Impact of Impurities on Crystallization and Product Quality: A Case Study with Paracetamol

09 Jun 2023 | Contributor(s): Urwin, SJ, Yerdelen, SHouson, I, ter;Horst, JH

A thorough, systematic study into the effect that structurally related impurities have on both the process and product quality during the crystallization of an active pharmaceutical ingredient is presented. The presence of acetanilide and metacetamol influences the crystallization and product...

Impact of material properties and process parameters on tablet quality in a continuous direct compression line

09 Aug 2023 | Peer-reviewed journal | Contributor(s): Pauline H.M. Janssen, Sara Fathollahi Bram Bekaert, Dirk Vanderroost, Timo Roelofs, Valerie Vanhoorne, Chris Vervaet, Bastiaan H.J. Dickhoff

The current paper shows how excipient properties impact the process parameters and the final tablet properties in a fully integrated continuous direct compression line. Blend properties of low-dose (1% w/w) and high-dose (40% w/w) paracetamol formulations were evaluated...

Impact of material properties and process variables on the residence time distribution in twin screw feeding equipment

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Van Snick, B, Kumar, A, Verstraeten, M, Pandelaere, K, Dhondt, J, Di Pretoro, G, De Beer, T, Vervaet, C, Vanhoorne, V

Screw feeders are integrated as dispensing units in most continuous manufacturing platforms. Hence, characterizing and modelling the residence time distribution (RTD) of materials in feeders is indispensable to understand the traceability of raw materials from the drum till tablet, enabling the...

Impact of screw configuration on the particle size distribution of granules produced by twin screw granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Vercruysse, J, Burggraeve, A., Fonteyne, M., Cappuyns, P., Delaet, U., Van Assche, I., De Beer, T., Remon, J. P., Vervaet, C.

Twin screw granulation (TSG) has been reported by different Research Article groups as an attractive technology for continuous wet granulation. However, in contrast to fluidized bed granulation, granules produced via this technique typically have a wide and multimodal particle size distribution...

Impact of surface roughness of pre-treated punches and powder properties on prevention of sticking during pharmaceutical tableting

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Takeuchi, Y, Murase, YTahara, K, Takeuchi, H

In the present study, surface-modified punches with different roughness were evaluated for their ability to prevent sticking during pharmaceutical tableting using a single punch machine. The surface roughness of the punch faces was assessed using a laser microscope. Acetaminophen and ibuprofen...

Impact of Vertical Blender Unit Parameters on Subsequent Process Parameters and Tablet Properties in a Continuous Direct Compression Line

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Kreiser, MJ, Wabel, C, Wagner, KG

The continuous manufacturing of solid oral-dosage forms represents an emerging technology among the pharmaceutical industry, where several process steps are combined in one production line. As all mixture components, including the lubricant (magnesium stearate), are passing simultaneously through...

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...

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

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra, Sahay, Abhishek, Karry, Krizia, Muzzio, Fernando, Ierapetritou, Marianthi, Ramachandran, Rohit

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...

Implementation of an online thermal imaging to study the effect of process parameters of roller compactor

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Omar, Chalak S., Hounslow, Michael J., Salman, Agba D.

During roller compaction, not only the properties of the primary powder affect the product quality but also the process parameters. Any change in the process parameters during roller compaction will result in changing the properties of the ribbon. In this study, the temperature of the ribbon...

Implementation of control system into continuous pharmaceutical manufacturing pilot plant (powder to tablet)

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Singh, Ravendra

Real-time process control 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....

Implementation of ICH Q13 Continuous Manufacturing Guidance

20 Nov 2023 | Workshop | Contributor(s): Rapti Madurawe

Continuous Manufacturing (CM) BasicsICH Q13 GuidanceFDA ExperienceFuture Directions and Enabling CM of GenericsPharmaceutical Quality Symposium 2023: Quality, Supply Chain & Advanced Manufacturing - 10/31/2023 | FDA

Implementation of Near-Infrared Spectroscopy for In-Line Monitoring of a Dehydration Reaction in a Tubular Laminar Reactor

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Mitic, A, Cervera-Padrell, AEMortensen, AR, Skovby, T, Dam-Johansen, K, Javakhishvili, I, Hvilsted, S, Gernaey, KV

Production of active pharmaceutical ingredients (APIs), fine chemicals, food products, and so on has in recent years been focused on implementing process intensification and process optimization tools. Lower costs and higher selectivity as well as better sustainability and competitiveness are the...

Implementing Continuous Manufacturing for the Final Methylation Step in the AMG 397 Process to Deliver Key Quality Attributes

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Tom, JK, Achmatowicz, MMBeaver, MG, Colyer, J, Ericson, A, Hwang, TL, Jiao, N, Langille, NF, Liu, M, Lovette, MA, Sangodkar, RP, Kumar, SS, Spada, S, Perera, D, Sheeran, J, Campbell, K, Doherty, T, Ford, DD, Fang, YQ, Rossi, E, Santoni, G, Cui, S, Walker, SD

In this article, we describe the process development efforts to improve the final methylation step in the AMG 397 drug substance process, culminating in the execution of a Good Manufacturing Practice (GMP) continuous manufacturing process. During the development, batch kinetic studies and...

