Resumen de Application of quality by design and near infrared spectroscopy in manufacturing and control of freeze-dried drug products
This thesis describes the application of Quality by Design for the development and qualification of the freeze-drying process of two drug products, named IFDA and IFDB, developed in Laboratorios Reig Jofre. IDFA is composed by an Active Principle Ingredient (API), and it is presented in two different strengths, while IDFB is more complex since, in addition to the API, it contains an excipient.
The freeze-drying process is used to transform solutions of active ingredients in more stable solid products. It is a time-consuming and expensive process; hence a successful development and optimization is a priority in the pharmaceutical industry. This process is divided in three stages: freezing, primary drying or sublimation and secondary drying or desorption. The freeze-drying process optimization was focused on the primary drying, since it is usually the longest stage and it is generally related with the highest impact to product quality.
First, characterization studies of both formulations were performed to define their thermal fingerprint using a variety of analytical techniques, such as differential scanning calorimetry, freeze-drying microscopy or X-ray powder diffraction. Then, the influence of primary drying shelf temperature and chamber pressure on product quality attributes and process efficiency was studied through a Doehlert design, and the design space was established at lab-scale. The process operational conditions for production manufacturing were selected focusing on process time reduction while preserving the quality of the product. Afterwards, the process was scale-up and qualified at industrial scale, and it was confirmed that all batches complied with product quality specifications after 12 month of ICH stability studies.
During freeze-drying qualification, extensive sampling was needed to guarantee the homogeneity of the drying process. This large number of samples cannot be effectively analysed by the conventional Karl Fischer method. Consequently, a non-destructive and fast near infrared spectroscopy (NIRS) method was developed and validated for residual moisture content determination in the two strengths of IFDA drug product.
The feasibility of using near infrared spectroscopy for the intended purpose was assessed using risk analysis tools and risk mitigation studies. A single model useful for two strengths of the injectable freeze-dried product was built up, with the final aim of obtaining the most simple and robust model with an acceptable predictive ability. During method validation, special attention was placed in the estimation of the limit of detection and a calculation approach was proposed. Finally, this NIRS model was applied to perform a moisture mapping of two industrial freeze-dryers, and to evaluate the potential application of the NIRS method to analyse samples subjected to different storage conditions.
