Manufacture Of Pharmaceutical Products Research Articles

Improving Continuous Loss-in-weight Feeding Accuracy by a Novel Hopper Design

PurposePowder feeding is a vital unit operation in the continuous manufacturing of pharmaceutical products. Loss-in-weight twin-screw feeders are commonly used in continuous manufacturing lines. The feeding performance, i.e., the accuracy and consistency of feeding, influences the content uniformity of the final drug product. In this study, a redesigned hopper for K-Tron KT20 twin-screw feeder was designed, implemented, and investigated to improve feeding performance. The basic idea was to design the hopper in such a way that the stresses on top of the screw entrance are independent of the fill level.MethodsOur study compared the novel system to that of the original cylindrical hopper. The effect of the redesigned hopper on the start-up, the process’ sensitivity to refill level, and the refill portion size were studied. A free-flowing, barely compressible powder and a compressible blend were used in this study to evaluate the feeding performance and the refill effects.ResultsWhen using compressible powders, the results showed a larger process window for refilling in the redesigned hopper and a lower refill-level sensitivity compared to the original hopper.ConclusionThe homogenization of stresses in the redesigned hopper allowed operating at lower refill levels, and variability, especially due to refilling, was reduced. This study demonstrates novel design approaches for successfully implementing hard-to-feed materials in continuous manufacturing.

Palatability evaluation of orally disintegrating tablets using a visual analog scale in clinical trials.

Visual analog scale (VAS) can be used to evaluate multiple parameters. There have been no reports on the verification of order effects or reproducibility of the VAS method for overall palatability of oral dosage forms. The purpose of this study was to assess the validity of a method for evaluating the palatability of orally disintegrating tablets (ODTs) using a 100-mm VAS. We conducted clinical trials to evaluate the overall palatability, taste, and scent of 3 ODTs (F1, F2, F3) that contained famotidine (20, 10, and 5mg, respectively). The study protocol was approved by the Research Ethics Committee of the University of Shizuoka, Japan (No. 21-36). To investigate the intergroup reproducibility of the VAS evaluation, 40 participants were divided into three groups, and each group underwent human gustatory sensation test of F1, F2, and F3, performed using a crossover design with 6 different tasting sequences. To evaluate intragroup reproducibility of the VAS evaluation, the participants assessed the same ODTs twice. The VAS scores for overall palatability followed the same order (F3>F2>F1) in all groups. The VAS scores for the overall palatability of F1, F2, and F3 did not significantly differ between the first and second evaluations. The Kruskal-Wallis test indicated a minimal impact of the assessment order on ODT evaluations. We confirm the reliability and reproducibility of the VAS method for evaluating ODT palatability. The VAS method for assessing ODT palatability provides accurate information and can contribute to the design and manufacture of patient-friendly pharmaceutical products.

Potential of Powder Rheology for Detecting Unforeseen Cross-Contamination of Foreign Active Pharmaceutical Ingredients.

Unexpected cross-contamination by foreign components during the manufacturing and quality control of pharmaceutical products poses a serious threat to the stable supply of drugs and the safety of customers. In Japan, in 2020, a mix-up containing a sleeping drug went undetected by liquid chromatography during the final quality test because the test focused only on the main active pharmaceutical ingredient (API) and known impurities. In this study, we assessed the ability of a powder rheometer to analyze powder characteristics in detail to determine whether it can detect the influence of foreign APIs on powder flow. Aspirin, which was used as the host API, was combined with the guest APIs (acetaminophen from two manufacturers and albumin tannate) and subsequently subjected to shear and stability tests. The influence of known lubricants (magnesium stearate and leucine) on powder flow was also evaluated for standardized comparison. Using microscopic morphological analysis, the surface of the powder was observed to confirm physical interactions between the host and guest APIs. In most cases, the guest APIs were statistically detected due to characteristics such as their powder diameter, pre-milling, and cohesion properties. Furthermore, we evaluated the flowability of a formulation incorporating guest APIs for direct compression method along with additives such as microcrystalline cellulose, potato starch, and lactose. Even in the presence of several additives, the influence of the added guest APIs was successfully detected. In conclusion, powder rheometry is a promising method for ensuring stable product quality and reducing the risk of unforeseen cross-contamination by foreign APIs.

