FDA Implementing New CMC Review Process Through Revamped Office

FDA is changing its review of chemistry, manufacturing and controls submissions with a new quality assessment office that will involve greater staff specialization.

As part of the agency's "Pharmaceutical cGMPs for the 21 Century" initiative, the new Office of New Drug Quality Assessment (ONDQA) will take the place of the Office of New Drug Chemistry (ONDC) within the Office of Pharmaceutical Science.

The new CDER office, designed to "facilitate the implementation of a modern, risk-based pharmaceutical quality assessment system," will be responsible for evaluating the CMC sections of INDs, NDAs and NDA supplements, FDA said Oct. 4.

The new review system emphasizes science-based review, communication, flexibility and a shift in quality control from the end-product to critical process steps. ONDQA will employ quality-by-design principles, product knowledge and process understanding when evaluating applications.

FDA reviewers will collaborate with investigators in the field, allowing for a more integrated approach to applications, ONDC Director Moheb Nasr said at the American Association of Pharmaceutical Scientists Quality Assessment Workshop Oct. 5.

"During the review, the reviewer will communicate findings and share reviews with investigators, [and] during the whole inspection, investigators will share findings with the reviewer," Nasr said.

ONDC will continue to operate under its current CMC review system until Nov. 1.

To facilitate a smooth transition period, CMC reviewers will complete review of any outstanding applications and have current ONDC team leaders sign off on them to minimize reassignment of pending applications.

The transition should appear seamless to those in the industry, Nasr said. Although the internal review system is changing, the application submission process will remain the same.

ONDQA's four-division structure will replace the existing three-division structure of ONDC (see ¹ Office of New Drug Quality Assessment graph).

The new office will be made up of three pre-marketing divisions and a post-marketing division. In addition, the Division of Pre-Marketing Assessment III will include a manufacturing science component.

The new structure "will streamline the process to bring focus, to increase efficiency, to come with a faster review and to have people with individual technical expertise in different areas of the review," Nasr said in an interview. Under ONDC, there is little specialization of staff.

ONDC Director Nasr and Deputy Director Chi-Wan Chen will retain their positions in the new office. John Simmons will be director of the Division of Pre-Marketing Assessment III & Manufacturing Science; Eric Duffy will serve as director of the Division of Post-Marketing Assessment. Both Simmons and Duffy are currently directors of ONDC divisions.

Office of Pharmaceutical Science Deputy Director Ajaz Hussain, who was integral in FDA's 21 Century quality initiative, will leave the agency Oct. 28 to become VP-biopharmaceutical development at Sandoz, Novartis' generic arm.

Although Hussain is departing ahead of the implementation of the new quality assessment office, "one of Ajaz's contributions...was to put in place a very solid team that will be capable and will move this initiative forward and we're quite dedicated to make that continue to work," Office of Pharmaceutical Science Director Helen Winkle told the AAPS workshop on Oct. 5.

FDA will develop more detailed criteria for the new quality assessment system through its CMC pilot program (² (Also see "FDA Creates CMC Pilots To Put Quality Assessment Principles Into Practice" - Pink Sheet, 12 Sep, 2005.), p. 24).

The application deadline to participate in the pilot has been extended from Oct. 31 to March 31, 2006, with NDA submissions for pilot participants required by March 31, 2007.

The CMC pilot program was created to facilitate greater exchange of scientific knowledge between the industry and FDA, Nasr said.

Nasr noted that the current applications that the agency receives do not have "extensive pharmaceutical development information." They lack "in-depth" science information when describing the drug development process in terms of both manufacturing and quality, he said.

Industry is afraid to share additional information with FDA because of concerns that such information will lead to further questions from regulators or delay approval, Nasr said. Also, the industry worries reviewers do not have enough knowledge to understand more scientific applications.

The pilot will be conducted by a specialized team with knowledge in science, technology and the regulatory process. As part of the pilot, "people will have the freedom to submit any scientific information they have without the fear...of regulatory consequences," Nasr said.

"At this stage, we do not expect in the current submission...a full implementation of quality-by-design principles in all manufacturing unit operations," Nasr said.

"But we should start interacting now, so that when the design state is there, and we give the full-fledged submission, we have the full-fledged knowledgeable organization that can deal with it."

"Once we have a better understanding, I would expect that this kind of submission will be across the entire office. But we have to start somewhere," Nasr said.

"The FDA is changing much faster than industry is. So I'm challenging you, the industry, to change as well, because if you don't change, we go back to our old ways."

Winkle noted that FDA has already received five or six applications for the pilot program; the agency plans to accept up to 12 applications.

Merck CEO Richard Clark told the AAPS workshop on Oct. 7 that Merck has submitted an application and is "eager" to participate in the pilot program.

Clark, who took over as Merck CEO in May, spent 20 years as an executive in the company's manufacturing operations (³ (Also see "Merck Taps Clark As CEO In Nod To Medco Heritage; Gilmartin To Retire" - Pink Sheet, 9 May, 2005.), p. 14).

"This system also has the potential to create incentives for the industry," Clark said.

"If we perform the best science up front, that means there's less to do as the product continues to mature. We can use our resources better within the industry and the company."