Tablet Manufacturing Process Research Articles

Process Modification of Pharmaceutical Tablet Manufacturing Operations: An Eco-Efficiency Approach

A process improvement in a tablet manufacturing process within a pharmaceutical industry was carried out based on an eco-efficiency approach. As it is one of the most energy consuming processes in the production line, the tablet manufacturing process was considered. It has the highest production volume with a complicated and long manufacturing product life cycle. Data were collected on energy inputs and emissions data for the stages of powder direct mixing, particle size reduction, and tableting. A straightforward approach was then used to analyze environmental impacts in terms of GHG emissions. Non- added value steps were removed from the product life cycle process, which has led to significant time and cost savings, as well as to a reduction in the emission. Annual economic savings have been achieved, a time reduction of approximately 71% was attained, and the reduction in GHG emissions and energy cost were 73.2%. The g CO2eq per tablet reduction has been calculated within the process improvement to be 2.06 g CO2eq per tablet instead of 7.71 g CO2eq per tablet.

MONITORING OF CRITICAL PROCESS VARIABLES FOR PILOT PLANT SCALE-UP STUDIES OF PARACETAMOL TABLETS

The objective of the study was to undertake pilot plant scale-up batches of paracetamol immediate release tablets by designing, optimizing and validating the tablet manufacturing process. A process design was developed to define the critical process variables and monitor it throughout the manufacturing process. Critical processes such as blending of intragranular ingredients, drying of the granules, lubrication and tablet compression were optimized. The process optimization was carried out based on the critical quality attributes of the formulation and their predetermined limits. Process validation was carried out to assure reproducibility in the quality of the product. The scale-up process produced batches showing good reproducibility with a relative standard deviation of less than 2%.

Functional Overview of Process Validation of Tablets - A Critical Review

Purpose : Validation is a main tool in achieving and maintaining the quality and safety of the final product as per cGMP(current Good Manufacturing Practice). The purpose of this present work is to give introduction, general overview and how to plan, develop, execute process validation of pharmaceutical manufacturing process especially tablet manufacturing process. Approach : When we consider any product, quality is always an imperative pre requisite hence a highest quality levels must be included in the manufacturing of the drug. Findings : To assure the identity, purity, safety, efficacy and also maintaining the quality of final product process validation is the key element. Three consecutive batches were considered to execute the process validation activity. Conclusion : Process validation is a major requirement of cGMP's regulation. Process validation is a key element to maintain product quality, safety, identity and efficacy.

Engineered particles demonstrate improved flow properties at elevated drug loadings for direct compression manufacturing

Optimizing powder flow and compaction properties are critical for ensuring a robust tablet manufacturing process. The impact of flow and compaction properties of the active pharmaceutical ingredient (API) becomes progressively significant for higher drug load formulations, and for scaling up manufacturing processes. This study demonstrated that flow properties of a powder blend can be improved through API particle engineering, without critically impacting blend tabletability at elevated drug loadings. In studying a jet milled API (D50=24μm) and particle engineered wet milled API (D50=70μm and 90μm), flow functions of all API lots were similarly poor despite the vast difference in average particle size (ffc<4). This finding strays from the common notion that powder flow properties are directly correlated to particle size distribution. Upon adding excipients, however, clear trends in flow functions based on API particle size were observed. Wet milled API blends had a much improved flow function (ffc>10) compared with the jet milled API blends. Investigation of the compaction properties of both wet and jet milled powder blends also revealed that both jet and wet milled material produced robust tablets at the drug loadings used. The ability to practically demonstrate this uncommon observation that similarly poor flowing APIs can lead to a marked difference upon blending is important for pharmaceutical development. It is especially important in early phase development during API selection, and is advantageous particularly when material-sparing techniques are utilized.

