingdom). A Response Surface Methodology (RSM) using a central composite experimental design (CCD) was utilised to capture the data. The data was analysed using the collection of statistical models (ANOVA) to analyse the differences between the means and their associated procedures. Input variables investigated were: compression machine tooling shape, hardness, and loss on drying LOD (post drying). The significant value (α) of 0.05 helped to determine if the null hypothesis would be accepted or rejected. The DoE identified the factors that had the highest risk of affecting the output variables and helped to establish the design space. Post completion of the DoE, a confirmatory batch was made which served as a diagnostic tool for evaluating the effectiveness of the generated model. The establishment of a strategy to control the variables and responses is of critical importance in order to appropriately use the flexibility given to products developed or optimised using QbD principles. This study show that the structured approach used in Quality by Design methodology can be successfully applied to optimise a commercialised legacy product

Latent variable modeling approaches to assist the implementation of quality-by-design paradigms in pharmaceutical development and manufacturing

With the introduction of the Quality-by-Design (QbD) initiative, the American Food and Drug Administration and the other pharmaceutical regulatory Agencies aimed to change the traditional approaches to pharmaceutical development and manufacturing. Pharmaceutical companies have been encouraged to use systematic and science-based tools for the design and control of their processes, in order to demonstrate a full understanding of the driving forces acting on them. From an engineering perspective, this initiative can be seen as the need to apply modeling tools in pharmaceutical development and manufacturing activities. The aim of this Dissertation is to show how statistical modeling, and in particular latent variable models (LVMs), can be used to assist the practical implementation of QbD paradigms to streamline and accelerate product and process design activities in pharmaceutical industries, and to provide a better understanding and control of pharmaceutical manufacturing processes. Three main research areas are explored, wherein LVMs can be applied to support the practical implementation of the QbD paradigms: process understanding, product and process design, and process monitoring and control. General methodologies are proposed to guide the use of LVMs in different applications, and their effectiveness is demonstrated by applying them to industrial, laboratory and simulated case studies. With respect to process understanding, a general methodology for the use of LVMs is proposed to aid the development of continuous manufacturing systems. The methodology is tested on an industrial process for the continuous manufacturing of tablets. It is shown how LVMs can model jointly data referred to different raw materials and different units in the production line, allowing to understand which are the most important driving forces in each unit and which are the most critical units in the line. Results demonstrate how raw materials and process parameters impact on the intermediate and final product quality, enabling to identify paths along which the process moves depending on its settings. This provides a tool to assist quality risk assessment activities and to develop the control strategy for the process. In the area of product and process design, a general framework is proposed for the use of LVM inversion to support the development of new products and processes. The objective of model inversion is to estimate the best set of inputs (e.g., raw material properties, process parameters) that ensure a desired set of outputs (e.g., product quality attributes). Since the inversion of an LVM may have infinite solutions, generating the so-called null space, an optimization framework allowing to assign the most suitable objectives and constraints is used to select the optimal solution. The effectiveness of the framework is demonstrated in an industrial particle engineering problem to design the raw material properties that are needed to produce granules with desired characteristics from a high-shear wet granulation process. Results show how the framework can be used to design experiments for new products design. The analogy between the null space and the Agencies’ definition of design space is also demonstrated and a strategy to estimate the uncertainties in the design and in the null space determination is provided. The proposed framework for LVM inversion is also applied to assist the design of the formulation for a new product, namely the selection of the best excipient type and amount to mix with a given active pharmaceutical ingredient (API) to obtain a blend of desired properties. The optimization framework is extended to include constraints on the material selection, the API dose or the final tablet weight. A user-friendly interface is developed to aid formulators in providing the constraints and objectives of the problem. Experiments performed industrially on the formulation designed in-silico confirm that model predictions are in good agreement with the experimental values. LVM inversion is shown to be useful also to address product transfer problems, namely the problem of transferring the manufacturing of a product from a source plant, wherein most of the experimentation has been carried out, to a target plant which may differ for size, lay-out or involved units. An experimental process for pharmaceutical nanoparticles production is used as a test bed. An LVM built on different plant data is inverted to estimate the most suitable process conditions in a target plant to produce nanoparticles of desired mean size. Experiments designed on the basis of the proposed LVM inversion procedure demonstrate that the desired nanoparticles sizes are obtained, within experimental uncertainty. Furthermore, the null space concept is validated experimentally. Finally, with respect to the process monitoring and control area, the problem of transferring monitoring models between different plants is studied. The objective is to monitor a process in a target plant where the production is being started (e.g., a production plant) by exploiting the data available from a source plant (e.g., a pilot plant). A general framework is proposed to use LVMs to solve this problem. Several scenarios are identified on the basis of the available information, of the source of data and on the type of variables to include in the model. Data from the different plants are related through subsets of variables (common variables) measured in both plants, or through plant-independent variables obtained from conservation balances (e.g., dimensionless numbers). The framework is applied to define the process monitoring model for an industrial large-scale spray-drying process, using data available from a pilot-scale process. The effectiveness of the transfer is evaluated in terms of monitoring performances in the detection of a real fault occurring in the target process. The proposed methodologies are then extended to batch systems, considering a simulated penicillin fermentation process. In both cases, results demonstrate that the transfer of knowledge from the source plant enables better monitoring performances than considering only the data available from the target plant