The politics and governance of drug production in public-private partnerships: Brazil’s response to hepatitis C

ABSTRACT The local manufacture of advanced pharmaceutical products has been a long-standing objective of health and industry policy in many developing countries, including in Latin America. This strategy has been applied to fight epidemics such as HIV/AIDS, malaria, and the COVID-19 pandemic. However, we still know little about the politics and governance that enable such arrangements, especially when there is no consent from the originator company. This study focuses on the case of Brazil, a country that is well-known for its health-industry policy, which includes the local production of direct-acting antivirals (DAAs), a new treatment for hepatitis C. We seek to explain the factors that have contributed to Brazil’s successful production of generic versions of DAAs, and, later, to the decision by the Ministry of Health (MoH) to procure drugs from multinational pharmaceutical companies rather than from local laboratories. A lack of support for domestic production by important stakeholders, the patent holder’s attempt to block domestic production and the MoH’s adoption of more modern treatment guidelines under a different procurement logic all created an unfavourable environment for local production and procurement of DAAs. Our study draws implications for middle-income countries that wish to produce drugs domestically without voluntary license agreements.

Efficient Strategic Pricing in a Dual-Channel Stackelberg Supply Chain: Incorporating Remanufacturing and Sales Commissions across Multiple Periods

The rise of e-commerce has significantly impacted consumer shopping habits, resulting in profit loss for traditional supply chains. In response to intense competition, numerous companies have transitioned their business models to embrace dual-channel configurations, seeking to captivate customers and increase their market share. Nonetheless, research on decentralized dual-channel supply chain configurations is scarce and predominantly concentrates on single-period pricing. This paper addresses this gap by employing Stackelberg’s game theory to investigate the multi-periodic pricing and remanufacturing decisions within a decentralized dual-channel supply chain with reverse logistics, specialized in the manufacturing and sales of pharmaceutical products. Moreover, this work considers that the online channel pays a sales commission to the pharmacy in return for the provided after-sales services, aiming to incorporate the aspect of sharing revenues. A mathematical formulation is proposed in a multi-periodic environment allowing us to simultaneously maximize the total profits of the manufacturer, the pharmacy and the online channel, by optimizing the pricing and remanufacturing strategies. Numerical analyses examine the customer purchasing preference’s effect on the demand and pricing decisions of each channel, the impact of the collection cost on the optimal remanufacturing strategy, and assess the break-even point of the total profits generated in both channels according to the sales commission. This study’s novelty lies in employing Stackelberg’s game theory to develop a mathematical formulation for the multi-periodic pricing and remanufacturing problem within a decentralized dual-channel supply chain, incorporating a sales commission between both distributors.

Binder jetting 3D printing in fabricating pharmaceutical solid products for precision medicine.

Current treatment strategies are moving towards patient-centricity, which emphasizes the need for new solutions allowing for medication tailored to a patient. This can be realized by precision medicine where patient diversity is considered during treatment. However, the broader use of precision medicine is restricted by the current technological solutions and rigid manufacturing of pharmaceutical products by mass production principles. Additive manufacturing of pharmaceutical products can provide a feasible solution to this challenge. In this review, a particular subtype of additive manufacturing, that is, binder jetting 3D printing, is introduced as a solution for fabricating pharmaceutical solid products that can be considered as precision medicine. Technical aspects, practical applications, unique advantages and challenges related to this technique are discussed, indicating that binder jetting 3D printing possesses the potential for fabricating already new product prototypes, where diversity in patient treatment in terms of the needs for specific drug type, dose and drug release can be accounted. To further advance this type of mass customization of pharmaceuticals, multidisciplinary research initiatives are needed not only to cover the engineering aspects but also to bridge these innovations with patient-centric perspectives.

