5.1.1. Pneumatic dry granulation (PDG) is a recent advance in dry granulation technology. In this method, a blended powder containing API and excipients is mildly compressed by roller compaction to create a compacted mass with a mixture of granules and fine particles. The finer particles are removed from the granules of preferred size by a pneumatic system. The correctly sized granules have good flowability and compressibility characteristics and are processed into tablets. The removed particles are usually returned to the system for another cycle of compaction.
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5.2.1. There are numerous variations on wet granulation methods, each with their own specific use cases. An overview of all granulation techniques is presented in Figure 11. As a very brief summary, some advances include the following:
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5.3.1. The core challenge in all granulation methods is to produce uniform-sized granules of consistent mixture of API and excipients that have suitable flowability and compressibility characteristics. No one method is appropriate for every API, and so matching the method best suited to the needs of a given project, facility, scale, and cost requirements is an ongoing puzzle for manufacturers and developers to determine. A high-level overview of some key attributes for different technologies is presented in Table 13.
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5.4.1. While manufacturing of nearly every type of pharmaceutical, including APIs, biologics, and advanced therapies, includes some processing of dry powders, OSD manufacturing is a particular challenge. Large quantities of powders are incorporated as raw materials, intermediate steps, and even final dosage form in the case of dry powder inhalers (DPI). Raw materials for granulation projects must be delumped or otherwise preprocessed before weighing and dispensing. Manufacturing is often centered around creating the appropriate-sized granules or powders for incorporation into a tablet or capsule, and DPIs are packaged into therapeutic devices.
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5.5.1. Continuous manufacturing (CM) methods have largely been implemented across the OSD CDMO industry because they significantly lower the energy costs, process wastage, and downtime while increasing the reproducibility from lot to lot. Many firms worldwide now utilize at least some CM within their plants. Continuous direct compression systems have proven to be the easiest to implement and are quickly becoming industry standard. Beyond direct compression systems, continuous feed of excipients and APIs and fully automated tablet testing are often the next steps to convert to CM. Some plants are moving toward fully CM systems that encompass powders in to tablets out. This can be achieved with both dry and wet granulation methods, tablet coating, and final dosage form collection.[68]
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5.6.1. Wet granulation methods have been more challenging to adapt to CM, in part because the methods are newer and continuous processing equipment hasn’t yet become mainstream. Some notable advances in equipment have improved the adoption of CM, however, and include loss-in-weight feeders and integrated granulation and tablet compression lines, along with some PATs.
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5.7.1. Although it is a common process, capsule manufacturing is just as complex as other types of pharmaceutical manufacturing. Due to the nature of the process, capsule manufacturing is very sensitive to environmental moisture and temperature changes. During mixing of the molten gelatin with colorants and other compounds, it is challenging to maintain the same temperature throughout the jelly, and mixing of viscous compounds always requires special consideration. Not only does the manufacturer need to ensure proper mixing of a system that is difficult to engineer, but the formation of bubbles in the bulk jelly can lead to improperly formed capsules. Once the capsules are formed, drying them requires constant temperature and humidity for the entirety of the drying process.
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5.8.1. Despite its advantages, spray-drying presents significant challenges, particularly for biopharmaceuticals and heat-sensitive drugs. The high temperatures required for solvent evaporation can lead to denaturation, aggregation, or degradation of proteins and peptides, compromising their therapeutic efficacy.[70][71] This is a major limitation compared with freeze-drying (lyophilization), which avoids thermal exposure but is more time-consuming and expensive. To mitigate heat-related degradation, strategies such as lowering outlet temperatures, adjusting drying kinetics, and incorporating stabilizing excipients (e.g., trehalose, sorbitol) are employed.[72] Additionally, the physical and chemical stability of spray-dried powders must be carefully controlled to prevent residual moisture accumulation, phase separation, and recrystallization, all of which can affect drug solubility and bioavailability.[73]
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5.9.1. Wet granulation is the most commonly used tablet manufacturing process, but investigators have begun studying HME as an alternative continuous granulation process using co-rotating intermeshing TSEs. The versatility of the technology has been demonstrated in applications for taste-masking, solubility enhancement, controlled or extended release, and targeted drug delivery of APIs.[54]
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5.10.1. A successful HME process depends heavily on the miscibility of the drug–polymer system, which is difficult to predict in silico. Not only must different systems be tested in an HME process, but long-term stability testing is required before the final HME components can be validated. HME development programs, therefore, rely on a number of advanced screening methods, such as solvent evaporation studies and hot-stage microscopy.[54]
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5.11.1. The market approval of Spritam (levetiracetam) demonstrated the applicability of three-dimensional (3D) printing to the pharmaceutical industry. Also known as additive manufacturing, the technology marries computer-aided design with the need for personalized drug manufacturing. Because 3D printing enables production of complex API and API formulations in very small batches, it has applicability in nearly all stages of the drug development life cycle (Table 16).[81]
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5.12.1. OSD pharmaceuticals, especially generics, are under significant cost pressures, and over the past two decades energy usage has become a significant portion of the cost.[82] Manufacturers are therefore incentivized to implement energy-efficient procedures at every step in their facility. Connecting every piece of equipment in a facility to create an internet of things (IoT) is becoming common practice. This enables big data analysis of sensors from across the facility, the creation of key performance indicators (KPIs), and continuous performance improvements. Wet granulation, drying, and milling are typically the most energy-intensive steps in a process. Using the IoT to create digital models of the process enables definition of critical quality attributes (CQAs) and allows for better consistency from batch to batch, as well as reduced waste and energy expenditure. Implementation of IoT enables techno-economic analysis, as well as traditional pharmaceutical monitoring.[83]
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