Development of Suitable Plant-Scale Drying Conditions That Prevent API Agglomeration and Dehydration

Abstract

Alisertib sodium, an investigational oral oncology drug, posed some challenges toward developing a robust and scalable drying process employing an agitated filter dryer that manifested themselves during the technical transfer to a new manufacturing site. The API studied was a monohydrate that was found to readily dehydrate and agglomerate, impacting both drug product (DP) manufacture and in vitro dissolution. A scale down agitated filter dryer was designed that was used to study the drying unit operation and identify key process parameters. Through a combination of lab-and pilot plant-scale experiments, suitable drying conditions were developed that minimized agglomeration, eliminated dehydration, and produced API that behaved acceptably in downstream DP manufacture.

Understanding API Static Drying with Hot Gas Flow: Design and Test of a Drying Rig Prototype and Drying Modeling Development

“…The outlet temperature initially decreases at the start of drying, demonstrating the effect of the evaporative cooling. 17 The outlet temperature tends to plateau at a minimum temperature, until a sudden increase occurs in the form of an inflection, indicated by the arrows in Figure 6.…”

Development of a Novel Screening Methodology for the Assessment of the Risk of Particle Size Attrition during Agitated Drying

“…If the compound still scores as medium or high risk, the plant-scale drying operation should proceed with a conservative protocol, with the caveat that insufficient or no agitation may result in negative outcomes, such as cake hardening or solid-bridging interactions, which can result in agglomeration. 2,5 As can be seen from the citric acid data, some particle morphologies may be more susceptible to breakage by impact than by shear and therefore may not show the same attrition risk in the agitated dryer as in the LabRAM.…”

“…Control of particle properties during the final steps of the production of active pharmaceutical ingredient (APIs) is often overlooked and not fully understood until later in the development cycle, typically in response to issues that arise because of an increase in scale or transfer to a different equipment train. − In many instances, drying is the last step of manufacturing and is a unit operation that is poorly understood, especially within the pharmaceutical industry. This is primarily due to the lack of both analytical methods for examining and understanding the process in real time and representative scale-down models that allow its study in the laboratory with lower material requirements. − Operating parameters (such as agitation rate and regime, liquid content of the particle bed, and drying temperature and pressure), equipment configuration (such as impeller blade design), and material properties (such as crystal morphology, strength, and size) can all impact a product’s final bulk and physiochemical properties. A poorly designed and controlled drying process can result in a number of undesirable outcomes, including agglomeration, attrition, and chemical and physical instability, that ultimately affect the manufacturability and performance of the drug product. − …”

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Implementation and In Situ Control of Downstream Production

“…Drying processes for pharmaceutical powders present a variety of challenges, often involving the formation of aggregates and decomposition of temperature-sensitive compounds. − Ciprofloxacin is prone to the formation of lumps during the drying process, especially during agitated drying at dry matter contents below 70 wt % and to dehydration for temperatures higher than 85 °C at 0.5 bar. , On top of that, drying times can fluctuate significantly depending on the starting dry matter content of the cake, which in turn is affected by fluctuations in pressure and filter resistance during the wash solvent deliquoring step. To ensure that the drug substance is consistently isolated as a dry powder and to prevent dehydration of the hydrate API, two feedback control systems were implemented in the drying process.…”