Drug development requires an average overall investment of USD 1.5 – 4.5 billion and remains at high risk due to the huge attrition rate phase after phase [1; 2]. The pre-clinical development phase and the phase 1 clinical trial show the highest attrition rate due to toxicity or drug metabolism & pharmacokinetic issues [3; 4]. Mitigating the risk during a new drug candidate development program starting from the discovery phase onwards remains essential for drug development efficiency and success. The challenge is to perform the necessary steps in a structured and predictive manner which is also tailored to the project at hand. This can be achieved by committing the resources to stage-appropriate steps and confirming their suitability for the following steps. This structured and stepwise project plan reduces the level of investments into future work prior to receiving positive results from the earlier stage which would justify such investments.
For small molecules and biologics, development of the compound synthesis including analytical development is the starting point into the pre-clinical and clinical program. Drug synthesis for toxicology and animal studies is a critical development step as it also serves the clinical trial program. The evaluation of toxicity depends on the chemical structure of the active compound and the purity achieved in the drug synthesis. The route of synthesis, the raw materials and solvents used, as well as the process conditions applied are important factors for the potential formation of harmful impurities. To assure the validity of the outcomes of the toxicology study, a robust and efficient drug synthesis including reliable analytical procedures is essential as this provides the necessary consistency throughout the program.
Developing a robust drug substance synthesis
Setting the compound profile targets and performing an intensive risk assessment using a structured approach, as well as prior knowledge and compound synthesis expertise ensure that the resulting material fulfills the defined quality criteria. Developing the drug substance synthesis has to be accompanied by a thorough understanding of the physicochemical properties and their relevance for drug development . For example, chemical structures that are prone to drug instability or degradation, residual solvents, or formation of chemical artefacts might have a negative impact on the toxicology profile that would be preventable . Other critical factors like salt selection, druggability, solubility, BA, or potential risk for polymorphs, etc. might also arise from the risk assessment and can be addressed. The expected outcome is the definition of potential Critical Material Attributes (CMA) and Critical Quality Attributes (CQA), summarized in preliminary/target specifications, at early stages in order to prevent issues with the compound and its synthesis [7; 8]. Drug substance synthesis must therefore be accompanied by scientifically
sound, product-specific analytical procedures for the characterization of the active and residual byproducts. The analytical methods will establish a comprehensive drug substance profile which will be the benchmark for the clinical and commercial phase.