To meaningfully discuss the process validation and regulatory approval strategies required for drugs that have been designated Fast Track, Breakthrough Therapy or Accelerated Approval drugs, we must first clarify these designations and briefly remind ourselves what the Process Validation guidance looks like. Then we will be able to clearly identify challenges and approaches to these barriers when working to bring a Fast Track, Accelerated Approval or Breakthrough Therapy drug to market.
Fast Track designation – Fast Track drugs treat serious conditions where there is an unmet medical need. Concluding that a condition is serious and that there is an unmet medical need most definitely leaves room for judgement, but generally speaking, the conditions these drugs treat are life-threatening, and the drug in question is expected to contribute to survival, daily functioning or the likelihood that a condition will advance to a very serious state. Fast Track drugs receive the benefit of more frequent meetings and communication with the FDA, and the drug qualifies for Accelerated Approval and rolling review of the Biologic License Application (BLA) or New Drug Application (NDA).
Breakthrough Therapy – Breakthrough Therapy status can be assigned to drugs that treat a serious condition when preliminary clinical data show significantly improved outcomes compared to treatments currently on the market. Breakthrough Therapies are eligible for: Fast Track designation benefits, extensive FDA guidance on effective drug development early in the development process and organizational commitment, including access to FDA senior managers.
Accelerated Approval – The FDA established accelerated approval regulations in 1992. Accelerated Approval could be given to drugs that met a serious unmet medical need, and approval was based on a surrogate endpoint. Fast forward to 2012 when Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). This amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act) allowed approval to be based on either a surrogate endpoint per the 1992 regulations or approval based on an intermediate clinical endpoint. For example, as a result of the 2012 legislation, a cancer drug could be approved based on the surrogate endpoint of increasing the probability of cancer to going into remission or the intermediate clinical endpoint of shrinking tumor size—an outcome that is strongly correlated with the ability to much more successfully treat cancer and induce remission.
These FDA designations are clearly designed to increase the availability and speed to market of drugs treating serious conditions where unmet medical needs exist. Given that nimbleness and speed has historically not been the pharmaceutical industry’s nor FDA’s strong suit—commercialization of a drug has historically taken on average 12 years and cost up to $2.5B (including expenditure outlays and opportunity costs). The ability for these designations to save both time and money is very attractive. However, given the slow-moving nature of the industry, changes in both mindset and approaches are needed by both drug innovators and regulators to validate processes and ensure drug quality within the faster-moving constructs.
Let’s now turn to the most recent Process Validation guidance so that we may juxtapose that system with the nimble needs of Fast Track Designation, Breakthrough Therapy and Accelerated Approval drugs—ultimately, making some observations regarding needed Process Validation and overall regulatory approval approaches as the industry moves towards accelerated development processes for an increasing number of drugs.
WHAT IS PROCESS VALIDATION?
According to the FDA’s 2011 Process Validation (PV) guidance, "For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process.”
The Three Stages of Process Validation:
Stage 1: Process Design–manufacturing process is defined during this stage and is based on knowledge acquired through development and scale-up activities.
Stage 2: Process Qualification–process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3: Continued Process Verification–ongoing assurance during manufacturing that the process is controlled and the outcome predictable.
Keys for Successful Validation Include:
• Gaining knowledge from the product and process development
• Understanding sources of variation in the production process
• Determining the presence of and degree of variation
• Understanding the impact of variation on the process and end product
• Controlling variation in a manner aligned with Critical Quality Attributes (CQA) and the risk a given attribute introduces to the process
Process Qualification, a key component of Process Validation, should be based on overall level of product and process understanding, level of demonstrable control, data from lab, pilot and commercial batches, effect of scale and previous experience with similar products and processes. Process Qualification is generally recommended to be based on higher levels of sampling, additional testing and greater scrutiny of process performance than would be typical of routine commercial production.