CONTENT UNIFORMITY DETERMINATION OF IBUPROFEN INTACT TABLETS BY REFLECTANCE NIR SPECTROSCOPY

Content uniformity (CU) is a critical quality attribute in tablet manufacturing process. The active pharmaceutical ingredient (API) is usually determined off-line techniques such as, high performance liquid chromatography (HPLC) which is a slow, destructive technique and requires sample preparation. Therefore, Near Infrared (NIR) spectroscopy was employed as a process analytical technology (PAT) tool to determine the API and consequently the content uniformity of tablets. NIR spectroscopy is a fast, non-destructive technique and requires minimal sample preparation. The purpose of this work was to develop and validate NIR reflectance method for the determination of the ibuprofen content (mg) for the content uniformity for ibuprofen tablet. Partial least squares (PLS) model for the NIR reflectance was constructed by using calibration laboratory tablets with different ibuprofen (IBU) contentsspanning from 146.47 mg to 243.91 mg. The predictive performance of the proposed method was evaluated by traditional chemometric criteria. The corresponding values for the root mean square error of prediction (RMSEP) were equal to 0.96% for NIR reflectance method. Besides, the proposed NIR method was successfully validated and implemented for the determination of the content uniformity for three batches that represent three levels of IBU content (160 mg, 200 mg and 240 mg).

The Impact of Granule Density on Tabletting and Pharmaceutical Product Performance.

The impact of granule densification in high-shear wet granulation on tabletting and product performance was investigated, at pharmaceutical production scale. Product performance criteria need to be balanced with the need to deliver manufacturability criteria to assure robust industrial scale tablet manufacturing processes. A Quality by Design approach was used to determine in-process control specifications for tabletting, propose a design space for disintegration and dissolution, and to understand the permitted operating limits and required controls for an industrial tabletting process. Granules of varying density (filling density) were made by varying water amount added, spray rate, and wet massing time in a design of experiment (DoE) approach. Granules were compressed into tablets to a range of thicknesses to obtain tablets of varying breaking force. Disintegration and dissolution performance was evaluated for the tablets made. The impact of granule filling density on tabletting was rationalised with compressibility, tabletability and compactibility. Tabletting and product performance criteria provided competing requirements for porosity. An increase in granule filling density impacted tabletability and compactability and limited the ability to achieve tablets of adequate mechanical strength. An increase in tablet solid fraction (decreased porosity) impacted disintegration and dissolution. An attribute-based design space for disintegration and dissolution was specified to achieve both product performance and manufacturability. The method of granulation and resulting granule filling density is a key design consideration to achieve both product performance and manufacturability required for modern industrial scale pharmaceutical product manufacture and distribution.

Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release Tablets by Terahertz Transmission Measurements

ABSTRACTPurposeThe aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale.MethodsSamples of 18 batches of biconvex tablets from a production-scale design of experiments study into exploring the design space of a commercial tablet manufacturing process were used. The tablet production involved the process steps of high-shear wet granulation, fluid-bed drying and subsequent compaction. The 18 batches were produced using a 4 factor split plot design to study the effects of process changes on the disintegration time. Non-destructive and contactless terahertz transmission measurements of the whole tablets without prior sample preparation were performed to measure the effective refractive index and absorption coefficient of 6 tablets per batch.ResultsThe disintegration time (R2 = 0.86) and API dissolved after 15 min (R2 = 0.96) linearly correlates with the effective refractive index, neff, measured at terahertz frequencies. In contrast, no such correlation could be established from conventional hardness measurements. The magnitude of neff represents the optical density of the sample and thus it reflects both changes in tablet porosity as well as granule density. For the absorption coefficient, αeff, we observed a better correlation with dissolution after 20 min (R2 = 0.96) and a weaker correlation with disintegration (R2 = 0.83) compared to neff.ConclusionThe measurements of neff and αeff provide promising predictors for the disintegration and dissolution time of tablets. The high penetration power of terahertz radiation makes it possible to sample a significant volume proportion of a tablet without any prior sample preparation. Together with the short measurement time (seconds), the potential to measure content uniformity and the fact that the method requires no chemometric models this technology shows clear promise to be established as a process analyser to non-destructively predict critical quality attributes of tablets.

Employing Customer Value Criteria to Address Networks of Contradictions in Complex Technical Systems

The diffusion of TRIZ in the industry is still under the expectations of the scientific community. According to authors’ experience, barriers to industrial adoption are constituted, among the others, by difficulties in approaching problems characterized by tangled networks of parameters and, consequently, very large number of contradictions.The most tailored tools to face this problem aim at managing networks of contradictions. They try to establish the starting point for an effective problem solving process. The task suffers from subjective evaluations or difficulties with applying complex algorithmic procedures. Besides, the existing approaches overlook the potential benefits descending from overcoming each single contradiction. The authors illustrate a strategy to prioritize technical contradictions, which includes metrics concerning customer value. More specifically, the implemented criteria feature the probability of succeeding in the marketplace. Thus, a business perspective is introduced in the problem solving process. The proposal has been experimented through an application to a mature phase included in the manufacturing process of pharmaceutical tablets. Said production phase, taken as the reference technical system, figures out 239 different contradictions. The application of the developed approach allowed to individuate contradictions whose solution has considerably influenced the technical evolution of the treated industrial sector.

