The ultimate quality system begins with the development of active ingredients and excipients and moves through product formulation,
manufacturing process development, design of container closure and packaging, product release, storage, and eventual distribution,
explained Jean-Louis Robert, representing EU authorities at the ISPE–PDA workshop. Such an approach features systematic methods
for information collection, storage, and dissemination through the product life cycle.
Many of the elements in this science-based, QbD approach are similar to policies and guidances developed under FDA's good
manufacturing practice (GMP) modernization initiative, according to Karen Main of AstraZeneca. FDA issued a guidance to help
manufacturers adopt process analytical technology (PAT) systems in September 2004. In fall 2006, the agency published a guidance
designed to encourage industry to establish quality systems.
The Q8 guidance explains how manufacturers should provide information on product development and quality manufacturing in
the P.2. section of the ICH-developed Common Technical Document for new drugs and biologics. This section provides a place
to present the product-development report traditionally included in European dossiers. Manufacturers in the United States
have been reluctant to share extensive development information with regulators, but industry globalization makes a more harmonized
approach important, Main noted.
Although Q8 started off fairly targeted, it expanded during the ICH guidance development process to describe more fully how
a manufacturer can establish effective quality control and design systems. The resulting document describes the scope of QbD,
the ways that starting materials and process parameters affect product quality, and how the process should be monitored, evaluated,
and updated to ensure consistent quality over time. The key is to identify and control critical sources of variability to
adopt appropriate control strategies.
An important concept is to establish a design space for the product, noted Susanne Keitel of Germany's Federal Institute for
Drugs and Medical Devices. This multidimensional construct consists of process parameters and material attributes that can
ensure desired product quality reliably and reflects in-depth product knowledge and process understanding. The positive response
to the Q8 guidance is encouraging further expansion. An ICH working group is developing annexes on oral dosage forms and moving
on to parenterals in the future.
Manufacturers that display a high level of understanding about how a product is vulnerable to change and how its system can
detect and control the production process may gain approval more quickly and enjoy reduced oversight of manufacturing changes
after a product comes to market. For example, working within the design space is not considered making a change in the product
or process from the regulatory viewpoint, pointed out Moheb Nasr, director of the Office of New Drug Quality Assessment (ONDQA)
in FDA's Center for Drug Evaluation and Research (CDER). This kind of regulatory flexibility may permit manufacturing-process
improvements without further regulatory review and reductions in end-product release testing.
Formalizing flexibility. The full implementation of Q8 and QbD methods ultimately could lead to a more-formal regulatory agreement between a manufacturer
and regulator about what kind of postapproval regulatory flexibility would result from the adoption of modern quality-systems
approaches. If a manufacturer provides very specific information about how it controls a manufacturing process as part of
its application, that could lead to some kind of "compliance commitment" from FDA, explains Nasr. The agency is inviting manufacturers
to propose such regulatory agreements, and FDA officials and lawyers are discussing internally how such agreements could fit
within the existing compliance system.
So far, FDA has not negotiated any formal agreements, but has been discussing generally how it could implement the concept
and how such information would be shared with the public. As part of its CMC pilot-review program (see sidebar, "Testing new
approaches"), applicants have requested regulatory flexibility, and ONDQA has agreed to certain regulatory modifications.
These changes include replacing end-product testing with in-process testing of blend uniformity, and allowing postapproval
changes within an established design space to be filed in an annual report.
Regulatory agreements would have to be negotiated separately for each product and dosage form, which admittedly would be a
time-consuming process. Nasr expects that a manufacturer would submit a proposed agreement in an application for FDA to evaluate
as part of the approval process. FDA would need to devise an agreement document enforceable under CMC review and compliance
policies, and additional FDA guidance would be needed to implement such a policy.