(CordenPharma Photo) Roller compactor in our CordenPharma Plankstadt (DE) OSD facility.
In the world of oral solid dose formulation, multi-station high-speed tablet presses are extraordinary pieces of equipment, where the entire process of feeding, compression and ejection takes less than a second. According to GMP drug product manufacturing standards, the resulting tablets must fulfill strict quality requirements, which include specifications like content uniformity, mass variability, and tensile strength. It is therefore easy to understand why innovators have high expectations from CDMOs for the powder that is fed to such machines. Indeed, for a powder to qualify to be processed in a tableting machine, it should generally be homogeneous, free flowing, and show a suitable tabletability profile. Next to the drug substance, such powder contains multiple solid excipients, each of which has a specific functionality. The analysis of individual powdery components reveals that each component has a different density, particle size distribution, shape, as well as mechanical properties.
In order to gain a successful outcome, it is important to understand that powder mixes are prone to artifacts that may prevent direct compression or direct filling into capsules:
- First, segregation (or demixing). This occurs primarily due to differences in the size and density of the components of a mixture. When a powder bed moves or is subject to vibrations, smaller and/or denser particles tend to concentrate at the base of a container, while larger and/or less dense particles rise to the top, which generates inhomogeneity.
- Second, poor powder flow. Many powders, because of their small size, irregular shape or surface characteristics are cohesive, meaning they do not flow well. Such poor powder flow will often result in an unacceptable mass variability within the final drug product due to variable fill of tablet dies or capsule shells.
- Third and finally, poor tablet compression characteristics. Some primary powder particles are difficult to compact into tablets.
Granulation – additional processing step considerations
Granulation is a process by which dry primary powder particles are processed to form larger particle entities that are sufficiently robust to withstand handling. Usually, granulation is applied to make intermediate products that may be further mixed with other excipients prior to tablet compression or capsule filling. Such granular intermediates typically show a narrow granule size distribution and a size of about 0.2 to 0.5 mm.
The main reasons for employing expert granulation services are:
- to prevent segregation
- to improve flow properties
- to improve compression characteristics
An ideal granulation will produce granules that contain all the constituents of the mix in the right proportion, thus preventing any segregation of individual components in the powder mixture. Granules made from smaller irregularly shaped primary particles are larger in size and typical granules have roughly the same length, width, and height. When these considerations of proportion, size and shape are properly addressed, the resulting formulation generally has better flow properties. Additionally, granules coming from the same formulation often show better tablet compression characteristics as compared to a powder blend, including the fact that granules reduce the generation of dust during handling, which is of particular interest for highly potent or toxic drug substances.
(CordenPharma Photo) Small-scale roller compactor producing ribbons at CordenPharma Plankstadt.
Granulation – pharmaceutical processes
Two types of pharmaceutical process categories can be distinguished – wet and dry granulation methods. Wet granulation consists of high shear or fluid bed granulation, both of which mainly use water followed by drying, whereas dry granulation is the result of an aggregation by high pressure, leading to a pre-densification of the powder bed. Milling and sieving then provide the desired granules for further processing. It is important to keep in mind here that granules obtained by different processes do not have the same tableting properties and the processes are not freely interchangeable.
Dry granulation – often a process of choice
In order to avoid any granulation liquid and the loss of energy needed for drying, dry granulation is often the best alternative for heat and moisture sensitive products. Nowadays, dry granulation is mainly done by roller compaction for all kinds of molecules, independent of heat and moisture sensitivity. In roller compaction, a powder bed is squeezed between two counter rotating rollers to form a compressed ribbon. The ribbon density is a critical quality attribute prior to breaking down the ribbon into granules by milling. Per its design, roller compaction is also an essential tool in pharmaceutical continuous manufacturing. Here, when powder is fed to the rolls, ribbons are produced that are immediately milled to provide the desired granules for further processing.
(CordenPharma Photo) Typical fraction of ribbons as obtained by roller compaction.
Compaction simulation: assessing key dry granulation process parameters
To exhibit consistent tableting behavior on the tablet press, constant pre-densification and granule size distribution, as well as ribbon density, is achieved by controlling the feeding rate and applied pressure of the rolls at a given roll gap, both by an automatic feedback loop.
Because different suppliers provide roller compactors of various sizes and throughput, all showing slightly different features and geometries, it is important to account for instrument differences and ensure a smooth and successful process transfer from one roll compactor to another by employing, for example, a compaction simulator to explore the densification process. A compaction simulator is a single punch press that allows for compression simulation using minimal quantities of material. In addition, they are instrumented, meaning they have inner sensors that capture all necessary data like force and displacement of upper and lower punches as a function of time during the entire compaction process.
CordenPharma routinely uses a compaction simulator for the development and characterization of roller compaction and tableting processes. We have developed and implemented an efficient process to generate data with the smallest amount of material possible. The generated data provides process understanding that is critical to the implementation of robust processes at commercial speed and scale. Demonstrating process understanding is also an important aspect of any regulatory filing and helps to justify process parameters and settings.
(CordenPharma Photo) CordenPharma’s compaction simulator is used for the development and characterization of roller compaction processes.
CordenPharma is your partner of choice for OSD formulation development and manufacturing
We support you during the entire lifecycle of your OSD drug products, from early phase development, clinical supplies, late-stage registration and validation to commercial manufacturing and packaging. We place an emphasis on early phase formulation screening considering biopharmaceutic principles, formulation development considering compatibility, performance and scalability, and process development, transfer, and characterization to reach filing readiness. Our experts take care to bring your molecules from preclinical through all clinical phases to market. Additionally, we handle APIs with OELs down to the picogram per cubic meter level.