Investigation of the tableting process in continuous production: influence of feeding and extended dwell time during compression on dependent process variables and tablet properties

Despite the high quantities of tablets produced daily, a lot of the established processes and formulations are the results of (suboptimal) trial-and-error experiments, contributing to the image that the entire field of pharmaceutical powder technology is more “an art than a science” [1]. Also, a large number of contributing papers to the field date from roughly two or three decades ago. Although the operation mode and press lay-out stayed basically unchanged since its invention, the instrumentation improved largely in terms of quality, accuracy and sensitivity. Moreover, due to the increased competition through generic manufacturing and the shift towards a more patient-centered production, more advanced tablet formulations exhibiting e.g. prolonged, extended, delayed or immediate release profiles have emerged. This, together with the Process Analytical Technology (PAT) – initiative, proposed by the American Food and Drug Administration (FDA) in 2004, encourages a shift towards a more scientifically based technology. The goal of the initiative is to stimulate the pharmaceutical industry to “design and develop processes that can consistently ensure a predefined quality at the end of the manufacturing process”. By identifying all sources of variation of importance for the product performance and quality, and by increased process understanding and continuous monitoring, quality could be built rather than tested into the product [2]. Together with the International Conference on Harmonization (ICH) Q8 guideline on Pharmaceutical Development, focusing on the Quality-by-Design (QbD) concept, it forms the regulatory framework to catalyze the shift of the pharmaceutical industry towards a redesigning of the current approach [3-5]. Seen in the light of these new movements within the tablet manufacturing area, it appears obvious that there is a need for new knowledge to fund a base for a thorough understanding of the continuous tableting process. This thesis aims to contribute in this large context by the investigation of the tableting process on a high-speed rotary tablet press. The goal was to increase the understanding of the influence of the properties of the starting material and process parameters on dependent process parameters and tablet properties. Since the PAT-initiative stimulates the introduction of new analytical tools to enhance process understanding and product quality, additional analytical chemistry tools, next to the built-in instrumentation were used. Moreover, due to the large amount of data obtained, Design of Experiments (DoE) and Multivariate Data Analysis (MVA) were administered to perform experiments and analyze data in a structured manner. Three main topics were addressed: - The role of the forced feeder: its influence on the properties of the starting material, on the die-filling process and on the final tablet properties. - The mechanism of (double) compression: its influence on dependent process parameters and on the final tablet properties. - The role of additional analytical chemistry tools in a continuous tableting process: its applicability to asses tablet properties, produced from starting material with different characteristics