Critical review on the role of excipient properties in pharmaceutical powder-to-tablet continuous manufacturing

13 Aug 2024 | Peer-reviewed journal | Contributor(s): Sara Fathollahi, Pauline H. M. Janssen, Bastiaan H. J. Dickhoff, Henderik W. Frijlink

The pharmaceutical industry is gradually changing batch-wise manufacturing processes to continuous manufacturing processes, due to the advantages it has to offer. The final product quality and process efficiency of continuous manufacturing processes is among others impacted by the properties of...

Non-destructive detection of disintegrant levels in compressed oral solid dosage forms

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Sultan, Tipu, Rozin, Enamul Hasan, Dave, Vivek S., Cetinkaya, Cetin

Quality issues related to compressed oral solid dosage (OSD) forms, such as tablets, arise during the design, development, and production stages, despite established processes and robust production tools. One of the primary quality concerns is the disintegration properties and drug release...

Machine learning framework for extracting micro-viscoelastic and micro-structural properties of compressed oral solid dosage forms

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Sultan, Tipu, Rozin, Enamul Hasan, Paul, Shubhajit, Tseng, Yin-Chao, Cetinkaya, Cetin

A compressed pharmaceutical oral solid dosage (OSD) form is a strongly micro-viscoelastic material composite arranged as a network of agglomerated particles due to its constituent powders and their bonding and fractural mechanical properties. An OSD product's Critical Quality Attributes, such as...

Machine learning modeling for ultrasonic quality attribute assessment of pharmaceutical tablets for continuous manufacturing and real-time release testing

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Sultan, Tipu, Rozin, Enamul Hasan, Paul, Shubhajit, Tseng, Yin-Chao, Dave, Vivek S., Cetinkaya, Cetin

In in-process quality monitoring for Continuous Manufacturing (CM) and Critical Quality Attributes (CQA) assessment for Real-time Release (RTR) testing, ultrasonic characterization is a critical technology for its direct, non-invasive, rapid, and cost-effective nature. In quality evaluation with...

Orodispersible films: Product transfer from lab-scale to continuous manufacturing

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Thabet, Yasmin, Breitkreutz, Joerg

Orodispersible films have been described as new beneficial dosage forms for special patient populations. Due to various production settings, different requirements on film formulations are required for non- continuous and continuous manufacturing. In this study, a continuous coating machine was...

Optimization of Critical Quality Attributes in Tablet Film Coating and Design Space Determination Using Pilot-Scale Experimental Data

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Liu, Huolong, Meyer, Robert, Flamm, Matthew, Wareham, Laura, Metzger, Matthew, Tantuccio, Anthony, Yoon, Seongkyu

In this study, the novel high-speed tablet film coating process in the continuous manufacturing was investigated. The influence of key process variables (inlet air flow rate, inlet air temperature, and suspension spray rate) were investigated using a Box-Behnken experimental design method....

Matrix-assisted cocrystallization (MAC) simultaneous production and formulation of pharmaceutical cocrystals by hot-melt extrusion

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Boksa, Kevin, Otte, Andrew, Pinal, Rodolfo

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine...

The Use of a Closed Feed Frame for the Development of Near-Infrared Spectroscopic Calibration Model to Determine Drug Concentration

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Movilla-Meza, Nathaly A., Sierra-Vega, Nobel O., Alvarado-Hernández, Bárbara B., Méndez, Rafael, Romañach, Rodolfo J.

Purpose: This study evaluates the use of the closed feed frame as a material sparing approach to develop near-infrared (NIR) spectroscopic calibration models for monitoring blend uniformity. The effect of shear induced by recirculation on NIR spectra was also studied. Methods: Calibration models...

Effect of shape on the physical properties of pharmaceutical tablets

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Sultan, Tipu, Cetinkaya, Cetin

Despite a well-established process understanding, quality issues for compressed oral solid dosage forms are frequently encountered during various drug product development and production stages. In the current work, a non-destructive contact ultrasonic experimental rig integrated with a...

