4.4. QbD aiming to minimize variability in R&D suces rates

As discussed so far QbD driven development was initially advocated to increase understanding and minimise variability at the product, process and interface level. By doing so however, it also increases the efficiency of value chain activities and as such it may also be able to actually reduce the variability of the outcome of R&D, at least at the level of CMC related development. Since failure rates are excessively high in the development of new drug products any reduction of this rate will have a huge effect on R&D expenses and the profitability of pharmaceutical companies.

Obviously drop out rates of candidates during drug development are highest at the level of drug compound screening and profiling, but these early stages are also the least expensive phases, especially when compared to the costs for clinical studies for chronic indications which require study durations of several months at a level of thousands of patients, thereby often adding up to more than 100 million US$ for a single study. Therefore, a reduction of failure rates during clinical development will have the most significant impact on overall development costs for new drug products.

Even though failure will always happen at the level when new drugs demonstrate to be not sufficiently efficacious or show too many severe side effects during clinical development, many failures and delays of development projects are caused by issues, which could have been avoided and were even foreseeable to happen. In this context there are especially CMC related issues to blame causing significant delays, increased development costs and losses from sales due to postponed launch dates. These CMC related issues range from

• delays in the supply of a suitable formulations for FIH studies or other clinical phases due to problems in defining, manufacturing or supplying adequate medication in time
• failure of FIH studies due to previously inadequate exposure during GLP toxicity studies in the relevant animal species due to poor solubility of the drug compound
• instability of compounds over storage, detected too late in the development when primary clinical studies have already been conducted with batches of this formulation or process
• variability in product attributes caused by raw materials, process parameters or in the worst case by unknown conditions
• failure of timely transfer to the production unit or incapable processes at production scale delaying or even preventing launch to the market
• excessive need for trouble shooting and low yields in production requiring reformulation and changes in the process, which then again need to be authorised by the health authority prior to implementation
• products too difficult or inconvenient for administration by the health care provider or patient impairing compliance and thus eventually the efficacy of the drug product
• unexpected variability in the efficacy or safety at the patient level due to physiological, pathological, chrono-pharmacological, behavioural and other factors, that could have been addressed successfully via a suitable formulation or dosage form of a drug product, if considered upfront
• .....

Therefore, if these problems can be either avoided or at least addressed and resolved early during the development, the overall success rate of new drug development could increase significantly and actually at reduced timelines, thereby also shortening the overall development time. And even clinical failure may be prevented by providing the optimal dosage form and formulation for the specific drug compound, the targeted disease condition and each patient segment (e.g. children, elderly people).

In this aspect a QbD driven approach, if applied already early on or ideally from the start of each new project, will increase success rates of selecting the best candidate, for each of the clinical phases, the transfer to production, the probability of marketing authorisation and successful launch with capable processes. This includes:

• pursuing a risk based, systematic and science driven development already at the candidate stage and the selection of the formulation for pre-clinical investigations
• selecting the dosage form and formulation for FIH studies based only on those CQAs (reduced number) essential at this phase
• prioritise all development activities based on their criticality and relevance for the current stage of development and the next milestones
• continue to develop and optimise the formulation and manufacturing process throughout further clinical development based on prior experience, scientific experimentation, risk based timing of development activities, systematic data acquisition and interpretation in an extended team approach (including pre-clinical, clinical, pharmacokinetic, engineering and other expertise)
• demonstrate the rationale and scientific validity of the data, assumptions and proposals in the NDA to support risk based regulatory decisions
• establish and assess process capability at transfer to production and opportunities for Continual Improvement based on PQS and Knowledge Management systems

Even though this does require substantial frontloading of activities to development stages when failure due to efficacy and safety related issues is still very high, it can eventually decrease overall development timelines and increase the probability of success for later phases substantially. The payoff for the investments made in early phases for resources and equipment will then occur during later phases of development, which can be carried out faster, more efficiently and at a higher probability of success.