As you mentioned, ICH Q10 focuses on a life-cycle approach by adopting a quality system. What are some ways that industry
can best apply this approach?
The life-cycle approach is at the heart of FDA's quality systems guidance published several years ago and has now been superseded
internationally by ICH Q10 (see Figure 1). The challenge can be met by harnessing the data amassed in a commercial process
to drive continual improvement.
Table I: Quality-by-design (QbD) programs in progress at the US Food and Drug Administration.
An important PQS element is the process-performance and product-quality monitoring system. That system will confirm whether
predictions made in development have provided a good understanding of the process. QbD approaches to development will [also
help a firm] to learn from the process in a knowledge management system (a PQS enabler).... The newer regulatory approaches
derived from ICH Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 will allow companies to drive continual improvement. Processes will not be fixed by commitments made in applications
that may not reflect an adequate understanding of the manufacturing process because of limited knowledge.
Why is it recommend that a company begin to think about QbD concepts at the end of Phase II? Is there ever an ending point
for applying a quality-based approach (e.g., should it affect sales and marketing)?
Paraphrasing Qbd, it means a systematic approach to development, which is worthwhile at any phase of development. The intensity
of certain development studies may increase at the end of Phase II (e.g., in deciding to use a design of experiment more extensively,
whether or not to develop a design space for a particular unit operation, and whether certain technologies such as PAT are
being considered for the commercial process). There will also be considerations as to what types of process controls will
be used and consideration of real-time release testing (RTRT). ICH Q10 illustrates consideration for each phase of the product
life cycle and the OC's Division of Manufacturing and Product Quality (DMPQ) has looked at proposals at various phases, especially
when new facilities or manufacturing technologies are being considered. They can be contacted via subject matter experts listed on the website (
A PQS should extend throughout all parts of a firm's operations from preclinical, clinical, and marketing. This is a challenge
CDER has seen firms meet by creating an opportunity to have lower deviations, fewer complaints, and to make better linkages
from clinical to quality.
Lessons learned thus far
Now that the Chemistry, Manufacturing, and Controls (CMC) Pilot Program is winding down, will FDA be changing the way QbD-based
applications for new drugs need to be submitted?
Applications for QbD and traditional approaches are submitted in the same manner. From an administrative standpoint, it is
helpful to us if the applicant mentions the QbD aspects or other unique features of the application in the cover letter.
What were some of the major lessons learned by FDA as a result of the CMC pilot?
We learned how to make science- and risk-based regulatory decisions based on QbD data and proposed manufacturing approaches.
Importantly, we gained experience dealing with different types of flexible regulatory approaches such as design spaces, in-process
testing, and RTRT. We found that having a reviewer on Prior Approval Inspections was synergistic in that it benefitted both
the review and inspection.
One of the major findings through the pilot was that quality risk-management and a pharmaceutical quality system are equally
important to pharmaceutical development for the success of a QbD approach. As we get additional applications containing QbD
approaches, we are continuing to refine our review practices, and are sorting out questions such as what detail of information
should be in an application. We are further looking at how best to maintain our internal knowledge management and information-sharing
FDA has received more QbD-based submissions (12 new drug applications [NDAs], 18 investigational new drug applications [INDs],
and 3 supplemental NDAs as of May 2009) than it did under the CMC Pilot Program. Does industry seem to have a hold on what
FDA is looking for when it comes to QbD-based submissions?
The early applications under the CMC pilot had most of their development complete by the time the pilot was announced. The
applications were more like hybrids, containing both traditional and QbD approaches. Some of the newer applications that we
are seeing were wholly developed using QbD approaches. Every application is different and we are still learning and coalescing
our review approaches. For example, we don't have much experience in changes to approved design spaces.