Continuous Manufacturing Technology Research Articles

Continuous manufacturing technologies in upstream pharmaceutical supply chains: Combining engineering and managerial criteria

AbstractThe COVID‐19 pandemic exposed vulnerabilities in upstream pharmaceutical supply chains (PSC). One is that the global supply of active pharmaceutical ingredients (APIs) is overly dependent on few locations and large‐scale batch manufacturing. Regulators hope to enable more dependable location decisions and improved processing quality with the adoption of advanced technologies such as process intensification through continuous manufacturing (CM). Conceptual work suggests that the benefits of shifting from batch to CM accrue end‐to‐end across the PSC. Yet detailed quantitative information about CM is limited at an early stage of evaluation, and too specialised to inform managerial decisions about PSC reconfiguration. Supply chain and engineering criteria are rarely combined in the early‐stage evaluation of alternative CM technologies. Extant CM research typically overlooks implications for supply chain managers. To address the current gap, this article evaluates, at an early stage of adoption, alternative CM reactor technologies for the synthesis of APIs in selected therapeutic areas. With evidence from secondary data, relevant technologies and criteria are identified, and their relative importance is evaluated in a semi‐quantitative fashion following analytical hierarchy process (AHP) principles, ensuring that findings are intelligible to both engineers and managers. The proposed empirical work enriches previous conceptual frameworks predicated on volume‐variety considerations. Specifically, findings suggest that, all things considered, microreactor technologies outperform alternatives. However, PSC managerial considerations introduce nuances in specific therapeutic areas, for example, antivirals where a tension between complex chemistry and the need for flexibility in unit operations may favour batch manufacturing. For analgesics the need to exploit the existing manufacturing base whilst addressing inventory reduction favours technologies that incorporate elements of batch and CM. The proposed analysis is in line with real‐world decisions that global medicines manufacturers are increasingly facing, as governments seek to develop local health countermeasures to the COVID‐19 pandemic in the absence of detailed information.

A systematic techno-economic approach to decide between continuous and batch operation modes for injectable manufacturing

A comprehensive approach is proposed to systematically determine the optimal mode of operation between continuous and batch injectable manufacturing considering product and market conditions. At the core of this approach are two integrated complete mathematical modules for discrete and continuous injectable manufacturing, which are supplemented with an economic evaluation module that can then be used to explore the impact of all relevant process parameters (e.g., lot-size, number of operators, solubility, product demand, raw material costs). When the developed approach was applied to two case studies, it was found that batch production was preferred at low to moderate solution (raw material) costs. In contrast, at higher solution costs, the preference for batch and continuous production processes changed back and forth as the annual product demand changed. The study also found that continuous production processes became increasingly preferred at medium to large final dosage volumes and a competitive alternative even at moderate solution costs. From a decision-making point of view, batch injectable manufacturing will be preferred over the novel continuous manufacturing technology unless there is a significant economic incentive to overcome the perceived technology risk. The proposed approach is intended as a decision-support tool for pharmaceutical process engineers.

Continuous Twin Screw Granulation: A Review of Recent Progress and Opportunities in Formulation and Equipment Design.

Continuous twin screw wet granulation is one of the key continuous manufacturing technologies that have gained significant interest in the pharmaceutical industry as well as in academia over the last ten years. Given its considerable advantages compared to wet granulation techniques operated in batch mode such as high shear granulation and fluid bed granulation, several equipment manufacturers have designed their own manufacturing setup. This has led to a steep increase in the research output in this field. However, most studies still focused on a single (often placebo) formulation, hence making it difficult to assess the general validity of the obtained results. Therefore, current review provides an overview of recent progress in the field of continuous twin screw wet granulation, with special focus on the importance of the formulation aspect and raw material properties. It gives practical guidance for novel and more experienced users of this technique and highlights some of the unmet needs that require further research.

US backs domestic drug production

As a new administration gets to work in Washington, DC, projects launched by the previous administration to secure domestic pharmaceutical production are moving ahead. On Jan. 15, the US awarded a $69.3 million contract to Continuus Pharmaceuticals to build a facility in Woburn, Massachusetts, that will produce three medicines that are currently imported. A week later, Civica Rx said it will use government funding to build a $124.5 million sterile injectable-drug facility in Petersburg, Virginia. The grant to Continuus is from the US Department of Defense in conjunction with the Department of Health and Human Services. It will fund construction of what the firm says will be the first facility to employ continuous manufacturing technology in the end-to-end production of small-molecule active pharmaceutical ingredients (APIs) and finished drugs. Continuus, which grew out of a partnership between the Massachusetts Institute of Technology and Novartis, is among the companies pioneering continuous technologies