A Bayesian approach for evaluating equivalence over multiple groups, and comparison with frequentist tost

Manufacturing and testing of pharmaceutical products frequently occur in multiple facilities within a company’s network. It is of interest to demonstrate equivalence among the alternative testing/manufacturing facilities to ensure product consistency and quality regardless of the facility where it was manufactured/tested. In the Frequentist framework, equivalence testing is well established when comparing two labs or manufacturing facilities; however, when considering more than two labs or production sites, the Frequentist approach may not always offer appropriate or interpretable estimates for demonstrating equivalence among all of them simultaneously. This paper demonstrates the utility of Bayesian methods to the equivalence assessment of multiple groups means, with a comparison against traditional Frequentist methods. We conclude that a Bayesian strategy is very useful for addressing the problem of multi-group equivalence. While it is not our intention to argue that Bayesian methods should always replace Frequentist ones, we show that among the advantages of a Bayesian analysis is that it provides a more nuanced understanding of the degree of similarity among sites than the hypothesis testing underpinning the Frequentist approach.

Quantitative analysis of the effects of multi-component formulation parameters on granule and tablet properties via a combined population balance and statistical predictive model

In pharmaceutical drug product manufacturing, the use of multi-component mixtures in the formulation is a common practice. However, the introduction of each material alters the powder blend properties and affects the granule growth mechanisms in a wet granulation process. In this study, we quantified the effects of varying formulation parameters on granule growth rate, expressed by the liquid amount required for granulation to reach completion, and on granule and tablet quality attributes. Process models, including population balance and statistical models, were developed to represent the granulation, milling, and tableting process, and predict relevant granule and tablet properties. Overall, prediction of granule properties had an accuracy of above 80% and the prediction of different tablet properties ranged from an R2 of 0.68 to 0.9. These models are computationally efficient and can be simulated serially to predict the performance of different multi-component formulations by using the pre-blend properties as model inputs.

Continuous manufacturing of pharmaceutical products: A density-insensitive near infrared method for the in-line monitoring of continuous powder streams

Near infrared (NIR) spectroscopy is a valuable analytical technique for monitoring chemical composition of powder blends in continuous pharmaceutical processes. However, the variation in density captured by NIR during spectral collection of dynamic powder streams at different flow rates often reduces the performance and robustness of NIR models. To overcome this challenge, quantitative NIR measurements are commonly collected across all potential manufacturing conditions, including multiple flow rates to account for the physical variations. The utility of this approach is limited by the considerable quantity of resources required to run and analyze an extensive calibration design at variable flow rates in a continuous manufacturing (CM) process. It is hypothesized that the primary variation introduced to NIR spectra from changing flow rates is a change in the density of the powder from which NIR spectra are collected. In this work, powder stream density was used as an efficient surrogate for flow rate in developing a quantitative NIR method with enhanced robustness against process rate variation. A density design space of two process parameters was generated to determine the conditions required to encompass the apparent density and spectral variance from increases in process rate. This apparent density variance was included in calibration at a constant low flow rate to enable the development of a density-insensitive NIR quantitative model with limited consumption of materials. The density-insensitive NIR model demonstrated comparable prediction performance and flow rate robustness to a traditional NIR model including flow rate variation (“gold standard” model) when applied to monitoring drug content in continuous runs at varying flow rates. The proposed platform for the development of in-line density-insensitive NIR methods is expected to facilitate robust analytical model performance across variable continuous manufacturing production scales while improving the material efficiency over traditional robust modeling approaches for calibration development.

Application of the Quality by Design Concept (QbD) in the Development of Hydrogel-Based Drug Delivery Systems.

Hydrogel-based drug delivery systems are of interest to researchers for many reasons, such as biocompatibility, high diversity, and the possibility of administration from different routes. Despite these advantages, there are challenges, such as controlling the drug release rate and their mechanical properties during the manufacturing of these systems. For this reason, there is a need for the production and development of such drug delivery systems with a scientific strategy. For this reason, the quality by design (QbD) approach is used for the development of drug delivery systems. This approach, by identifying the most effective factors in the manufacturing of pharmaceutical products and controlling them, results in a product with the desired quality with the least number of errors. In this review article, an attempt is made to discuss the application and method of applying this approach in the development of hydrogel-based drug delivery systems. So that for the development and production of these systems, according to the type of drug delivery system, what target characteristics should be considered (QTPP) and what factors, such as material properties (CMA) or process parameters (CPP), should be taken into account to reach the critical quality attributes of the product (CQA).

