4.5. Combining QbD with a „less is better“ Minimalism approach

Despite the described benefits most companies still prefer to postpone the substantial investments of a QbD approach to later clinical phases, such as phase IIb or phase III, where overall failure rates are lower compared to preclinical or phase I. They do this to justify the resources and investments needed by the potential benefits perceived from QbD during marketing authorisation (regulatory flexibility) and in production (increased efficiency, higher contribution margins, Continual Improvement), denying the net value of QbD during earlier phases of development.

The benefits of starting a QbD driven development approach already during the pre-clinical and early clinical phases can, however, be maximised when combining QbD with Minimalism in a way as proposed in Chapter 2.2. Focussing only on these attributes and activities, which provide the relevant information, risk mitigation or flexibility for the current phase of development and the steps needed to proceed to the next phase. This approach limits the activities and data generated during early stages to those that are really relevant according to joint risk assessment and evaluation in the team, rather than following a rigid scheme as has been the traditional approach in the pharmaceutical industry.

The traditional approach without QbD often includes using a suspension of the drug for pre-clinical studies and either a solution, capsule or simple tablet for FIH studies. No optimisation of the formulation or process development is usually done to safe drug compound, time and resources. Release of medication for the studies is based on limited stability information (compatibility studies, short time stress testing, and real time stability of clinical batches) and release specifications focus on assay, content uniformity and impurities. If FIH is successful limited optimisation and process development will be done for the desired dosage form for phase II studies, mostly selecting the formulation and manufacturing process for the market form prior to phase III studies and the manufacturing of primary clinical batches for these studies to confirm efficacy and safety for the NDA.

Applying a full QbD approach in contrast would require to follow the scheme presented in Figure 2 for each of these phases, thereby requiring substantial time and resources in the face of the consistent risk of discontinuation of the project after this phase and a waste of the investments made.

However, according to the Minimalism approach the benefits received from the systematic, risk based and science driven QbD philosophy could be combined with the savings, minimising costs and time for doing this at the same time. The utmost focus thereby needs to be on, when and how to do which activities to generate the biggest value for the current phase, the next steps or milestones and the overall project. And as such each of these decisions needs to be made following a consistent risk assessment process.

A prerequisite for applying this approach as a routine and effective methodology throughout all projects and the whole company thus will be the integration of the QbD philosophy in the company’s culture, its management systems (QRM, PQS), and the operational processes in all functions as outlined in Figure 6. Only then will a company be able to conduct the essential processes and routines for this approach in an efficient way, minimising waste of time and resources needed to establish and run the processes.

All development activities can then be driven by agreeing on a phase specific QTPP (this can and should evolve over the course of development) between the stakeholders and a risk assessment as to the most critical quality attributes and potential impact on these for the specific phase. This risk assessment, risk acceptability and prioritisation of mitigations needs to be agreed between the stakeholders and accepted by the project team and management. It is then the basis for the actual investigations and activities during this phase of development. All obtained results, information and further knowledge are afterwards fed back into the risk assessment to determine acceptability of remaining risks and prioritisation for the next steps.

An example for such an approach is summarised briefly in Table 2 below.

Table 2: QbD and Minimalism translated to pharmaceutical development

This will allow a company to start QbD early on and to benefit from a systematic, customer driven development focus that evolves over the course of the development as the customers change and expand from the animal species, to the volunteers, to the patients, to production and the regulatory authorities. All activities will focus on the major needs for the different customer segments and prioritise the highest, most critical risks impacting the Critical Quality Attributes of the product addressing these needs. Therefore, actual costs and resources are rather limited and can be controlled very efficiently using again a risk based approach for when and where to cut back or not.

Doing only the important things at a time rather than performing all potentially possible investigations, helps to limit the resources needed to obtain the really critical information for each project and each development phase. This could then also be summarised as „doing the right things right and at the right time“ or „right first time“, as it increases the probability of success at each phase and the overall project, also improving the number of successful projects and the timelines needed for doing so.