Get Social With Us

QbD Leads to Breakthrough Therapy Jackpot

Is your innovative biotech medicine a Breakthrough Therapy? If it treats a serious disease, fills an unmet medical need and demonstrates substantial improvement over available therapy on a clinically significant endpoint, the FDA may give your product the Breakthrough Therapy designate. With this designation come all the Fast Track benefits, including Accelerated Approval based on a surrogate or an intermediate clinical endpoint and Priority Review. It also comes with intensive FDA guidance on an efficient drug development program, beginning as early as Phase 1. If all goes well, clinical data from a pivotal Phase 2b study might suffice to support a BLA submission, but only if the chemical, manufacturing and control (CMC) development is completed in time for early BLA submission.

Having a good understanding of each manufacturing process step early-on can streamline CMC development, focusing effort and resources on critical areas. This is one of the hallmarks of the Quality by Design (QbD) approach. PhRMA’s QbD working group has published a position paper that provides guidance for implementing QbD for biotechnology products. In addition, FDA has issued its own manual to guide the CMC review of QbD content in regulatory submissions.

While some challenges remain, the benefits of following through on ICH Guidelines Q8 – Q11 are well understood. From the start, the Target Product Profile (TPP) focuses the development efforts across all functional areas. The Quality Target Product Profile (QTPP) describes the design criteria with a focus on quality, safety and efficacy, as well as convenience, compliance and cost effectiveness. The QTPP forms the basis for determining the Critical Quality Attributes (CQAs), the Drug Substance and Drug Product Specifications, the Critical Process Parameters (CPP) and the Control Strategy.

The Breakthrough Therapy designation puts the CMC development activities on the critical path to BLA and launch from the moment the drug candidate enters development. The commercial manufacturing process and formulation have to be set prior to supplying drug product used in pivotal clinical studies. The required real-time stability data must be generated prior to BLA submission. Given the complexities of biotechnology process development along with the analytical, formulation and stability studies, getting the CMC development done in half the usual time is a challenge. Any major manufacturing changes will delay a Phase 2b-based BLA.

For Breakthrough Therapies, applying QbD concepts for product and process development from the pre-IND stage on reduces the program risk and focuses the CMC development to support an early BLA and commercial launch with an efficient, cost-effective commercial process. It also enables a more flexible regulatory reporting mechanism for post-approval changes, should the need arise.


Blog article by: Andreas Woppmann, Ph.D.