Essential oil in bentonite: Effect of organofunctionalization on antibacterial activities

Essential oils are natural molecules with intense bioactivity, mainly antimicrobial activity, and are used in several industries such as health and food. However, the high volatility of the essential oils limits their application. Therefore, the incorporation of essential oils into solid materials is a strategy to maintain their properties. In this study, the incorporation of nerolidol at 5–50% v/v concentrations in raw and organophilic bentonites was investigated. The antibacterial activities of the oil/clay hybrids against Staphylococcus aureus and Escherichia coli were evaluated using the direct contact test. Transmission electron microscopy and X-ray diffractometry patterns confirmed the intercalation of the oil in sodium bentonite, resulting in a 1.26–1.50 nm increase in basal spacing (d), and in cetyltrimethylammonium clay (CTAB-Bent), which showed a d value of 3 nm. Thermogravimetry indicated that the maximum amount of nerolidol incorporated was 41% by mass (1.84 mmol g−1) in the NE50/CTAB-Bent sample, suggesting a good affinity between the species. The Fourier transform infrared spectra were in concordance with the interactions between the oil and OH groups and the organic groups in the raw and organophilic samples, respectively. Transmission electron microscopy suggested that the layered structure of the samples was maintained without the formation of exfoliated phases. The antibacterial of the hybrids revealed 100% inhibition of both bacteria. The promising results associated with the slow release and effective antibacterial action of the oil-clay hybrids indicate that the obtained materials can be used in the manufacture of pharmaceutical, cosmetic, and healthcare products.

Effect of moisture on solid state stability

Water is omnipresent during pharmaceutical product manufacturing and may interact with the drug substance, excipients, and the drug product in either solvent or vapor form, resulting in several physico-chemical changes, ultimately affecting product performance. Therefore, understanding the mechanisms behind such moisture-induced changes is necessary at every stage of pharmaceutical development and manufacturing to obtain the target formulation. Characterization tools, such as water sorption, spectroscopy, thermal analysis, diffraction, and more sophisticated approaches like simulations and PAT techniques, can help in the selection of the appropriate solid form, manufacturing method, excipients, and storage conditions, enabling the manufacturing of a stable drug product formulation.

Biosimilars and Generics: A New Class Needed for Hormonal and Herbal Preparations

Strict regulations are in place for the manufacture and approval of pharmaceutical products. Specific drugs such as biological products are governed by specific rules, which take cognizance of the extra diligence required for their production. This communication describes two classes of drugs: hormones and herbal products, which should be subject to stringent regulations. It explains the rationale behind this, and calls for added vigilance in regulatory oversight.

Influence of Chemical reaction and heat generation/absorption on Unsteady magneto Casson Nanofluid flow past a non-linear stretching Riga plate with radiation

The use of Casson fluid is of considerable importance in the manufacturing of pharmaceutical products, including the incorporation of china clay and biological fluids such as synovial liquids. Therefore, the primary objective of this work is to examine the characteristics of the Casson fluid flow. The Casson fluid is a non-Newtonian model often used to analyze the unsteady magnetohydrodynamic (MHD) heat and mass transfer in nanofluid flow scenarios across a non-linearly stretched Riga plate. The heat and mass transfer equations include the analysis of radiation and chemical reactions, respectively. Furthermore, the process of heat transmission is intensified by the existence of an external heat source or heat sink. By applying appropriate similarity transformations, the partial differential equations (PDEs) are converted into a set of nonlinear ordinary differential equations (ODEs). These ODEs are then solved numerically by utilizing the Runge-Kutta-Fehlberg-45 method, with the help of a shooting strategy. The validity of the study is determined by a comparative analysis of the present results in relation to prior research. The main objective of this research is to assess the influence of relevant flow parameters on the fluid flow, temperature, and concentration gradients, which will be visually represented and reported in tabular form. The augmentation of the Casson fluid coefficient (β) hinders the advancement of both velocity and temperature. The augmentation of the thermophoresis parameter (Nt) and magnetic factor (M) results in an elevation of θ(η) and a reduction in the curves depicting the volume fraction of nanoparticles. This study establishes a significant connection between many biological and engineering applications, particularly in the analysis of blood samples and the administration of drugs via blood circulation.

