Christopher L. Burcham

Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions.

Continuous-flow technology is devised and implemented for manufacture of a drug candidate in clinical trials. Go with the flow in drug manufacturing Although many commodity chemicals are manufactured using continuous flow techniques, pharmaceuticals are still mostly produced in large single batches. Cole et al. report a protocol for the small-volume continuous preparation of multi-kilogram quantities of a cancer drug candidate, prexasertib monolactate monohydrate, under current good manufacturing practices. Advantages of the approach include safer handling of hazardous reagents and intermediates, as well as yield and selectivity improvements in both the reaction and purification stages. Concurrent analytical monitoring also facilitated rapid trouble-shooting during the manufacturing process. Science, this issue p. 1144 Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

Particle engineering: A strategy for establishing drug substance physical property specifications during small molecule development

A strategy for physical property control of a drug substance has been developed that utilizes a science-based approach to define key drivers for particle control. These drivers are based on in vivo performance (or expected performance), content uniformity of the drug substance in drug product, and manufacturability of drug product. Quality by design principles have been used in developing the strategy. The strategy has been designed to provide expectations in terms of particle control at each state of development, translating to early-phase projects and carrying through until launch and beyond.

Guidance on Drug Substance Particle Size Controls for Solid Oral Dose Forms

Drug substance particle size is a critical property affecting drug product performance. Smaller particles dissolve faster and may improve bioavailability of the drug as a result. Smaller particles are typically dispersed more uniformly, leading to lower inter-tablet potency variation. Unfortunately, smaller particles can also result in poor powder handling characteristics or other processing issues. For example, powders can fail to flow through hoppers or stick to tooling surfaces, leading to poor tablet weight uniformity or tablet appearance issues. During crystallization, smaller particles can also be difficult to filter from the crystallization media. This can lead to higher levels of residual solvents and other impurities. Particle design and size selection are therefore critical to achieving a balance between manufacturability, bioavailability, and content uniformity. In this chapter, the impact of particle size on bioavailability is introduced and the impact on content uniformity is considered in depth. Control of the variability of tablet potency is discussed in relation to the overall particle size distribution. The risk-based selection of a positive control such as a screen to limit the maximum allowable particle size is discussed in relation to the occurrence of rare, but highly super-potent tablets.

Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing

The pharmaceutical industry has found new applications for the use of continuous processing for the manufacture of new therapies currently in development. The transformation has been encouraged by regulatory bodies as well as driven by cost reduction, decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent drug product. Continuous drug product is currently used in approved processes. A few examples of production of APIs under current good manufacturing practice conditions using continuous processing steps have been published in the past five years, but they are lagging behind continuous drug product with respect to regulatory filings.

Attainable Regions in Crystallization Processes

Abstract Process alternatives for continuous crystallization, i.e., cascades of mixed suspension, mixed product removal crystallizers (MSMPRCs) and plug flow crystallizers (PFCs), as well as batch crystallizers are discussed and modelled using population balance equations. The attainable region approach that has previously been used in the design of chemical reactor networks and separation systems is applied to the above-mentioned alternatives for crystallization processes in order to identify attainable regions in a diagram of mean product particle size vs. total process residence time. It is demonstrated that the boundaries of these attainable regions can be found numerically by solving appropriate optimization problems and that the region enclosed by these boundaries is fully accessible. Knowing the attainable region of particle sizes, it is possible to generate feasible process alternatives that allow specific particle sizes to be obtained in a given process configuration. The influence of uncertainty in the kinetic parameters required for the determination of such attainable regions is also investigated as well. These concepts are illustrated using a case study on the cooling crystallization of paracetamol grown from ethanol.