FDA encourages a risk-based regulatory approach where relevant regulatory policies and procedures are modified to accommodate
the most current level of scientific knowledge. The change would focus on increasing the level of scientific understanding
of how formulation and manufacturing process factors affect product quality and performance. More focus in the development
stage is needed to design the capability of process-control strategies to prevent or mitigate the risk of producing a poor
This step is much more about a new philosophy and operational culture than it is about new standard operating procedures and
a new quality manual. There may be a need to vastly improve and retool cross-functional and cross-departmental communication
and coordination. A silo-based approach simply will not work. Every part of the organization that touches on the product life
cycle will need to operate in a much more integrated way. Most of the advances that have occurred, and are anticipated to
occur, are bringing the development, manufacturing, quality assurance, and information and knowledge-management functions
so closely together that these four areas should be coordinated in an integrated manner. There may be a need to also include
some of the not-so-obvious players such as regulatory, marketing, product surveillance, senior management, and so forth. Management
responsibility and involvement is absolutely critical to the quality system. The current business model based on speed-to-market
must strike a different balance and approach with more emphasis on doing it right.
Process design, process controls, and resource allocations will need to be based on risk assessment and risk management (10).
Long-standing concepts of hazard control that use failure mode and effects analysis (FMEA) as well as hazard analysis and
critical control point (HACCP) principles may not be familiar to the drug and biologics industries. FDA believes there will
be significant regulatory benefits by improved ability to understand and implement changes with less FDA oversight and preapproval,
faster and more predictable FDA review, analysis, and approval of new products and CMC changes, and fewer preapproval and
shorter GMP inspections. The real business benefits (in cost, time, and efforts) are:
- Better science, efficiency, predictability, and control
- Problem avoidance through knowledge
- Improved process control and yields
- Less waste, rejection of materials, and rework
- Greater ability to identify and correct root causes.
There is a practical relationship between quality and today's business realities (profit and cost-of-goods) where business
objectives can be used to drive quality-system improvements. An understanding is also needed of the basic operational and
scientific principles behind quality systems, quality by design, and PAT. There are core principles common to them all:
- Scientific knowledge
- Design for control
- Simple logic.
These principles boil down to one common theme: Know what you're doing, why, when, and how. The same core principles drove
the development of FDA's GMP regulations as well as the standards by the ISO and International Conference on Harmonization
and serve as the fundamental basis for the various operational excellence methods (Six Sigma, lean manufacturing, etc.).
Table I: Hazard control concepts.
The overarching context for the core principles are the application of hazard control—an umbrella term that broadly describes
the various risk-based concepts that FDA has been discussing (see Figure 4). Hazard control includes:
- Risk assessment
- Risk evaluation
- Risk management
- Risk mitigation.