Phycoremediation potential and agar yield of red macroalgae (Gracilaria corticata) against HEDP (hydroxyethylidene diphosphonic acid) and CAPB (cocoamidopropyl betaine) detergents and the heavy metal pollutants.

The discharge of raw industrial, agricultural, and domestic wastes leads to an increase in heavy metal (HM) burden and detergents in aquatic environs, which can have destructive effects on aquatic organisms. Agarophyte Gracilaria corticata, a major component of seaweed flora of the southern coast of Iran (Bushehr) that contains agar and red pigments, is one of the economically valuable red marine algae. Agar is one of the important polysaccharides with high economic value, widely used in pharmaceutical, medicinal, and cosmetic product manufacturing industries. The aim of this work was to investigate the effect of 5 HMs and two common surfactants in household and industrial detergents on the agar yield, appearance color, and the red algae's phycoremediation potential against HMs. The metal ions were Zn(II), Cu(II), Ni(II), Mn(II), and Cr(VI), and the surfactants were HEDP and CAPB. The analysis results of samples cultured for 60 days in seawater and polluted environments showed that G. corticata can accumulate copper and nickel. In the presence of detergents without HMs, the amount of extracted agar significantly increased compared to the control sample with no change in algae color. But with increasing concentration of HMs, the amount of agar in seaweed samples decreased significantly, and the algae discolored from red to dark green or yellowish-green color (signs of death in the algae). These results show that increasing of HM pollution and detergents can lead to toxicological effects and reduce the species diversity of red seaweeds in the future.

Simultaneous determination of low molecular weight nitrosamines in pharmaceutical products by fast gas chromatography mass spectrometry

Control of N-nitrosamines has been in the focus of health authorities in recent years because many of these compounds are probable human carcinogens. In July 2018 the U.S. Food and Drug Administration (FDA) announced a recall for valsartan-containing medicines due to contamination with the carcinogenic low molecular weight nitrosamine, N-nitrosodimethylamine (NDMA). It has become clear that the problem can not only exist in the case of sartans, but in any active pharmaceutical ingredient (API)/drug product in which secondary or tertiary amines are present (as API or as impurities) and a nitrosating agent is available. The decision was made by regulators, according to which manufacturers of pharmaceutical products are obliged to perform a risk assessment for the potential presence of nitrosamines in active pharmaceutical ingredients and drug products. This resulted in a high demand for validated analytical methods that are able to quantify N-nitrosamines at low ppb levels in pharmaceutical products.In this work we have developed and validated a generic fast GC-MS method suitable for the quantitative determination of a wide range of low molecular weight nitrosamines, which include N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), N-nitroso-diphenylamine (NDPh), N-nitrosodipropylamine (NDPA), N-nitrosomethylethylamine (NMEA), N-nitrosomorpholine (NMOR), N-nitrosopiperidine (NPIP), N-nitroso-ethylisopropylamine (EIPNA), N-nitroso-diisopropylamine (DIPNA), N-nitroso-N-methylaniline (NMPA), 1-Methyl-4-nitrosopiperazine (MeNP) and N-nitroso-pyrrolidine (NPYR). The advantage of the method is that it is possible to screen low molecular weight nitrosamines in low concentrations with a short analysis time in a wide range of APIs and drug products.

Selection of an appropriate tracer to measure the residence time distribution (RTD) of continuous powder blending operations

Residence time distributions (RTDs) are quickly becoming an important component of the quality control strategy for continuous manufacturing (CM) of pharmaceutical products. However, methodologies for determining RTDs, including appropriate selection of tracers and proper processing of RTD data, have not been fully developed, and there is potential to improve current methods.This work aims to implement protocols for tracer selection and establish a methodology for the determination and quantitative comparison of RTD curves obtained by the pulse method. We used an extensive material property data library and multivariate analyses to select appropriate tracers for active pharmaceutical ingredient (API) of interest. Tracer performance was evaluated in two continuous blenders using pulse input experiments. The equivalence of RTDs obtained from the API and the tracer was examined for formulations with widely different blend flow properties.For the most suitable tracer candidate, material properties were determined for mixtures with different API concentrations to ensure that blend properties containing varying amounts of tracer along the RTD profile remained similar to those of the target formulation. It was observed that even small changes in the physical properties of the target formulation would result in a different tracer RTD. This observation emphasized the importance of preserving the physical properties of the blend when characterizing the dynamical behavior of a unit operation.Further, the RTD of the tracer and the API in the blender were characterized under three different base flow properties. The outcome of these experiments enabled a fair side-by-side comparison of RTDs obtained using pulses of either API or tracer for powders with a varying range of properties. In finding an appropriate tracer, RTD profiles were compared quantitively using different methods. Multivariate analysis of variance (MANOVA) was shown to be a suitable tool for RTD profile comparisons.