Development of Continuous Manufacturing Technology for Solid Dosage form in Eisai

Development of Continuous Manufacturing Technology for Solid Dosage form in Eisai

Development and Scale-Up of Diversion Strategy for Twin Screw Granulation in Continuous Manufacturing

Successful implementation of Continuous Manufacturing technology requires real time product quality monitoring that can result into rejection strategies for material manufactured outside process control limits. In a twin screw granulation process, parameters like water content, powder feed rate, and granulator screw speed can influence granule quality. Deviations in any of these parameters from the set-point may affect granule quality. Having a sound diversion strategy in place can help divert these implicated granules to waste. Residence time distribution experiments were conducted on a 16-mm Thermo Fisher twin screw granulator (TSG) for a range of process parameters, and the data was modelled to predict the needed diversion time as a function of process parameters. Scale-up from the 16-mm to 24-mm granulator was evaluated and data was found to scale based on mass per unit volume of granulator (channel fill), thus enabling 16-mm data to scale to 24-mm. The diversion strategy proposed is based on utilizing a wash out curve derived from residence time distribution to quantify the maximum concentration of implicated material that could be present in the next downstream unit operation(s) (e.g. a fluid bed dryer) and ensuring it is less than a suitable threshold to prevent product quality impact.

Vibrations of Air-Coupled Web Systems

Abstract The prediction and measurement of vibrations of the low-frequency transverse modes of tensioned webs are of increasing interest for process monitoring, quality control, and process stability in roll-to-roll flexible hybrid and stretchable electronics manufacturing, nanomanufacturing, coated layer patterning, and other continuous manufacturing technologies. Acting as distributed added mass, the surrounding air significantly affects the frequency responses of taut thin webs in ambient roll-to-roll processes in comparison with those in vacuo. In this paper, we present closed-form, semi-analytical, universal hydrodynamic functions used to accurately predict the lowest symmetric and anti-symmetric transverse frequency response for any uniaxially tensioned web of arbitrary material and aspect ratio used in roll-to-roll processes. Experimental validation is carried out by using pointwise laser measurements of acoustically excited webs with different pre-tensions, web materials, and aspect ratios. These closed-form hydrodynamic functions provide roll-to-roll process designers a convenient way to predict the lowest frequencies of such web systems without the need to resort to computationally intensive methods; alternately, these functions allow for the quick identification of conditions when air-coupling is important to determine the web’s vibration response. The results presented herein are expected to help ongoing efforts to improve process monitoring and control in a variety of roll-to-roll continuous manufacturing technologies.

Continuous Pharmaceutical Manufacturing and Powder Technology

Continuous Pharmaceutical Manufacturing and Powder Technology

Continuous manufacturing of a pharmaceutical cream: Investigating continuous powder dispersing and residence time distribution (RTD)

Recently, an innovative continuous manufacturing technology for a pharmaceutical oral suspension was proposed, based on two consecutive mixing units. A limitation of this technology is the need to dissolve or disperse powder-based raw materials in a liquid via a batch step before continuous manufacturing. Therefore, the aim of the current study was to develop and investigate a method to introduce powders continuously into the existing equipment via the implementation of two upstream continuous unit operations: a powder feeder and powder dispersing unit. A pharmaceutical cream was selected as model formulation to demonstrate the flexibility of the continuous manufacturing technology towards different types of semi-solid and liquid formulations. The ability to continuously feed and disperse active pharmaceutical ingredient (API) using the proposed method was assessed via an experimental design, in which the impact of several process parameters of the powder dispersing unit on the API concentration (relative error (RE) and relative standard deviation (RSD)) was examined. A Raman spectroscopic method was developed to quantify the API concentration in-line after the powder dispersing step. The API concentration was independent of the process parameters and fell within the acceptance limits, except for two experimental runs where a deviating API concentration was observed. These results demonstrate that the continuous powder feeding and dispersing method was suitable, and that a completely continuous manufacturing system was obtained. To achieve raw material traceability and understanding the mixing behavior, the residence time distribution (RTD) of a tracer inside the continuous manufacturing equipment was determined using a colorimetric technique. The time required to remove all tracer from the powder dispersing unit operation was very long (1481 s) and therefore the volume inside this unit operation should be reduced by designing new equipment with smaller dimensions. At the two consecutive mixing units, the peak and mean residence time were influenced by throughput, whereas mixing speed in both mixing units had a significant impact on the degree of axial mixing. Finally, the continuously manufactured cream had a similar rheological behavior as the original batch-wise manufactured cream.

