Small scale to large scale: a major issue for the industrial transfer
The manufacturing of pharmaceutical tablets is a complex process involving several steps, like powder granulation or compression in which various problems can occur. The ultimate goal of the development teams is to result in a manufacturing process that guarantees the product quality.
One of the first steps of the pharmaceutical development is to explore the process “frontiers” and to determine which parameters are critical to obtain a product of quality. This early phase also called Quality-by-Design (QbD) includes a series of experiments most often executed at labscale in order to minimize API consumption and optimize operations duration.
However, it is commonly observed that the batch size of process itself is a parameter that influences the results of this process, so the challenge is:
how can one ensure that the work done at lab scale is representative of the production scale?
This article will focus on the scale-up rules that are applied at Skyepharma for the industrialization of wet granulation and powder compression processes.
Powder granulation
The wet granulation is commonly used to improve the flowability, compressibility and the stability of pharmaceutical powders in numerous cases, leading to process facilitation. The high shear granulator simply consists of a bowl and a pale at the bottom that mix powder and helps densification all along wetting. The granulators are also often equipped with a chopper that is usually used to break big agglomerates.
During process scale-up, some critical parameters must be considered to ensure consistent and reproducible results at any scale, such as:
- Filling level
- Impeller speed (speed of the pale, setting value in rpm on the equipment)
- Wetting flow rate
- Homogenization duration
- Chopper speed
- Overall liquid amount
At Skyepharma, we are able to perform granulation coupled with fluid-bed drying from lab scale (1L) to industrial scale (600 and 1200 liters). At granulation scale-up, some parameters have to be maintained as constant as possible to make sure to obtain a batch-to-batch final blend of similar compressibility. Among the critical parameters that must remain unchanged, one can cite the granulator bowl filling level, the wetting flow rate (that can be normalized in amount of liquid sprayed/min/kg of dry inner phase) as well as the angular velocity (speed at the extremity of the pale of granulator). This latter can be estimated with the following formula :
At Skyepharma, we have defined the values of impeller speed (in rpm) to apply on each granulator equipment in order to optimize products scale-up (see figure below).
Thanks to the knowledge of Skyepharma’s team on granulation and the transfer laws, performing the granulation process at lab scale is an essential step to gain knowledge on the product and anticipate the scale up parameters. Small scale process allows the team to provide expertise and to suggest improvements in order to perform the large-scale process with minimal risk of failure, and so, ensure a right first time at industrial scale with less cost and less consumption of raw material.
The main critical point at blend preparation is to ensure that the active ingredient is uniformely distributed into the final blend to be tabletted). This is achieved by maintaining same number of revolutions (speed x mixing duration) at mixing during lubrication and final blend preparation steps.
The final blend must also present suitable porosity in order to get tablets with targeted properties (mainly hardness, dissolution and disintegration). Skyepharma is equipped with a helium pycnometer that can help comparison between different blends and ease pharmaceutical product development.
Powder compression
The series manufacturing of tablet is performed on rotary presses, for instance on Hata, Fette or Kilian machines at Skyepharma. These equipments have amazing production rates: tens of thousands tablets per hour, consuming high quantities of granulated powder, the product of the previously described process.
The properties of the final tablets from a rotary press are mainly driven by
- The powder properties / quality
- The compression pressure
- The compression cycle and speed (i.e. the position of the punches according to the time during the compression step)
The powder quality is determined by the used excipients and by the granulation step, described previously. However, the other two listed parameters are determined by the rotary press type and settings, which is summarized in the following diagram.
If the compression cycle and compression pressure are not correctly set, important problems can occur and impact the quality of the tablet, like incorrect mass, incorrect release properties or defects (like lamination, chipping or sticking).
To accurately develop a tablet that avoid these problems, without mobilizing the rotary press, the developer teams of Skyepharma use the Styl’One Evolution (simulator of compression) to perform the compression experiments. This machine from Medelpharm is a single station tablet press that is instrumented and numerically controlled using incremental sensors. This device allows our teams to mimic the geometry of the rotary press that will be used for the large-scale production, and to easily play on all the press settings mentioned earlier. Everything is executed so that the compression on the Styl’One is a perfect reproduction of the compression on the large-scale machine, but with low raw material consumption.
Thus, the optimal parameters settings are determined in lab scale on the Styl’One, and can be precisely transposed to the large-scale to obtain the same compression step, resulting in tablets with the aimed properties and attributes. It is particularly useful to plot a hardness plateau or to define rejection limits to be applied on the industrial press.
Conclusion
With their fine expertise in granulation and compression operations, Skyepharma’s teams are able to upscale processes from laboratory to industrial. By using transfer laws in the case of granulation or by mimicking cycles in the case of powder compression, it is possible to reach the “right first time” at process scale-up, thus saving time and money for our customers.