The FDA has recognized that product development is now the weak link in the “critical path” from scientific discovery to commercial product. In response, the FDA has instituted sweeping changes that are beginning to have a tangible impact on the way pharmaceutical developers and manufacturers conduct their business. FDA’s “Pharmaceutical Quality for the 21st Century—A Risk-Based Approach” squarely takes aim at the current state and replaces it by the desired QbD state focused on product and process understanding.
|
Aspect |
Current State |
“Pain” to industry |
Desired QbD State |
|
Pharmaceutical development |
empirical; typically univariate experiments |
unscientific; relies on intuition; high risk of failure |
systematic; multivariate experiments |
|
Manufacturing process |
locked down; validation on 3 batches; focus on reproducibility |
ignores variation; high risk in moving to manufacturing |
adjustable within design space; continuous verification within design space; focus on control strategy |
|
Process control |
in-process testing for go/no-go; offline analysis |
slow response; lost batches; drug development delay |
PAT utilized for feedback and feed forward in real time |
|
Product specification |
primary means of quality control; based on batch data |
difficult to achieve right-first-time production |
part of overall quality control strategy; based on product performance |
|
Control strategy |
mainly by intermediate and end product testing |
delays batch release; low equipment utilization rate |
risk-based; controls shifted upstream; real-time release |
|
Lifecycle management |
reactive to problems & OOS; post-approval changes needed |
inefficient, costly processes; discourages changes |
continual improvement enabled within design space |
Quality by Design (QbD) provides “a framework for allowing regulatory processes to more readily-adopt state-of-the-art technological advances in drug development, production and quality assurance” and shifts focus from “quality by testing” to “quality by design”—that is, build quality into the process rather than rely on resource-intensive quality control systems to prevent defective products from leaving the factory. QbD practices are implemented at four levels:
· QbD Level 1: Process Understanding. Develop end-to-end process understanding based on multivariate analysis of designed experiments and/or historical data. Includes: (a) identification and characterization of critical-to-quality process parameters (CPP) and (b) identification of root causes of variability.
· QbD Level 2: Quality by Design. Design a process defined by a design space that is robust and where the variability is controlled.
· QbD Level 3: Monitor, Predict and Control. Monitor CPPs via off-line, in-line or on-line analyzers. Use real-time monitor feedback in conjunction with prediction to achieve process performance/quality supervision via real-time intervention of CPPs.
· QbD Level 4: Continuous Improvement. Use accumulating manufacturing data as the basis to modify and improve the process within the design space.
At this stage, the underlying concepts and rationale for implementing quality-by-design practices are well understood and accepted. Despite this progress, there remain critical impediments to QbD implementation including the following:
· From a practical standpoint, what comprises and how does one acquire process understanding?
· From a practical standpoint, how does one decide that a process parameter is critical?
· And most importantly, how do we know that the identified design space of the process links to the clinical design space of the patient? After all, the aim is to design a process that meets the needs of safety and efficacy for the patient.
These key questions will be the subject of subsequent posting.