Powder blending is a critical process within many pharmaceutical product manufacturing areas. The requirements for blend and content uniformity have been provided in numerous regulations and guidance documents. Blending and powder transfer operations have been the focus of many efforts to understand the parameters that affect the outcome and demonstrate performance. The vast majority of these processes are batch based, where the required quantities of each ingredient are added within a process vessel, which delivers a resulting fixed mass of blended material at the conclusion of its operating cycle.
Continuous manufacturing will be a significant component in the future of pharmaceutical manufacturing. The advantages of continuous manufacturing over batch manufacturing are well established.
When properly implemented, continuous processes are almost completely steady, can be designed at scale, and can be used reliably to minimize segregation and agglomeration of ingredients. Moreover, a continuous process is also the perfect scenario for implementation of Process Analytical Technology (PAT) methods are required to ensure closed-loop control of the continuous process. The business case for continuous manufacturing is very robust. In product development, continuous manufacturing systems allow the user to perform complex DOE matrices in just a few days, and using a tiny fraction of the material required to perform a comparable study in batch.
The design and operation of a continuous paddle blender differ significantly from that of a batch tumble blender. Moreover, the material is in the continuous blender for a much shorter time. In a continuous blending process, the material spends typically between a few seconds to a few minutes in the blender and experiences anywhere between 50 to a few hundred impeller revolutions.
The concept for continuous blending involves adding raw materials into one end of a processing unit, which are blended as they are conveyed to the outlet at the far end. Blending behavior becomes a function of how much interaction takes place relative to the advancement of the forming blend. With respect to the fundamental mechanisms given in the previous section, convection will occur in parallel to the primary flow of material through the blender, while diffusion will occur perpendicular to this movement. Shear forces can be added to break up agglomerates and disperse particles.
There have been recent efforts to develop continuous blending processes, which would rely on the behaviour of powder feed systems and the blending apparatus itself to act in a controllable manner, delivering finished powder at a mass per unit time basis. These types of processes have been used for many years in such industries as foods, chemicals and pet care products.
Continuous blending processes could alleviate some of the inefficiencies associated with batch handling, but process design would become much more important. Although the regulatory implications are an additional consideration, evaluating the requirements and performance of these systems for pharmaceutical production is essentially the same as in other industries.
All powder blending operations involve, to various extents, three fundamental blending mechanisms, being convection, diffusion and shear. Convection involves the gross movement of particles throughout the blender, either by a force action from a paddle or by gentle tumbling under rotational effects. Diffusion is the intermingling of individual particles at the small scale, and tends to be the slowest to occur and will generally pace the performance of a blender, particularly when smaller dose sizes are considered. Lastly, the shear mechanism involves the thorough incorporation of material passing along forced slip planes in a blender. Different types of blenders will tend to rely on some of these mechanisms more than others, and ultimately the need for each will be based on the properties of the powders being blended, along with the level of uniformity desired.
Continuous blending systems tend to fall into two broad categories: drum type systems, where an outer housing is rotated, and screw or paddle systems, where an inner shaft is rotated. The rotational action of both of these systems provides the primary blending mechanism as well as the motive force for conveying powder through the system.
Features in each can be added or tailored to enhance blending, such as baffles and segmented screw flights. . The rotational speed and blender inclination (if used) will have a strong influence on powder velocity through the system, while the overall size (cross section) and length will set capacity and residence time. There will be some interaction between these features as well.
Generally for these systems, feed hoppers or bins will be mounted on load cells, and they will use variable speed powder feeders (screw feeders, rotary valves or vibratory pan feeders) to maintain a predefined discharge rate from the vessel into the beginning of the continuous blender. The monitoring of each vessel’s contents and the calculation of discharge rate must consider the required variability. As an example, this means that the feeder cannot control to an average rate calculated over a 1 minute interval, while allowing wider variations over a 10 sec interval, if these smaller variations would impart step changes in blend composition that the blender could not recover from, given the powder residence time and blending behaviour.
Maintaining reliable powder flow of each ingredient to a continuous blending system is essential for its performance. Flow stoppages due to arching and ratholing within ingredient feed hoppers and bins are more than just a nuisance, since these problems will directly contribute to the composition of the final blend for a period of time. Any such interruptions will most likely result in material that cannot be reworked, and may call into question the acceptability of the remaining product run. The design requirement for each feed hopper must be considered in light of the application and the flow properties of the material .
Additionally, the order of addition may have an effect on the resulting distribution of the API by particle size. If the API particles have the potential to stick to carrier excipient particles, then the API should be added immediately following the excipient most representative of the final blend. A uniform distribution over a range of excipient particle sizes is desired, as this will help minimize the potential for segregation while ensuring API is not lost by dusting.
Once a continuous blending system is up and running, sampling should be used to gage its performance. Thief sampling could be used to collect material at regular intervals from the discharge area of the blender, but this type device can result in errors and questions regarding the recovery process. Full stream samples could be recovered after discharge from the blender and prior to dose formation in downstream equipment. However, the complexity of the sampling mechanism and the potential need of subdivision for analysis can make this a difficult approach. Given its mode of operation, a continuous blending system can more easily be assessed through final product sampling.