Crystallo – Co - Agglomeration: An Innovative Technique for Size Enlargement and Improved Flow Properties of Powders

Direct compression is the preferred method for tablet manufacturing due to the simplicity in processing and its cost effectiveness. However, for applying direct compression in tablet manufacturing, the drug used should have good flow properties and compaction characteristics. Many drugs are lacking these properties and so it is not possible to compress them directly into tablets. Crystallo co agglomeration (CCA) is an innovative technique developed with intends to provide the drugs with good micromeritic and mechanical characteristics. The process of CCA involves crystallisation followed by simultaneous agglomeration of the drug with the aid of a good solvent and /or a bridging liquid and a bad solvent. It is also possible to incorporate other drugs (to get a combination tablet), excipients (e.g. disintegrants for fast dissolving tablets) and different polymer combinations (to modify the drug release properties). In the recent years,attempts were made to produce Crystallo co agglomerates of various drugs, whichwere briefly discussed in this article. Even though large scale applications of CCA is not yet made possible, this technique gives a new line of opportunities to the tablet manufacturing process, ensuring low cost, single stepped production of particles with good micromeritic and mechanical characters which can be directly compressed

A REVIEW ON PHARMACEUTICAL PROCESS VALIDATION OF SOLID DOSAGE FORM [TABLETS

The article gives an introduction and general overview on process validation of pharmaceutical tablet manufacturing process. Process Validation is one of the important steps in achieving and maintaining the quality of final product. Process validation emphasizes the role of statistical tools and analyses, knowledge, detection, and control of variability and thus gives assurance on consistency of quality product. The validation study provides the accuracy, sensitivity, specificity and reproducibility of the established and documented test methods employed by the manufacturer. Thus, validation is an essential part of the quality assurance. This review examines the need for pharmaceutical validation, the various approaches, process and steps to be monitored during tablet manufacturing process. Key words: Process Validation, Types, Validation Stages, Guidelines and Process.Â

Real time monitoring of powder blend bulk density for coupled feed-forward/feed-back control of a continuous direct compaction tablet manufacturing process

The pharmaceutical industry is strictly regulated, where precise and accurate control of the end product quality is necessary to ensure the effectiveness of the drug products. For such control, the process and raw materials variability ideally need to be fed-forward in real time into an automatic control system so that a proactive action can be taken before it can affect the end product quality. Variations in raw material properties (e.g., particle size), feeder hopper level, amount of lubrication, milling and blending action, applied shear in different processing stages can affect the blend density significantly and thereby tablet weight, hardness and dissolution. Therefore, real time monitoring of powder bulk density variability and its incorporation into the automatic control system so that its effect can be mitigated proactively and efficiently is highly desired. However, real time monitoring of powder bulk density is still a challenging task because of different level of complexities. In this work, powder bulk density which has a significant effect on the critical quality attributes (CQA’s) has been monitored in real time in a pilot-plant facility, using a NIR sensor. The sensitivity of the powder bulk density on critical process parameters (CPP’s) and CQA’s has been analyzed and thereby feed-forward controller has been designed. The measured signal can be used for feed-forward control so that the corrective actions on the density variations can be taken before they can influence the product quality. The coupled feed-forward/feed-back control system demonstrates improved control performance and improvements in the final product quality in the presence of process and raw material variations.

Process validation: An essential process in pharmaceutical industry

The purpose of this work is to present an introduction and general overview on process validation of pharmaceutical manufacturing process especially tablet manufacturing process with special reference to the requirements stipulated by the US Food and Drug Administration (FDA).Quality is always an imperative prerequisite when we consider any product. Therefore, drugs must be manufactured to the highest quality levels. End-product testing by itself does not guarantee the quality of the product. Quality assurance techniques must be used to build the quality into the product at every step and not just tested for at the end. In pharmaceutical industry, Process Validation performs this task to build the quality into the product because according to ISO 9000:2000, it had proven to be an important tool for quality management of pharmaceuticals.

