As the pipeline of biologic drugs intended to treat complex diseases expands, the typical timeline for drug development and biologics testing seems to be shortening more frequently and with more intensity. There are many drivers to accelerate development. The potential to satisfy an otherwise unmet medical need for serious or life-threatening conditions is a common explanation for this phenomenon, with nearly 300 biologic drugs being granted fast-track designation in recent years. In order to support this, the US Food and Drug Administration (FDA) has constructed a pathway specifically designed for this scenario. Concurrent process development and analytical development are acceptable, especially when paired with a thorough risk assessment and the use of a restricted control strategy. However, despite the flexibility provided by the FDA for this approval pathway, the safety, efficacy, and evidence showing substantial improvement in patient outcomes remain central to the approval process.
The fast-track designation relies heavily on a scientifically justified Chemistry, Manufacturing, and Controls (CMC) strategy, and thus, many elements of the control strategy may be performed in parallel, or much earlier in the development process than therapeutics in standard regulatory pathways. For example, demonstration of product quality according to established guidelines must still be met, despite the expedited pathway, so it is prudent to begin method development in parallel with characterization studies. To further accelerate the timeline, characterization of the drug substance, impurity profile, and other analytical development activities can be performed simultaneously with process development. In addition, more stringent specifications, in-process controls, and risk assessments can be used to support the justification of the CMC strategy in lieu of a full library of analytical data.
In general, it is anticipated that manufacturing process validation activities may be deferred to the post-approval phase. The risks inherent to this approach may be mitigated via tighter controls throughout the manufacturing process. Mitigation may also be supported by a risk assessment-derived process whilst directly addressing residual risk where control isn’t feasible. Much of the risk mitigation can be accomplished by control of the raw materials, particularly when recombinant technologies are involved in the manufacturing process. In addition, minimizing the introduction of impurities, recognizing the critical process parameters, and having prior knowledge of the compound may all be used to help ensure quality product is available at the time of approval.
In order to achieve approval on an accelerated timeline, every opportunity for efficiency counts. For the small-to-medium biologics sponsor, an expedited pathway can be a distinct advantage for approval. This is particularly true in the case of cell and gene therapies, which are often designed to treat orphan indications and indications with severe detriment to patient health. In recognition of the potential for immediate need of a therapeutic granted fast-track designation, the FDA has given sponsors some flexibility in the context of clinical data and process validation. The current guidance permits the approval process to consider the totality of risk assessments, strict control of process parameters, and scientific justification of the approach. Nonetheless, the critical quality attributes must still be the primary concern of the CMC strategy. With that in mind, a coordinated, tactical approach must be employed.