Continuous Direct Compression Process for Low Dose Active Ingredients in a Solid Dosage Form
Dr Md Anawar Hossain
Continuous direct compression (CDC) can be a more suitable process to manufacture low-dose tablets. In addition, manufacturing by using a universal platform formulation seems to be a feasible way for producing low-dose products.
Introduction
Manufacturing low-dose solid dosage form encounters some challenging issues, because a homogenous distribution of active pharmaceutical ingredient (API) must be ensured to guarantee adequate end product quality (Ervasti et al., 2020). It is difficult to spread a small amount of API evenly into a big amount of excipient/excipients leading to heterogeneity in finished product potency. Adequate mixing can’t make sure for a good blend quality due to the post-mixing handling process, which might cause segregation, i.e., de-mixing of materials. There are differences in the physical properties of particles of API and excipients, such as size, density and morphology, which are presumed to be the main factors causing segregation.
Batch-wise tablets manufacturing process
In a batch-wise tablets manufacturing process, the mixture of APIs and excipients are transported in the container or loaded into the tablet press from a container. During this transportation process and time, segregation of APIs and excipients may occur. However, we can’t understand the uniformity of APIs or potency in tablets until the quality control process tests the tablets, which is the last stage of production before packaging. If the defect is identified, then the whole batch of tablets will be rejected or dumped into waste bin.
Continuous manufacturing process
Continuous manufacturing (CM) process has been under research, trial manufacturing and discussion for the last decade in pharmaceutical manufacturing. A lot of efforts of pharmaceutical companies have made this dream into reality and as a result, at the beginning of 2020 there were several FDA- and EMA-approved products on the market which were being manufactured by continuous manufacturing process. However, a very small fraction of the total amount of marketed oral solid dosage products are manufactured by this process.
Drawbacks
The pharmaceutical companies are still now using batch manufacturing process, because they are not clear about the best strategies to apply CM processes in pharmaceutical manufacturing, i.e., for what types of products does it offer the greatest advantages?
Advantages of continuous manufacturing process
- The disadvantages of batch processes in manufacturing of low-dose products can be overcome.
- CM processing could be beneficial in manufacturing of low-dose products.
- The very low amount of material can be processed in CM line.
- The operators don’t need to transfer large powder blends vertically into container, and thus decrease the risk of segregation during processing.
- Pneumatic transports, that also include free falls, are needed in certain cases in CM processing, but here also the tendency for de-mixing could be avoided by transporting only small quantities of blend within one cycle.
- In a direct compression process, there is, however, no need for any conveyors.
- Continuous mixing has been shown to be capable to produce more homogenous mixtures as compared to batch mixing,
- Therefore, a continuous direct compression (CDC) set-up is a reliable and excellent method for low-dose manufacturing.
- Karttunen et al. (2019) reported some promising results by comparing a CDC process with traditional batch manufacturing.
- The manufacturing line may be equipped with suitable process analytical technology (PAT) tools, enabling the monitoring of API concentration during processing (and capability to reveal if problems are about to occur), makes it even more attractive.
References
Ervasti T., Niinikoski H., Mäki-Lohiluoma E., Leppinen H., Ketolainen J., Korhonen O., Lakio S. (2020). The Comparison of Two Challenging Low Dose APIs in a Continuous Direct Compression Process. Pharmaceutics 12, 279.
Karttunen A., Wikström H., Tajarobi P., Fransson M., Sparén A., Marucci M., Ketolainen J., Folestad S, Korhonen O., Abrahmsén-Alami S. (2019) Comparison between integrated continuous direct compression line and batch processing—The effect of raw material properties. Eur. J. Pharm. Sci. 133, 40–53.