Assessment of potential risks at the pharmaceutical development stage of minitablets

The production of mini tablets (MTs) differs significantly from the production of regular-sized tablets and involves certain risks. The article analyzes scientific publications on the topic of MTs development and production, and based on the data obtained, assesses the risks associated with it. The aim: To conduct a risk assessment during the pharmaceutical development of MTs. Materials and methods. The research materials were based on the ICHQ8 guidelines for pharmaceutical development and ICHQ9 guidelines for quality risk management, State Pharmacopoeia of the Russian Federation XV edition, scientific publications on the pharmaceutical development and production of MTs. The study was conducted using the PHA (preliminary hazard analysis) method. The following were considered as critical quality attributes (CQAs) of MTs: disintegration, dissolution, uniformity of dosage units, uniformity of mass, crushing strength, and friability. Hazards were identified using the Ishikawa diagram method. Risk analysis was performed based on data from scientific publications on the development and production of MTs. Articles were searched for between 1990 and 2024 in the ScienceDirect, PubMed, Google Scholar, and elibrary.ru databases. Based on the information presented in these articles and using a logical method, the probability of occurrence and severity (consequences) of the risks were determined. Risk assessment was carried out using a risk matrix. Results. Among the parameters of the MTs production process, the compression and mixing stages pose a danger. The compression is associated with a high risk for the following CQAs: dissolution, uniformity of dosage units, uniformity of mass, and crushing strength. Mixing is critical to ensuring dosage uniformity. Parameters of the active pharmaceutical ingredient (API), such as particle size and shape, significantly affect dissolution. In addition, the compressibility and flowability of the API are risk factors for ensuring the uniformity of dosage and MTs mass. The choice of excipients (EPs) is of great importance in the development of MTs. The type and content of the filler are of the greatest risk to the studied MTs. An irrational choice of disintegrant and anti-friction EPs can lead to impaired disintegration and dissolution of MTs. Conclusion. As a result of the risk assessment, hazards were identified, and key risks associated with the pharmaceutical development of MTs were analyzed and evaluated. Particular attention was paid to the main groups of hazards — the influence of the properties of API, EPs, and production process parameters on MTs CQAs. It was found that during the development of MTs, the shape and size of the API particles, the compressibility and flowability of the powder mixture, the type and content of the filler and disintegrant, as well as such technological process parameters as pressing and mixing, pose a particular risk.