Documentation of QbD during companies' preinvestig-ational new drug meeting, end of Phase II meeting, and in regulatory submissions
with FDA might allow early review and analysis of the chemistry, manufacturing, and control (CMC) section of new or generic
drug applications by the agency. Addressing issues of concern and further QbD can result in classification of the drug substance
and drug process manufacturing process as low, medium, or high risk. In some cases, this approach is expected to result in
a less comprehensive inspection or to eliminate the preapproval inspection altogether.
With regard to chemistry and manufacturing controls, numerous guidance documents have come out in recent years related to
PAT as well as to product development (ICH Q8) (15) and quality risk management (ICH Q9) (16). There is also now a guideline
on quality systems (ICH Q10) (17). These guidances from the International Conference on Harmonization (ICH) address various
QbD elements of product development, including an understanding of all the potential variables and those interactions that
are likely to affect product quality. ICH Q9 specifically addresses risk-based strategies to determine the likely failures
and their consequences on product development and manufacturing. It is proposed that a new tripartite guideline, ICH Q10,
be developed describing the modern quality systems needed to establish and maintain a state of control that can ensure the
realization of a quality drug product and facilitate continual improvement over the lifecycle of a drug product (17).
Moving forward
Going forward, it would be beneficial for both FDA and industry to have a maximally efficient, agile, flexible pharmaceutical
manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight (18). 21 CFR 314.70 is effective in ensuring quality for consumers; however, it doesn't recognize recent manufacturing developments such
as the process and product understanding (19). FDA is currently evaluating how it might revise its regulations to accomodate
risk-based approaches that take into account an understanding of the manufacturing process, including prior knowledge of similar
products, and overall quality systems to provide an enhanced risk-based approach to the CMC regulatory process, which would
reduce the number of supplements (20).
FDA is also working to improve the regulatory process to encourage innovation. For example, the agency published "Innovation
or Stagnation? Challenge and Opportunity on the Critical Path to New Medical Products," in 2004, examining the critical path
needed to bring therapeutic products from discovery to market to make them available to those in need as quickly as possible
(21). The so-called Critical Path Initiative also emphasizes built-in quality in products and encourages innovators to bring
out the quality products with collaborations from regulatory agencies. It is an attempt to focus attention on modernizing
the evaluation of safety, efficacy, and quality of medical products as they move from product selection (discovery) to marketing
(delivery).
FDA has a significant role in enhancing the quality of pharmaceuticals, and looking ahead, the agency is exploring new paradigms
of manufacturing that assure continued product quality (19). The evolution of quality systems and manufacturing science with
control strategy promises a new approach toward ensuring pharmaceutical product quality. Major initiatives and guidelines
undertaken by FDA will require industry and regulators to confront the assumptions that have guided quality assessment in
the past and to move toward more novel approaches such as QbD and quality systems.
Rakhi B. Shah, PhD, is a pharmacologist in the US Food and Drug Administration's Division of Product Quality Research at the Center for Drug
Evaluation and Research. Mansoor A. Khan*, PhD, is director of the same division and a member of Pharmaceutical Technology's editorial advisory board, 10903 New Hampshire Avenue, LS Building 64, Silver Spring, MD 20993-002, tel. 301.796.0016, mansoor.khan@fda.hhs.gov
*To whom all correspondence should be addressed.
The views represented in this article are the authors' own.
Where were you 30 years ago?
Mansoor was aspiring to be a pharmacy student. He joined the BS in pharmacy program at Kakatiya University, India, in 1977.
Rakhi was not yet born.
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