FDA is applying a "six-system inspection model" in which the overarching quality system embodies five overlapping subsystems:
production, facilities and equipment; laboratory controls, materials, and packaging-and-labeling (8). FDA will continue to
monitor manufacturing plants through its inspection program and will continue to advance the training of its investigators
in the latest technologies. FDA will focus the detailed inspection of a system so that the findings reflect the state of control
in that system for every product (profile) class. A system is considered out of control based on GMP deficiencies that suggest
lack of quality assurance. If one of the six systems is out of control, then the firm is considered out of control.
FDA is being much more explicit about the industries' scientific and regulatory responsibilities by making product design
and process development part of the quality system and focusing on measurement and control (9). The agency has clearly placed
the burden of evaluating and demonstrating adequacy and acceptability on the manufacturer. This shift is going to take a substantial
effort and will affect research and development more than in the past. An ongoing dedication of more resources will be needed
on the "front end" of process design and development. A huge increase is needed in the early and very detailed understanding
of the process and product formulation. This will probably mean more time, effort, people, and money than the 1980s process
validation movement and may take years to realize the benefits on the "back end." GMP requirements will have much more impact
on pharmaceutical development.
Figure 2: Today's model.
With the quality system approach, FDA hopes manufacturers will apply an effective, knowledge-based scientific management of
the entire product life cycle, from research to nonclinical (in vitro and GLP) studies to pharmaceutical development, clinical manufacture, clinical development (human trials), approval, commercial
manufacture, and the postmarketing life of the product. This GMP paradigm shift will change the basic premise of the manufacturing
process, completely shifting the point of regulatory and scientific emphasis by moving the regulatory anchor from the fixed
process to fixed (constant) outputs (see Figures 2 and 3).
Figure 3: Tomorrow's promise.
For the industry to evolve to the new model, companies must be open to change. The change will be more complex than just reengineering
manufacturing processes where FDA will play a substantial role in the change. The current product life cycle is very inflexible
by the regulatory approach where the process is fixed within the operating ranges established in regulatory filings and approvals,
and change is difficult and often requires preapproval. Because of this, companies are reluctant to submit supplemental applications
and "reopen" product approvals. This reluctance is a result of substantial delay in implementing changes because of regulatory
review. There is usually a limited ability to fully understand the potential clinical impact of changes. Currently, the process
is not fully understood when a product is newly developed and standards and expectations change with time (e.g., analytical
methods, impurity profiles, limits of detection). Companies have chosen to live with poorly understood, inefficient, low-yield
processes instead of going through another round of regulatory review and approval and run the risk that additional clinical
trials and/or preapproval inspections might be required.
FDA's vision is for industry to focus on reducing variability through process understanding (e.g., application of knowledge
throughout the product life cycle). It is a "cradle-to-grave" systematic approach where product quality and performance are
ensured through the following:
- Design of effective and efficient manufacturing processes
- Product and process specifications based on a mechanistic understanding of how formulation and process factors affect product
- Application of continuous real-time quality assurance.