In its attempt to keep pace with drug manufacturing quality management, FDA has begun adopting risk-based approaches to its review, compliance, and inspectional activities. This work has been implemented stepwise, and in unison, across the Agency.

One of the hurdles still to overcome, however, remains updating the regulatory reporting requirements for changes to approved applications: 21 CFR 314.70. In its codification, 314.70 classifies change as: “major,” requiring a Prior Approval Supplement (PAS); “moderate,” requiring supplement submission at least 30 days prior to product distribution (CBE-30); or “minor,” requiring changes to be reported in the annual report. In a Guidance document [1], and as per 314.70(c)(6), FDA identifies the CBE-0 supplement—when the firm may commence distribution of drug product once FDA has received the supplement. These change categories and associated reporting requirements are also listed for large molecules in 21 CFR 601.12, and a Guidance document [2] issued jointly by CDER and CBER.
In 2007, for instance, more than 5,500 supplements were submitted to CDER. Since even very minor changes are subject to review, these supplements often burden the regulatory process and can prevent manufacturers from implementing continuous improvement or introducing technological advances. Change in real time is not only desirable, but a veritable necessity.

If manufacturers are to achieve the much-heralded desired state, it is vital to allow some manufacturing changes without prior FDA approval. These changes would be subject to process and product understanding, the firms’ internal change control systems, and a robust quality management system. Firms would still be responsible for ensuring product quality. As such, the number of post-approval CMC supplements would be drastically reduced.

Withdrawing the Guidances is not an acceptable option: the language of the CFR needs to be changed. In 2007 CDER, the Immediate Office of Pharmaceutical Science (OPS-IO), initiated public discourse to redraft 314.70 [3]. Also on the agenda was retaining aspects of the regulatory scheme to accommodate those manufacturers who would choose to continue operating within the existing regulatory framework. Rewriting 314.70 was not intended to mean deregulation.

The response from the public meeting to the stated objectives was resoundingly positive. Evolving manufacturing sciences facilitate a new approach to ensuring product quality, if the regulatory processes are aligned with risk-based methods and practices. FDA must foster a culture of innovation, in which manufacturers are both responsible and accountable for the quality of their products. A risk-based, quality-systems-oriented strategy for post-approval change was called for, and it was within reach. But it has not yet become reality.

Challenges to the redraft of 314.70 included the absence of a quality management system within CDER to manage change, and good risk management by both the FDA and manufacturers. The latter can be dealt with using risk-management standards. The former is currently underway within CDER, and on target.

The goal is well known, the components needing change are well understood and characterized; and the process well defined. Is it not, then, the right time to implement what was asked of OPS-IO in February of 2007, and to begin the redrafting of 314.70—which remains a major barrier to process optimization, enhanced product quality, and innovation?

References
1. Guidance for Industry: Changes to an Approved NDA or ANDA, CDER, April 2004.
2. Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products, CBER/CDER, July 1997.
3. http://www.fda.gov/OHRMS/DOCKETS/98fr/E6-22588.htm

About the Author
Ali Afnan, formerly a scientist at CDER’s Office of Pharmaceutical Sciences, and a member of FDA’s original PAT Team, is now principal of the consulting firm, Step Change Pharma. He can be reached at aafnan@stepchangepharma.com

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