Quality by Design (QbD) in the pharmaceutical industry is a systematic approach to development of drug products and drug manufacturing processes that begins with predefined objectives, emphasizes product and process understanding and sets up process control based on sound science and quality risk management. The FDA and similar regulatory groups elsewhere are actively promoting QbD applications, in which the manufacturer demonstrates understanding of the process and provides empirical evidence of the sensitivity of key parameters to process inputs. The manufacturer then enjoys much greater flexibility in production, with the ability to make process changes within a design space that has been authorized on the basis of the application. Designed experiments are an important tool in achieving the process understanding that is essential to a successful QbD drug approval application.
This article is a good example of a QbD project. It studies a liposome-based, controlled-release system, with the anti-viral drug Tenofovir used as a model compound. The team employed a sequence of experiments, beginning with a Plackett–Burman design to screen eight high-risk variables obtained from risk analysis and assess their impact on liposome characteristics (drug encapsulation efficiency, particle size, and physical stability). Only two of the eight high-risk variables had significant effects on the drug encapsulation efficiency. This prompted the second experiment, which employed a central composite design (CCD) to fully elucidate the relationship between lipid concentration, drug concentration and encapsulation efficiency. The resulting model was the basis for establishing the design space for Tenofovir liposomes preparation in a laboratory setting, within which the preparation variability is minimized. With regard to sample storage stability, it was shown that at 4 ◦C the prepared Tenofovir liposomes, dispersed in aqueous phase, achieved stability for at least 2 years. These principles are relevant for liposomes containing other hydrophilic substances, and can thus save time and expense and result in a more robust liposome preparation process.
Data from the experiments is included in the article.
Read the paper:
A quality by design (QbD) case study on liposomes containing hydrophilic API: II. Screening of critical variables, and establishment of design space at laboratory scale. Xiaoming Xu, Mansoor A. Khan, Diane J. Burgess. International Journal of Pharmaceutics (2012), 543-553.