Integrated Moving Horizon-Based Dynamic Real-Time Optimization and Hybrid MPC-PID Control of a Direct Compaction Continuous Tablet Manufacturing Process

In this manuscript, a moving horizon-based real-time optimization (MH-RTO) has been integrated with a hybrid model predictive control (MPC) system for a continuous tablet manufacturing process for quality by design (QbD)-based efficient continuous manufacturing. In the proposed approach, the integrated MH-RTO provides the optimal operational set points for the tablet production rate in real time. The MH-RTO takes into consideration the capital and operating cost, the market fluctuations, the product inventory, the product quality assurance strategy, the regulatory constraints, and the product rejections. An advanced hybrid model predictive control system then ensures that the required production rate with desired quality is met with minimum resources and time. A robust optimization strategy and an efficient control system have been integrated to achieve the maximum profit. The MH-RTO integrated with a hybrid control strategy ensures the maximum possible profit irrespective of the market demand fluctuations. The basic advantage of the MH-RTO framework is that it takes into consideration the future demand and thus can lead to increased profit compared to a standard real-time optimization approach.

A Combined Feed-Forward/Feed-Back Control System for a QbD-Based Continuous Tablet Manufacturing Process

Continuous pharmaceutical manufacturing together with PAT (Process Analytical Technology) provides a suitable platform for automatic control of the end product quality as desired by QbD (quality by design)-based efficient manufacturing. The precise control of the quality of the pharmaceutical product requires corrective actions in the process/raw material variability before product quality can be influenced. In this manuscript, a combined feed-forward/feed-back control system has been developed for a direct compaction continuous tablet manufacturing process. The feed-forward controller takes into account the effect of process disturbances proactively while the feed-back control system ensures the end product quality consistently. The coupled feed-forward/feed-back control system ensures the minimum variability in the final product quality irrespective of process and raw material variations. The performance of the combined control strategy has been evaluated through process simulation and is found to be more effective in comparison with a feed-back only control strategy and, therefore, demonstrates potential to further improve pharmaceutical tablet manufacturing operations.

Monitoring of the manufacturing process for ambroxol hydrochloride tablet using NIR-chemometric methods: compression effect on content uniformity model and relevant process parameters testing

This study aimed at using near-infrared (NIR) spectroscopy to monitor compaction pressure for simultaneously determining the tensile strength and content uniformity, as well as moisture and mean particle size of ambroxol hydrochloride tablets. The content uniformity, compression force and tensile strength of the laboratory samples were obtained by pressing a mixture of active principle and excipient components into tablets. To reduce the spectral baseline shift of the laboratory samples, the compaction pressure applied to the mixture was assessed by a variable pressure test. Production samples were added to the test and subjected to principal component analysis. The expanded partial least-squares (PLS) calibration model used to quantify the active content was more accurate than the model constructed from laboratory samples using the production tablets included in the calibration set. The model showed good predictability, with correlation coefficient (R) 0.9977. The validation and reliability of the content model were evaluated to determine trueness and reliability for the measurement of individual production tablets and the laboratory tablets with drug content ranging from 24 to 36 mg. The PLS calibration models for compression force and tensile strength were constructed using the same spectral set assuming both were highly related. These models yielded high R values (0.9955 and 0.9910). The R values of the moisture and mean particle size were 0.9994 and 0.9919, respectively. This study demonstrated that NIR spectroscopy combined with chemometric techniques can be successfully used to quantitatively monitor the tablet manufacturing process in the pharmaceutical industry.

Effect of simulated precompression, compression pressure and tableting speed on an offline diffuse transmittance and reflectance near-infrared spectral information of model intact caffeine tablets

Near-infrared spectroscopy (NIRS) is used in the pharmaceutical industry for monitoring drug content during the tablet manufacturing process. It is of critical importance to understand the effect of process factors on NIRS performance. Design of Experiments (DoE) methodology was applied in this work for the systematic study of the effects of compression pressure, precompression pressure and tableting speed on an average Euclidean distance (AED), which reflects spectral features of the tablets, and root mean-squared error of prediction (RMSEP) as key performance indicator of NIRS calibration models. Caffeine tablets were manufactured in 17 experimental runs in accordance with D-optimal design. Developed diffuse transmittance (DT) and diffuse reflectance (DR) calibration models were tested on five independent test sets to confirm the conclusions of the DoE. Compression pressure and tableting speed have shown significant effect on the studied responses in DT mode, whereas all three studied factors have shown a significant effect in DR mode. Significant factors were considered in the development of the global calibration models. The authors suggest further study of RMSEP and AED responses to draw reliable conclusions on the effects of tableting process factors. The global calibration model in DT mode has shown superior performance compared to DR mode.