Natural Products Extraction of the Future—Sustainable Manufacturing Solutions for Societal Needs

The production of plant-based extracts is significantly influenced by traditional techniques and the natural variability of feedstock. For that reason, the discussion of innovative approaches to improve the manufacturing of established products and the development of new products within the regulatory framework is essential to adapt to shifting quality standards. This perspective of members of the DECHEMA/ProcessNet working group on plant-based extracts outlines extraction business models and the regulatory framework regarding the extraction of traditional herbal medicines as complex extracts. Consequently, modern approaches to innovative process design methods like QbD (Quality by Design) and quality control in the form of PAT (Process Analytical Technology) are necessary. Further, the benefit of standardized laboratory equipment combined with physico-chemical predictive process modelling and innovative modular, flexible batch or continuous manufacturing technologies which are fully automated by advanced process control methods are described. A significant reduction of the cost of goods, i.e., by a factor of 4–10, and decreased investments of about 1–5 mil. € show the potential for new products which are in line with market requirements.

A continuous manufacturing concept for a pharmaceutical oral suspension

The aim of this study was to investigate the applicability of an innovative continuous manufacturing system for semi-solid and liquid pharmaceutical formulations. A commercially available pharmaceutical oral suspension was selected as model formulation. Premixes of the raw materials were dosed via peristaltic pumps to the mixing compartment, which consists of two consecutive mixing units. An experimental design was used to study the influence of several process parameters (throughput, mixing speed in mixing unit 1 and mixing speed in mixing unit 2) on the quality attributes of the oral suspension. The pH, density, active pharmaceutical ingredient (API) concentration, sedimentation after 30 days (expressed by the sedimentation volume) and rheological characteristic (yield stress) of the suspension were determined. No significant influence of the process parameters on the pH, density and API concentration was observed. The throughput and mixing speed in mixing unit 1 had a significant impact on both the sedimentation volume and yield stress, and were therefore critical to acquire physical stable suspensions. Furthermore, the yield stress measured one day after production was predictive for the occurrence of sedimentation in the suspensions after 30 days. When selecting the optimal process settings, the continuously manufactured suspension had a similar product quality as the original batch-processed suspension and even possessed a higher yield stress. This study demonstrated that the investigated innovative continuous manufacturing technology is suitable for the manufacturing of a commercially available pharmaceutical suspension and that the product quality can be optimized by adjusting the process parameters.

Potential of Continuous Manufacturing for Liposomal Drug Products.

Over the last several years, continuous manufacturing of pharmaceuticals has evolved from bulk APIs and solid oral dosages into the more complex realm of biologics. The development of continuous downstream processing techniques has allowed biologics manufacturing to realize the benefits (e.g., improved economics, more consistent quality) that come with continuous processing. If relevant processing techniques and principles are selected, the opportunity arises to develop continuous manufacturing designs for additional pharmaceutical products including liposomal drug formulations. Liposome manufacturing has some inherent aspects that make it favorable for a continuous process. Other aspects such as formulation refinement, materials of construction, and aseptic processing need development, but present an achievable challenge. This paper reviews the current state of continuous manufacturing technology applicable to liposomal drug product manufacturing and an assessment of the challenges and potential of this application.

Microstructure and Properties of ZL101 Alloy Affected by Substrate Movement Speed of a Novel Semisolid Continuous Micro Fused-Casting for Metal Process

A novel semisolid continuous Micro Fused-Casting additive manufacturing technology for producing a ZL101 alloy strip was developed, Micro Fused-Casting means that the semisolid metal slurry was pressed out from the outlet of bottom of crucible to the movable plate. The degree of sub-cooling was easily provided by movement of substrate in the micro fused-casting area. Under the aid of 3D manufacturing software, the ZL101 alloy strip was solidified and formed layer by layer. The microstructure and properties of ZL101 semisolid slurry were improved by the cooling conditions. The results showed that the ZL101 alloy strip samples fabricated by Micro Fused-Casting had uniform structures and good performances with the substrate movement speed at 20 mm/s and the temperature at 590 °C, the ultimate tensile strength and elongation of the ZL101 alloy strip reached 242.59 MPa and 7.71%, while the average Vickers hardness was 82.55 HV.

