Application of Quality-by-Design Approach to Justify the Composition and Technology of Two-component Suppositories

Abstract

Introduction. One of the modern remedies used to treat vaginal infections are suppositories "Depantol", which have an antiseptic, regenerating effect due to the combination of chlorhexidine and dexpanthenol. The initial stage in the life cycle of any medicinal product (MP) is pharmaceutical development, a systematic approach to which implies the principle of Quality-by-Design (QbD), which is based on obtaining reliable scientific data and risk management for quality. With this approach, pharmaceutical development begins with a preliminary determination of significant factors in the creation of a drug.Aim. Aim of study was to design Quality Target Product Profile, Critical Quality Attributes, Critical Material Attributes – the initial data necessary for the development of composition and technology of a generic drug in accordance with the QbD methodology of ICH Guidance Q8 "Pharmaceutical Development".Materials and methods. Objects of study: chlorhexidine bigluconate, dexpanthenol, PEG-400 and PEG-1500, pharmaceutical development documents. Methods of study: content analysis, system analysis; FMECA method (Failure Modes, Effects and Criticality Analysis).Results and discussion. In order to implement the QbD for the production of a drug of good quality, initial data for the development of the composition and technology of two-component suppositories were obtained. Quality Target Product Profile (QTPP) was compiled taking into account the data of the original drug was used as reference. Based on the compiled QTPP, Critical Quality Attributes (CQAs) were identified. The determination of CQAs from QTPP parameters was based on the strength of the potential harm to the product. Due to the fact that we developed a well-known dosage form, quality indicators were chosen that are standard for hydrophilic suppositories. In order to determine the parameters of the drug components that affect the Critical Quality Attributes, for each of the active pharmaceutical ingredients (APIs) suppositories contain, the Critical Material Attributes (CMAs) were determined. For example, for liquid ingredients, according to the specification of the substance manufacturer, these are pH, viscosity, impurities, identification, assay, refraction index. For the initial risk assessment, risk assessment matrices of the influence of the Сritical Material Attributes of the components on the Critical Quality Attributes were compiled. When evaluating the effect of chlorhexidine bigluconate on the critical characteristics of the final product, attention was paid to all parameters from the manufacturer's specification, since any deviations in pH, density, presence of related substances and extraneous impurities, assay and identification of the substance may signal the chemical unsuitability of the component. The weight uniformity of suppositories is affected only by the parameters of the technological process. The influence of CMAs of dexpanthenol on the Critical Quality Attributes of the finished product is generally similar to the influence of the parameters of chlorhexidine bigluconate. The difference in the influence of pH and water content on the microbial limits: unlike chlorhexidine bigluconate, which has antiseptic properties, dexpanthenol is more susceptible to microbial contamination. The effect of base CMAs on identification, content uniformity, and assay is not critical. Whereas the pH, assay and identification of PEG-400 and PEG-1500 have a significant impact on the dissolution profile of the active ingredients from the finished dosage form.Conclusion. The data required for the pharmaceutical development of a generic drug, two-component suppositories, was obtained: Quality Target Product Profile, Critical Quality Attributes, Critical Material Parameters. The impact of the critical characteristics of the raw materials on the critical quality attributes of the developed suppositories was assessed.