Critical Factors to Consider when Implementing Quality by Design for Biopharmaceuticals
The concept of Quality by Design is that the quality of a drug product cannot be created by testing, but must be designed into the product during the development stages. The methods used to produce synthetic drugs involve defined chemical processes whose outcome can be accurately projected. By contrast, a biological or biopharmaceutical is manufactured by a living system. While the desired function of the target molecule (usually a protein) can be written down, the actual three-dimensional structure of the molecule (and thus its performance in the human subject) depends strongly on the living system used to manufacture it. This performance can only be determined by testing, often in living systems. These test systems have their own variability. Therefore, the critical factors which influence our ability to design and produce quality biologicals are those which determine how nature’s intrinsic variability can be controlled and measured. These include:
- Ensuring the stability of the genetic construct which governs the expression of the target protein, by the design of the plasmid and selection of the correct cell strain, promoter and vector systems
- Controlling the effect of the manufacturing processes on protein function, by selection of a suitable expression system for glycosylation (if required) and avoiding certain down-stream processes which may affect refolding of the protein structure
- Limiting the presence of impurities derived from the expression system and the purification media, by using defined culture media and the newer chromatographic resins
- Qualifying and validating critical analytical methods, especially assay of biological properties, to limit test variability and increase reliance on the results.