(585c) Application of Quality by Design Principles to Development of Freeze-Dried Parenteral Dosage Forms

The case study emphasizes a science and risk-based approach to product and process development. This report presents a summary of the pharmaceutical development of the Ethacrynate Sodium for Injection.

The chosen drug is a good representative of small molecule freeze dried parenterals and has some stability issues. Key degradation pathways, namely dimerization of drug and hydration of methylene double bond, already identified in the literature were also verified as part of this case study.

The Quality by Design (QbD) process started by selecting the desired performance attributes via a Target Product Profile. From the Target Product Profile, an initial list of measurable Critical Quality Attributes (CQA) was derived. In Six Sigma world this part of QbD process is analogous to building a Critical to Quality (CTQ) tree where the Target Product Profile represents customer requirements and critical quality attributes that are the key measurable characteristics of a product or process whose performance standards or specification limits must be met in order to satisfy the customer. The pharmaceutical development was conceptually subdivided into several Focus Areas from Design to Freeze-Drying. A risk assessment was performed to identify the variables and unit operations that most likely impact the CQAs for each Focus Area. Ishikawa diagrams were employed for the variable identification purposes. The risk assessment also helped to establish functional relationships between key inputs (Design/Process Parameters) and key outputs (CQAs). Design/Process Parameters were then prioritized in order to focus development activities on potentially high-risk areas. Cause and Effect (C&E) Matrix, another Six Sigma tool, was employed for risk assessment. It should be noted that there is a natural relationship between C&E Matrix and Failure Mode and Effects Analysis (FMEA). FMEA may be utilized during the risk assessment activities as well. Once C&E Matrix was defined an experimental approach was assigned to all critical Design/Process Parameters. Based on experimental results and previous knowledge the design space was defined.

The experimental step of QbD process included formulation and process optimization. In general, the experimental work was driven by overall risk assessment process. However, it was found that in some instances concurrent execution of risk assessment and experimental steps may prove to be beneficial from scientific insight and overall development time perspective. The stability of drug was identified as CQA. In order to gain more experience about the effect of various common excipients and bulking agents on the stability of final dosage form the initial characterization and formulation pre-screening was initiated. The formulations of pure drug in different concentrations, of drug with manitol in different concentrations, and of drug with trehalose were considered. Based on the results of accelerated stability at 60ºC over 2 month period it was determined that pure drug is most stable.

API solubility was also identified as CQA. The solubility study, namely determination of the effect of pH and temperature on solubility of pure drug, followed immediately. It was found that solubility both at room temperature and 5ºC is essentially independent of pH in the range from 6 to 8. Also, it was determined that solubility in water at room temperature is approximately 50 mg/mL (consistent with the value reported by Merck Index) while at 5ºC the solubility decreased to 20 mg/mL. With the aid of Thermo Gravimetric Analysis (TGA) it was determined that the compound is capable of forming dihydrate during precipitation from supernatant solution. However, only insignificant water loss was observed for the freeze-dried solid. It indicates that the freeze-dried solid is predominantly anhydrate. The formation of dihydrate was also confirmed by X-ray Powder Diffraction. In both studies, previous knowledge about the drug was not adequate to make a sound scientific judgment and experimentation was deemed necessary.

Another CQA which requires immediate attention is aqueous solution stability. Preliminary experimental studies in order to determine the effects of pH and buffer concentration on the aqueous solution stability were started well before C&E Matrix was completed and experimental strategy assigned. The study was performed over two week period at room temperature. It was determined that lower buffer concentrations and lower pH cause less degradation in the aqueous solution. Consistent with the findings reported in the literature it was established that the primary degradation pathway in aqueous solution involves hydration of methylene double bond in the presence of water. Preliminary studies on the effect of pH, buffer concentration, and annealing conditions on stability of freeze-dried solid were also initiated even before the experimental strategy for the Design Focus Area was formally defined. The study demonstrated that stability of drug increases with higher pH and lower buffer concentrations. The annealing effect was insignificant in contrary to expectations. Consistently with the findings reported in the literature it was established that the primary degradation pathway in the freeze-dried solid involves dimerization. The take away from those ?deviations? is that some preliminary experimentation is required to fill the gaps in the scientific knowledge and actually facilitate risk assessment by providing more data.

The formulation optimization culminated with the study of effects of API concentration, pH, buffer concentration, and buffer type on the stability of freeze-dried solid and crystallinity of the drug. Sodium phosphate and citrate were considered as possible buffers. Based on the results of accelerated stability study at 40ºC over one month duration it was determined that the effect of pH and API concentration as well as their interaction is significant. The effects of buffer concentration and buffer type were found insignificant. X-ray powder diffraction showed that those factors did not have any effect on crystallinity. The optimum formulation was found to be 20 mg/mL API in 5mM sodium phosphate buffer at neutral pH.

The effects of Critical Process Parameters such as pre-freeze hold time, ramp rate to freeze temperature, and annealing conditions were determined experimentally by employing response surface design. In order to determine optimum primary drying conditions a pseudo-steady state heat and mass transfer model was utilized. The model defines functional relationships between primary drying temperature, chamber pressure, and target product temperature. The residual moisture study was conducted to determine optimum secondary drying duration.

The QbD process concluded with the identification of appropriate controls during manufacturing. Since drug degrades rather quickly in the liquid solution the control identified was to limit the duration of Ethacrynate Sodium being in liquid state to 24 hours. It should be noted that once more experience about the drug and associated risks is gained a reassessment of knowledge gained may have to be performed.

By following the principles of QbD we were able to design a formulation different from commercial without sacrificing the quality. We found that mannitol used in commercial formulation is not required as a bulking agent. In fact, the research performed as part of case study shows that formulation with pure drug is more stable. Another improvement was a five-fold decrease in vial size. It shows that the application of QbD process for a small molecule freeze-dried parenteral development leads to more robust product and process.