System model of a tablet manufacturing process

A novel process system model of a roll compaction tablet manufacturing process has been developed. The model couples together multiple unit operations, namely roller compaction, milling and tablet press, providing a framework to simulate cause and effect relationships between process parameters and product performance. Models for tablet tensile strength and dissolution are implemented to evaluate tablet performance. The models for the milling and the dissolution units are based on the solution of population balance equations. The model is validated by comparison with experimental data. This work demonstrates that it is possible to develop a model for tablet manufacturing that is based on fundamental process understanding and that the resulting simulation tool, requiring limited experimental calibration, can be used easily and effectively in the workflow of pharmaceutical product development.

Implementation of an advanced hybrid MPC–PID control system using PAT tools into a direct compaction continuous pharmaceutical tablet manufacturing pilot plant

It is desirable for a pharmaceutical final dosage form to be manufactured through a quality by design (QbD)-based approach rather than a quality by testing (QbT) approach. An automatic feedback control system coupled with PAT tools that is part of the QbD paradigm shift, has the potential to ensure that the pre-defined end product quality attributes are met in a time and cost efficient manner. In this work, an advanced hybrid MPC–PID control architecture coupled with real time inline/online monitoring tools and principal components analysis (PCA) based additional supervisory control layer has been proposed for a continuous direct compaction tablet manufacturing process. The advantages of both MPC and PID have been utilized in a hybrid scheme. The control hardware and software integration and implementation of the control system has been demonstrated using feeders and blending unit operation of a continuous tablet manufacturing pilot plant and an NIR based PAT tool. The advanced hybrid MPC–PID control scheme leads to enhanced control loop performance of the critical quality attributes in comparison to a regulatory (e.g. PID) control scheme indicating its potential to improve pharmaceutical product quality.

Preparation and scale up of extended-release tablets of bromopride

Reproducibility of the tablet manufacturing process and control of its pharmaceutics properties depends on the optimization of formulation aspects and process parameters. Computer simulation such as Design of Experiments (DOE) can be used to scale up the production of this formulation, in particular for obtaining sustained-release tablets. Bromopride formulations are marketed in the form of extended-release pellets, which makes the product more expensive and difficult to manufacture. The aim of this study was to formulate new bromopride sustained release formulations as tablets, and to develop mathematical models to standardize the scale up of this formulation, controlling weight and hardness of the tablets during manufacture according to the USP 34th edition. DOE studies were conducted using Minitab(tm) software. Different excipient combinations were evaluated in order to produce bromopride sustained-release matrix tablets. In the scale-up study, data were collected and variations in tableting machine parameters were measured. Data were processed by Minitab(tm) software, generating mathematical equations used for prediction of powder compaction behavior, according to the settings of the tableting machine suitable for scale-up purposes. Bromopride matrix tablets with appropriate characteristics for sustained release were developed. The scale-up of the formulation with the most suitable sustained release profile was established by using mathematical models, indicating that the formulation can be a substitute for the pellets currently marketed.

A systematic framework for onsite design and implementation of a control system in a continuous tablet manufacturing process

A novel manufacturing strategy based on continuous processing integrated with online/inline monitoring tools coupled with an advanced control system is highly desired for efficient Quality by Design (QbD)-based pharmaceutical manufacturing. A control system ensures the predefined end product quality, satisfies the high regulatory constraints, facilitates real time release of the product, and optimizes the resources. In this work, a systematic framework for the onsite design and implementation of the control system in continuous tablet manufacturing process has been developed. The framework includes a generic methodology and supporting tools through which the control system can be designed at the manufacturing site and can be implemented for closed-loop operation. The control framework has different novel features such as the option to run the plant in closed-loop (MPC/PID), open-loop and simulation mode. NIR sensor, an online prediction tool, a PAT data management tool, and a control platform have been used to close the control loop.