Micro-viscoelastic characterization of compressed oral solid dosage forms with ultrasonic wave dispersion analysis

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Sultan, Tipu, Paul, Shubhajit, Rozin, Enamul Hasan, Tseng, Yin-Chao, Bazzocchi, Michael C. F., Cetinkaya, Cetin

Due to their constituent powders, the materials of advanced compressed oral solid dosage (OSD) forms are micro-composites and strongly visco-elastic at macro- and micro-length scales. The disintegration, drug release, and mechanical strength of OSD forms depend on its micro-texture (such as...

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

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Pawar, Jaywant, Narkhede, Rajkiran, Amin, Purnima, Tawde, Vaishali

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...

Development of a novel method for the continuous blending of carrier-based dry powders for inhalation using a co-rotating twin-screw extruder

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Spahn, Jamie E., Hefnawy, Amr, Smyth, Hugh D. C., Zhang, Feng

Twin-screw extruders are useful in tuning certain product characteristics due to the ability to greatly modify screw profiles as well as operating parameters. However, their use has not yet been applied to dry powder inhalation. In this study the feasibility of using a twin-screw extruder to...

Formulation development of a continuously manufactured orodispersible film containing warfarin sodium for individualized dosing

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Niese, Svenja, Quodbach, Julian

Continuously manufactured orodispersible films (ODFs) offer a promising approach for individualized therapy with an easy to administer solid dosage form. The aim of this study was to develop a long ODF containing warfarin sodium to enable safe and more flexible dosing. Formulation development was...

The effect of binder types on the breakage and drying behavior of granules in a semi-continuous fluid bed dryer after twin screw wet granulation

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Vandevivere, L., Denduyver, P., Portier, C., Häusler, O., De Beer, T., Vervaet, C., Vanhoorne, V.

Current study investigated the effect of different binder types on the granule drying process and the granule breakage behavior in a semi-continuous fluid bed dryer integrated in the C25 ConsiGma-system. The studied binders (i.e. hydroxypropyl pea starch, hydroxypropyl methylcellulose E15,...

Delta-mannitol to enable continuous twin-screw granulation of a highly dosed, poorly compactable formulation

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Vanhoorne, V., Almey, R., De Beer, T., Vervaet, C.

In current study, it was investigated if the moisture-mediated polymorphic transition from δ- to β-mannitol during twin screw granulation (TSG) also took place in high drug loaded formulations and if the specific granule morphology associated with the polymorphic transition could enable tableting...

Managing active pharmaceutical ingredient raw material variability during twin-screw blend feeding

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Stauffer, F., Vanhoorne, V., Pilcer, G., Chavez, Pierre-François, Schubert, M. A., Vervaet, C., De Beer, T.

Continuous powder feeding is a critical step in continuous manufacturing of solid dosage forms, as this unit operation should ensure the mass flow consistency at the desired powder feed rate to guarantee the process throughput and final product consistency. In this study, twin-screw feeding of a...

Twin Screw Melt Granulation: Alternative Approach for Improving Solubility and Permeability of a Non-steroidal Anti-inflammatory Drug Ibuprofen

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Nyavanandi, Dinesh, Narala, Sagar, Mandati, Preethi, Alzahrani, Abdullah, Kolimi, Praveen, Almotairy, Ahmed, Repka, Michael A.

The current research is focused on investigating the suitability of the twin screw melt granulation (TSMG) approach for improving the solubility of a non-steroidal anti-inflammatory (NSAIDs) drug (ibuprofen), by developing granules using lipid surfactants. The solubility of the drug within the...

Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Gu, Xingxian, Zhao, Jibin, Chen, Like, Li, Yunzhong, Yu, Bo, Tian, Xiangguang, Min, Zhongcheng, Xu, Su, Gu, Huijuan, Sun, Junjie, Lu, Xiaoquan, Chang, Meng, Wang, Xufan, Zhao, Liqun, Ye, Shengqing, Yang, Hongwei, Tian, Yingtao, Gao, Feng, Gai, Yu, Jia, Guanghua, Wu, Jingjing, Wang, Yan, Zhang, Jianghua, Zhang, Xuesong, Liu, Weichun, Gu, Xin, Luo, Xi, Dong, Hai, Wang, Huaimin, Schenkel, Berthold, Venturoni, Francesco, Filipponi, Paolo, Guelat, Bertrand, Allmendinger, Thomas, Wietfeld, Bernhard, Hoehn, Pascale, Kovacic, Nikola, Hermann, Luca, Schlama, Thierry, Ruch, Thomas, Derrien, Nadine, Piechon, Philippe, Kleinbeck, Florian

LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial...

One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Salehi Marzijarani, Nastaran, Snead, David R., McMullen, Jonathan P., Lévesque, François, Weisel, Mark, Varsolona, Richard J., Lam, Yu-hong, Liu, Zhijian, Naber, John R.

We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity...

Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Parvaresh, Rojan, Nagy, Zoltan K.

Continuous manufacturing can show potential benefits over batch processing in lower turnaround times and smaller footprint in addition to higher productivity, adaptability, and consistent product quality. Although these possible benefits exist, there are also challenges in integrating the various...

Cleaning of direct compression continuous manufacturing equipment through displacement of API residues by excipients

23 Jul 2024 | Peer-reviewed journal | Contributor(s): Patel, Dhavalkumar S, Méndez, Rafael, Romañach, Rodolfo J

This feasibility study evaluates a cleaning process designed to avoid the use of detergents and reduce operator exposure to the active pharmaceutical ingredient (API). The continuous manufacturing equipment was cleaned using excipients to displace ibuprofen residues from the system. The cleaning...

Process analytics for the new era of continuous RNA manufacturing

23 Jul 2024 | Website | Contributor(s): Botonjic-Sehic, Edita

In this article, Edita Botonjic-Sehic, Head of Process Analytics and Data Science at ReciBioPharm, examines the need for a digitally controlled continuous manufacturing process to correct the shortcomings of the current standard of batch processing. She highlights the critical role in-line...

Control oriented modeling of twin-screw granulation in the ConsiGmaTM-25 production plant

09 Jul 2024 | Peer-reviewed journal | Contributor(s): Johannes Khinast, Martin Horn, Jakob Rehrl, Selma Celikovic, Johannes Poms

ConsiGmaTM-25 is a continuous production plant integrating a twin-screw granulation, fluid bed drying, granule conditioning, and a tableting unit. The particle size distribution (PSD), active pharmaceutical ingredient (API) content, and liquid content of wet granules after twin-screw...

Implementation of a fully integrated continuous manufacturing line for direct compression and coating at a commercial pharmaceutical facility – Part 1: Operational considerations and control strategy

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Conway, Stephen L., Rosas, Juan G., Overton, Paul, Tugby, Neil, Cryan, Phillip, Witulski, Frank, Hurley, Samantha, Wareham, Laura, Tantuccio, Anthony, Ramasamy, Manoharan, Lalloo, Anita, Gibbs, Mason, Meyer, Robert F.

We implement a fully integrated continuous manufacturing (CM) line for direct compression and coating of a pharmaceutical oral solid dosage form in a commercial production facility. In this first paper of a two-part series, we describe process design and operational choices made to introduce CM...

Implementation of a fully integrated CM direct compression and coating process at a commercial pharmaceutical facility - Part 2: PAT and RTD results for normal operational conditions batches.

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Rosas, JG, Brush, P, Thompson, B, Miller, C, Overton, P, Tugby, N, Stoliarskaia, D, Hurley, S, Ramasamy, M, Conway, SL

This is the second of two articles detailing the continuous manufacturing (CM) development and implementation activities for an marketed product which have been realized in novel, qualified equipment, using validated control strategy elements to enable manufacture of batches under current good...