A Training on: Continuous Manufacturing (Direct Compaction) of Solid Dose Pharmaceutical Products

As the pharmaceutical industry increasingly adopts continuous manufacturing technology, significant attention must be paid to process analytical technology (PAT), process integration, and process control. Published information is no substitute for hands-on comprehensive training, which is critical to implementing and operating continuous pharmaceutical manufacturing systems effectively and efficiently. In this article, an intensive hands-on training course has been developed and implemented at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based on 15 years of experience and several implemented systems. Here, we brought the details of the four integral components in a continuous direct compression manufacturing process: (1) unit operations, (2) PAT, (3) modeling and process controls, and (4) material characterization. Each section built-in classroom lectures with a brief overview on the theoretical aspects of each topic, followed by a hands-on session covering the classroom theory. The training program is described here in sufficient detail to enable creation of similar programs at other institutions.

Design and Evaluation of Topical Diclofenac Sodium Gel Using Hot Melt Extrusion Technology as a Continuous Manufacturing Process with Kolliphor® P407.

The aim of the present context was to develop and evaluate a Kolliphor® P407-based transdermal gel formulation of diclofenac sodium by hot melt extrusion (HME) technology; central composite design was used to optimize the formulation process. In this study, we have explored first time ever HME as an industrially feasible and continuous manufacturing technology for the manufacturing of gel formulation using Kolliphor® P407 and Kollisolv® PEG400 as a gel base. Diclofenac sodium was used as a model drug. The HME parameters such as feeding rate, screw speed, and barrel temperature were crucial for the semisolid product development, and were optimized after preliminary trials. For the processing of the gel formulation by HME, a modified screw design was used to obtain a uniform product. The obtained product was evaluated for physicochemical characterization such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), pH measurement, rheology, surface tension, and texture profile analysis. Moreover, it was analyzed for general appearance, spreadibility, surface morphology, and drug content. The optimized gel formulation showed homogeneity and transparent film when applied on a glass slide under microscope, pH was 7.02 and uniform drug content of 100.04 ± 2.74 (SD = 3). The DSC and XRD analysis of the HME gel formulation showed complete melting of crystalline API into an amorphous form. The Kolliphor® P407 and Kollisolv® PEG400 formed excellent gel formulation using HME with consistent viscoelastic properties of the product. An improved drug release was found for the HME gel, which showed a 100% drug release than that of a marketed product which showed only 88% of drug release at the end of 12h. The Flux value of the HME gel was 106 than that of a marketed formulation, which showed only about 60 value, inferring a significant difference (P < 0.05) at the end of 1h. This study demonstrates a novel application of the hot melt extrusion process for manufacturing of topical semisolid products.

Throughput Optimization of Continuous Biopharmaceutical Manufacturing Facilities.

In order to operate profitably under different product demand scenarios, biopharmaceutical companies must design their facilities with mass output flexibility in mind. Traditional biologics manufacturing technologies pose operational challenges in this regard due to their high costs and slow equipment turnaround times, restricting the types of products and mass quantities that can be processed. Modern plant design, however, has facilitated the development of lean and efficient bioprocessing facilities through footprint reduction and adoption of disposable and continuous manufacturing technologies. These development efforts have proven to be crucial in seeking to drastically reduce the high costs typically associated with the manufacturing of recombinant proteins. In this work, mathematical modeling is used to optimize annual production schedules for a single-product commercial facility operating with a continuous upstream and discrete batch downstream platform. Utilizing cell culture duration and volumetric productivity as process variables in the model, and annual plant throughput as the optimization objective, 3-D surface plots are created to understand the effect of process and facility design on expected mass output. The model shows that once a plant has been fully debottlenecked it is capable of processing well over a metric ton of product per year. Moreover, the analysis helped to uncover a major limiting constraint on plant performance, the stability of the neutralized viral inactivated pool, which may indicate that this should be a focus of attention during future process development efforts.LAY ABSTRACT: Biopharmaceutical process modeling can be used to design and optimize manufacturing facilities and help companies achieve a predetermined set of goals. One way to perform optimization is by making the most efficient use of process equipment in order to minimize the expenditure of capital, labor and plant resources. To that end, this paper introduces a novel mathematical algorithm used to determine the most optimal equipment scheduling configuration that maximizes the mass output for a facility producing a single product. The paper also illustrates how different scheduling arrangements can have a profound impact on the availability of plant resources, and identifies limiting constraints on the plant design. In addition, simulation data is presented using visualization techniques that aid in the interpretation of the scientific concepts discussed.

Advanced Implantable Drug Delivery Systems via Continuous Manufacturing.