Exploring Biopharmaceutical Analysis with Compact Capillary Liquid Chromatography Instrumentation.

A recent trend in the design of liquid chromatography (LC) instrumentation is the move towards miniaturized and portable systems. These smaller platforms provide wider flexibility in operation, with the opportunity for conducting analysis directly at the point of sample collection rather than transporting the sample to a centralized laboratory facility. For the manufacturing of pharmaceutical and biopharmaceutical products, these platforms can be implemented for process monitoring and product characterization directly in manufacturing environments. This article describes a portable, miniaturized LC instrument coupled to a mass spectrometer (MS) for characterization of a biopharmaceutical monoclonal antibody (mAb).

Quality Control and Quality Assurance in Pharmaceutical Industry

Quality assurance can be defined as “the part of quality management aimed at ensuring confidence that quality must be performed”. The trust provided by quality assurance is dual internal to management and external to clients, government agencies, regulators, certification bodies and third parties. An alternative definition is “the complete performance of targeted and organized activities within the framework of a quality method that can be documented to provide assurance that the commodity or service will meet the required quality. Quality assurance is comprehensive and does not have to do with the specific necessity of the product being developed. Quality Assurance (QA), Quality Control (QC), and Good Manufacturing Practice (GMP) are major considerations in the manufacturing, distribution, and marketing of pharmaceutical products to ensure their identification, potency, purity, pharmacological safety, and efficacy and effectiveness. (8) The terms Quality Assurance, Quality Control and Good Manufacturing Practices are defined in most international regulatory documents including WHO, USFDA, MHRA,TGA, MCC, etc. The quality of a pharmaceutical manufacturer's products depends on the fact that up to what satisfactory level of QA, QC and GMP system has been adopted in the process of production, distribution and marketing of products during their total shelf life. The main objective of this article is to demonstrate the fundamental difference between quality assurance, quality control and good manufacturing practice (GMP) and to emphasize their necessity for a pharmaceutical product. (8) This overview describes quality by design and identifies some of its elements. Process parameters and quality attributes are identified for every unit operation. The advantages, opportunities and steps involved in Quality by Design for pharmaceutical products are described. It is based on ICH guidelines Q8 for pharmaceutical development, Q9 for quality risk management and Q10 for pharmaceutical quality systems. It also provides the application of Quality by Design in pharmaceutical drug development and manufacturing.

Use of Artificial Intelligence in Drug Discovery and its Application in Drug Development

Artificial intelligence is an area of computer science that deals with the ability to solve problems using symbolic programming. Artificial intelligence can help solve health-care issues with large-scale applications. Expert system development is a significant and effective application of artificial intelligence. Artificial intelligence (AI) is a technology-based system that uses a variety of advanced tools and networks to simulate human intelligence. AI makes use of systems and software that can read and learn from data and to make independent judgments in order to achieve certain goals. Its applications in the pharmaceutical area are constantly being expanded, as discussed in this chapter. Recently, healthcare sector is facing some complex challenges, such as the increased cost of drugs and therapies, and society needs specific significant changes in this area. Personalized medications with the necessary dose, release parameters, and other required aspects can be manufactured according to individual patient need with the use of AI in pharmaceutical product manufacturing. Using the latest AI-based technologies will not only reduce the time it takes for products to reach the market, but it will also improve product quality and overall safety of the manufacturing process, as well as provide better resource utilization and cost-effectiveness, emphasize the importance of automation. This chapter emphasizes the importance of artificial intelligence (AI) in the pharmaceutical sector, including drug research and development, medication repurposing, enhancing pharmaceutical productivity, and clinical trials And its current and future applications in drug discovery development.