(318b) Quality By Design Using An Integrated Active Pharmaceutical Ingredient-Drug Product Approach To Development

The design and development of a solid oral drug product was pursued using a holistic, quality by design (QbD) approach that integrated the active pharmaceutical ingredient (API) and drug product processes. The basic principles of this approach include i) conducting a team-based risk assessment process; ii) planning experiments to mitigate those risks; iii) prioritizing the experimental plans to intentionally focus development efforts in a staged manner; and iv) conducting the experiments with development of functional relationships between process parameters and quality attributes. This QbD approach is exemplified through a case study that transcends API synthesis through to the final drug product.

A critical quality attribute of the drug product was determined to be tablet content uniformity. The particle size of the API, which was a critical quality attribute for the drug substance, was identified as being a critical process parameter for the drug product. API particle size is controlled through crystallization temperature, and the normal operating range is 15-25oC. The final particle size specification was determined to be D[4,3] not more than 35 microns with a D(v,0.9) not more than 100 microns. A second critical process parameter identified for the drug product is the point at which the tablet press is shut off at the conclusion of the batch. The granulation possessed excellent flow properties, which resulted in the maintenance of weight uniformity until approximately 300 grams of blend remained. At this point, a mechanically induced segregation of the blend occurred, due to the lack of head pressure on the blend being fed to the tablet dies. As a result, the press shut-off implemented to eliminate the risk of high potency tablets was set at a level approximately 1.5 kg of blend remaining. Acceptable control of the process was accomplished through the stratified sampling of in-process tablet cores throughout the compression run. Control of these process parameters, as demonstrated by the results of testing of stratified samples of tablet cores, has resulted in the production of tablets that consistently exceed quality standards for content uniformity.