6.5.2. QbD improves quality of drug products and overall project quality

In parallel with the early focus on customers’ needs and the determination, control and monitoring of the associated CQAs of a drug product, these need to be related to the in-vivo performance of the product in the targeted customer segment. Only then will the developed product really demonstrate superior excellence over competitors’ products.

In this respect the set up of bio-relevant dissolution tests and dissolution specifications, which correlate with the in-vivo bioavailability of the drug product provides an important tool to assess the product performance analytically and optimise the drug product during development to improve its bioavailability, e.g. in the toxicology species to improve exposure in the animals and thus maximise the safety margin of a new drug compound for FIH. The bigger the achieved exposure, the larger the safety margin that can be allocated for a potential FIH dose and then justify a larger dose as safe, thereby providing a higher probability for the drug compound to achieve efficacious drug levels in humans.

Setting up a systematic risk analysis in the extended project team at the beginning of the development project, i.e. after candidate nomination, enables such issues to be identified and addressed proactively. If drug solubility is too low to achieve sufficient exposure in the animal species extra effort and time may be needed to develop a dosage form with improved solubility of the drug already for the pre-clinical studies, demonstrating superiority over the traditional approach of a simple drug suspension. This drug formulation then achieves higher bioavailability and exposure in the toxicology species and thus supports a safety margin for higher doses in FIH, improving not only the quality (with focus to the customer = volunteer) of the product but also the quality of the whole project. In reducing the overall time needed for the dose escalation during the FIH study and establishing a wide dose range as safe in humans significantly increases the probability of demonstrating efficacy and dose proportionality during later studies. It also enables the project to get relevant information on how big the chances are going to be for this drug to demonstrate efficacy within an acceptable safety margin early during development.

Besides insufficient toxicology coverage FIH studies may also fail when blood levels achieved for increasing doses are not proportional as bioavailability often decreases dramatically with increasing dose for poorly soluble compounds. Having to extend or repeat a toxicology study or a FIH study does not only increase development costs but also impacts overall development times considerably, as repetition of a failed 4 week toxicology study as required for most FIH studies may easily cause a delay of up to 6 months for the start of the FIH study and the complete project.

Thereby the QbD approach and its systematic risk assessment actually help to identify and focus on the most critical aspects during each development phase. Thereby, not only product quality but overall project quality improves and probability of success for the project also increases – and not just the probability for the success of CMC related activities, but overall project success.