Polymeric implantable drug delivery systems have remarkable potential for systemic delivery of various therapeutic agents. Generally, drug-loaded implants do not require a vehicle for delivery and can be used to attain prolonged delivery into the systemic circulation of active pharmaceutical ingredients (APIs) with enhanced drug bioavailability. Furthermore, implants can provide drug release ranging from months to years, which improves patient compliance, especially for poorly bioavailable and rapidly metabolized compounds. Continuous manufacturing technology (e.g., hot-melt extrusion, or HME) has been successfully employed to prepare drug-loaded single-unit polymeric implants. Employing heat and mechanical shear, such systems retain the stability of thermolabile therapeutics (e.g., proteins) in implants. HME has emerged as important because of its varied applications that combine economic viability with solvent-free and easy scale-up processing. Moreover, it has been recognized from a quality-by-design (QbD) viewpoint by the FDA.

Continuous Drying of Small Particles for Pharmaceutical Applications—An Evaluation of Selected Lab-Scale Systems

Moving toward continuous manufacturing in the pharmaceutical industry offers new possibilities, such as reducing costs and improving flexibility and product quality. However, this paradigm change requires new small-scale continuous manufacturing technologies. Since drying is one of the crucial elements of pharmaceutical production, we performed an evaluation of existing drying technologies suitable for continuous production. We focused on small-scale equipment for handling preconcentrated slurries at the kg/h scale. Lactose (soluble) and ibuprofen (poorly soluble) suspensions were dried, first, in two fluidized bed spray dryers, second, in a small-scale spray dryer, third, in a spin flash dryer, fourth, in a paddle dryer, and, finally, in a corotating twin-screw extruder. During these trials we evaluated the performance of the equipment and its advantages and disadvantages with regard to pharmaceutical production. An analysis was performed to compare the different technologies. Our findings confirm that t...

Effect of supercritical CO2plasticization on the degradation and residual crystallinity of melt-extruded spironolactone

Immediate-release solid dispersions of a slowly dissolving active pharmaceutical ingredient, spironolactone, were prepared by supercritical-CO2-assisted melt extrusion (a solvent-free and continuous manufacturing technology) using Eudragit E as matrix. Through optimizing process parameters (i.e. temperature, melt throughput, pressure and CO2 flow), stable foams with high porosity, homogeneous structure and thin (even submicronic) walls could be prepared, as revealed by scanning electron microscopy. The samples were found to be rigid enough to mill, enabling further processing, as is necessary to formulate tablets. The influence of extrusion temperature and melt throughput on residual drug crystallinity was measured using non-invasive confocal Raman mapping coupled with chemometric analysis, while the influence on the degree of drug degradation was determined using high performance liquid chromatography. The plasticizing effect of supercritical CO2 was shown to reasonably improve the purity of the prepared solid dispersions by enabling high-yield production at lower temperature ranges. At the same time, shorter residence time and lower temperature slightly increased residual drug crystallinity. The obtained foamy structures ensured immediate drug dissolution in an acidic medium. Copyright © 2014 John Wiley & Sons, Ltd.

Scalable, Semicontinuous Production of Micelles Encapsulating Nanoparticles via Electrospray

Nanoparticle encapsulation within micelles has been demonstrated as a versatile platform for creating water-soluble nanocomposites. However, in contrast to typical micelle encapsulants, such as small molecule drugs and proteins, nanoparticles are substantially larger, which creates significant challenges in micelle synthesis, especially at large scale. Here, we describe a new nanocomposite synthesis method that combines electrospray, a top-down, continuous manufacturing technology currently used for polymer microparticle fabrication, with bottom-up micellar self-assembly to yield a scalable, semicontinuous micelle synthesis method: i.e., micellar electrospray. Empty micelles and micellar nanocomposites containing quantum dots (QDs), superparamagnetic iron oxide nanoparticles (SPIONs), and their combination were produced using micellar electrospray with a 30-fold increase in yield by weight over batch methods. Particles were characterized using dynamic light scattering, transmission electron microscopy, and scanning mobility particle sizing, with remarkable agreement between methods, which indicated size distributions with variations of as little as ~5%. In addition, new methodologies for qualitatively evaluating nanoparticle loading in the resultant micelles are presented. Micellar electrospray is a broad, scalable nanomanufacturing approach that should be easily adapted to virtually any hydrophobic molecule or nanoparticle with a diameter smaller than the micelle core, potentially enabling synthesis of a vast array of nanocomposites and self-assembled nanostructures.