Implementing Feedback Granule Size Control in a Continuous DryGranulation Line Using Controlled Impeller Speed of the GranulationUnit, Compaction Force and Gap Width

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Wilms, Annika, Teske, Andreas, Meier, Robin, Wiedey, Raphael, Kleinebudde, Peter

Purpose: In continuous manufacturing of pharmaceuticals, dry granulation is of interest because of its large throughput capacity and energy efficiency. In order to manufacture solid oral dosage forms continuously, valid control strategies for critical quality attributes should be established. To...

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

25 Jun 2024 | Peer-reviewed journal | Contributor(s): Chen, Jian, Przyuski, Katrin, Roemmele, Renee, Bakale, Roger P.

In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation...

Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Vanhoorne, V., Bekaert, B., Peeters, E., De Beer, T., Remon, J-P., Vervaet, C.

In most formulations processed via continuous twin screw granulation microcrystalline cellulose (MCC) and/or lactose are used as excipients, but mannitol is also a preferred excipient for wet granulation and tableting due to its non-hygroscopicity and inertness. Therefore, the aim of the current...

Improvement of a pharmaceutical powder mixing process in a tote blender via DEM simulations

04 Jun 2024 | Peer-reviewed journal | Contributor(s): Benedict Benque, Luca Orefice, Thomas Forgber, Matthias Habeler, Beate Schmid, Johan Remmelgas, Johannes Khinast

An industrial-scale pharmaceutical powder blending process was studied via discrete element method (DEM) simulations. A DEM model of two active pharmaceutical ingredient (API) components and a combined excipient component was calibrated by matching the simulated response in a dynamic angle of...

Improving chemical synthesis using flow reactors

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Wiles, C, Watts, P

Owing to the competitive nature of the pharmaceutical industry, Research Articleers involved in lead compound generation are under continued pressure to identify and develop promising programmes of Research Article in order to secure intellectual property. The potential of a compound for...

Improving Feedability of Highly Adhesive Active Pharmaceutical Ingredients by Silication

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Escotet-Espinoza, M. Sebastian, Moghtadernejad, Sara, Sanchez, Eric, Cappuyns, Philippe, Van Assche, Ivo, Di Pretoro, Giustino, Ierapetritou, Marianthi, Scicolone, James V., Muzzio, Fernando J.

Purpose: Loss-in-weight feeders play a vital role in assuring blend and content uniformity as well as lot-to-lot powder traceability in continuous manufacturing. Irregular flow from the feeders propagates through the system, potentially resulting in out-of-specification product. Powder properties...

Improving Pellet Quality in a Pharmaceutical Hot Melt Extrusion Process via PID Control and LOLIMOT-Based MPC

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Rehrl, J, Kirchengast, MCelikovic, S, Sacher, S, Kruisz, J, Khinast, J, Horn, M

Purpose The aim of this paper is the development of a process control concept for a hot melt extrusion (HME) and pelletization process. The new concept should improve the particle size distribution of the pellets produced. Methods Production of pellets containing an active pharmaceutical...

In line monitoring of the powder flow behavior and drug content in a Fette 3090 feed frame at different operating conditions using Near Infrared spectroscopy

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Sierra-Vega, Nobel, Sánchez-Paternina, Adriluz, Maldonado, Nadja, Cárdenas, Vanessa, Romañach, Rodolfo, Mendez, Rafael

Near infrared (NIR) spectroscopy was used to determine the drug concentration in 3% (w/w) acetaminophen blends within the complex flow regime of the tablet press feed frame just before tablet compaction. NIR spectra also provided valuable information on the powder flow behavior within the feed...

In Situ Characterization of Waters of Hydration in a Variable-Hydrate Active Pharmaceutical Ingredient Using Cl-35 Solid-State NMR and X-ray Diffraction

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Hirsh, DA, Holmes, STChakravarty, P, Peach, AA, DiPasquale, AG, Nagapudi, K, Schurko, RW

Variable-hydrate active pharmaceutical ingredients (APIs) are known to form thermodynamically and kinetically stabilized solid phases over a continuous range of nonstoichiometric hydration levels. Some of these forms can be problematic in the production of solid dosage forms (e.g., tablets and...

In Vitro Performance Tests for Continuous Manufacturing: The Impact on the Current Compendial Framework from the Viewpoint of the USP New Advancements in Product Performance Testing Expert

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Li, Hanlin Li, Nir, Ishai, Hermans, Andre, Fahmy, Raafat, Lu, Xujin, Biba, Edmond, Coutant, Carrie A.

As continuous manufacturing (CM) evolves from an emerging to widely adopted technology by industry in drug productmanufacturing, the compendiaI framework in product performance testing is also being evaluated for its applicability inCM. As such, the CM Working Group of the New Advancements in...

In-Depth Evaluation of Data Collected During a Continuous Pharmaceutical Manufacturing Process: A Multivariate Statistical Process Monitoring Approach

09 Jun 2023 | Peer-reviewed journal | Contributor(s): Silva, Ana F., Vercruysse, Jurgen, Vervaet, Chris, Remon, Jean P., Lopes, João A., De Beer, Thomas, Sarraguça, Mafalda C.

The present work presents an in-depth evaluation of continuously collected data during a twin-screw granulation and drying process performed on a continuous manufacturing line. During operation, the continuous line logs 49 univariate process variables, hence generating a large amount of data....