Critical Differences
This fundamental philosophical difference between the two agencies—a focus on access and end product at the EMEA versus safety
and process at the FDA—help account for some important differences between GAMP 5 and cGMP1 in three critical areas: requirements
for validation, QA/QC policy, and process monitoring.
The GAMP 5 guidelines have "automated" built into the name and the philosophy—they envision process and system (computer)
validation as integrated entities. An automated process is tested with an installation, operational, and performance qualification
to be certain that the automated procedure has been properly installed, tested, and used.
By contrast, the FDA's cGMP1 document assumes a manual process with only tangential reference to the reality of automated
process systems (covered by the FDA in a separate document, 21 CFR Part 11, which defines system validation and provides guidelines for it). In keeping with the agencies' philosophical differences,
the EMEA stresses bottom-line performance, while the FDA stresses the process itself (procedurally and with automation). Under
GAMP 5, a Phase 1 investigator would validate the results of an automated analysis system as a functioning analytical unit.
Under cGMP1, an investigator would validate the analytical process and, perhaps, depending on risk, separately validate the
analytical system that conducts the procedure.
Similarly, the EMEA focuses on quality assurance (QA)—the general overview questions—regarding a study: does it produce a
reliable result with appropriate quality oversight? While still emphasizing QA, the FDA approach puts equal weight on the
quality control (QC) process, including all aspects of production and operation as well as the final QA overview. The EMEA
would potentially rely more heavily on a final quarantine and testing for the release procedure, whereas the FDA would augment
it with step-by-step reviews of the manufacturing and clinical testing plan.
As for process monitoring, the EMEA GAMP 5 de-emphasizing of process differs significantly from the FDA's process analytical
technology (PAT) initiative. Potentially, PAT provides near continuous and self-correcting cybernetic monitoring of a procedure,
method, practice, or course of action. The result is, again, greater reliance at the FDA on analysis at all phases, with a
contrary reliance at EMEA on the final result rather than the interim steps that lead to that result—in short, process understanding
versus process outcome.
The Path to Harmonization: QbD
The FDA's PAT initiative is just the first of three components of Quality by Design, a rigorously science-based approach to
drug safety. QbD integrates an understanding of design space, a risk-based approach to compliance, and PAT monitoring. Together,
those three elements can help satisfy both the results-focused outlook of the EMEA and the process-focused outlook of the
FDA:
- Design space is defined in ICH Q8 as "the multi-dimensional combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to provide assurance of quality."1 Successfully defining the design space means achieving a full understanding of the various permutations of input variables
and process parameters that ensure an in-specification product. Design space analysis establishes flexible operating parameters
within which fluctuations are permitted, thus satisfying the FDA's emphasis on quality control.
- A full understanding of the multiple, complex interactions among variables makes it possible to predict the outcome from particular
permutations. It is then possible to ensure an acceptably low risk of failing to achieve the desired clinical attributes,
thus opening the way for a risk-based approach to compliance.
- PAT's continuous and cybernetic monitoring of process parameters automates process control, satisfying EMEA's emphasis on
testing and quality assurance.
Thus QbD promises to effectively harmonize the safety goals of the FDA with the access goals of the EMEA, without compromising
either.
Even more promisingly, QbD can ultimately satisfy the QA bent of the EMEA and the QC emphasis of the FDA in a way that improves
both. The ability to design-in product and performance characteristics from the beginning rather than deriving them through
testing after the fact more efficiently meets EMEA's results and testing-focused requirements. Meanwhile, the analysis of
design space satisfies the FDA's thirst for process understanding, while avoiding cumbersome re-filings every time a process
parameter is changed. Biotechs that adopt QbD will not only be able to meet the differing EMEA and FDA requirements, but do
so in a way that could significantly lighten their regulatory burden.
Sandy Weinberg, PhD, is a senior consultant and Siddharth J. Advant, PhD, is a principal, both at Tunnell Consulting, King of Prussia, PA, 610.337.0820, advant@tunnellconsulting.com
Weinberg is also associate professor of healthcare management in the College of Professional Studies at Clayton State University,
Morrow, GA.
REFERENCES
1. International Conference on Harmonization. Q8, Pharmaceutical development. Geneva, Switzerland; 2005.
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