New Quality Assessment Office Will Enhance CMC Review Efficiency – Winkle

The establishment of CDER's new Office of New Drug Quality Assessment (ONDQA) will help to make the CMC review process more efficient and will address workload problems, according to Office of Pharmaceutical Science Director Helen Winkle, MD.

Winkle cited increasing workload as one driver behind the agency's efforts to revise its review of the chemical, manufacturing & controls (CMC) portion of new drug applications.

FDA announced Oct. 4 that ONDQA will replace the Office of New Drug Chemistry to "facilitate the implementation of a modern, risk-based pharmaceutical quality assessment system." The office will become effective Nov. 1.

ONDQA will be headed by Moheb Nasr, MD, who currently serves as director of ONDC. The office will take on all new CMC applications received on or after Nov. 1.

Winkle addressed workload concerns when she spoke at the Consumer Healthcare Products Association's Manufacturing Controls Seminar in Morristown, N.J. Oct. 5-6.

For example, the number of original ANDAs received by the office has more than doubled in the past six years, Winkle said. There were 326 ANDAs received in 1999 and 806 in 2005.

"Last year we were bragging that we got one a day. Now we're getting more than one a day. It's almost more than we can keep up with," Winkle stated, adding that there has been "exactly no increase in resources" to accompany the increase in applications.

"The amount of work coming in...is really way beyond our current capacity to keep up," she concluded.

While FDA used to devote the same resources to both high- and low-risk products, the agency will now "focus review on the highest risk products. And you will know what the high-risk products are so you can anticipate, as you prepare your applications, where the focus needs to be."

FDA first announced its intent to revise the CMC review process in a September 2004 white paper issued by ONDC as part of FDA's final report on "Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach."

Previously, a single chemistry reviewer was responsible for evaluating the CMC portion of a drug application as it proceeded from IND to NDA, the 2004 white paper indicates.

Under the new restructuring, there will be a four-division structure within ONDQA, as opposed to the three divisions under the previous structure. Separate divisions will review premarket (IND and NDA) and postmarket (NDA supplement) applications.

In addition to concerns about workload under the old review process, "we really felt like the whole review process was more process-driven than science-driven," Winkle said.

"I know that comes as a surprise to some people...but when we went back to look at the process we realized that we were more concerned about who looked at what and when the tertiary review was done and how fast it met the timelines than we were worried about the science that was behind it."

"It wasn't that there wasn't science being applied to the application, it's just that the process was driving everything."

There was also a need for change in CMC review because the agency "felt like there was a lack of scientific and technical expertise in some of the critical CMC areas," Winkle said.

With an increasing number of drug combination products and advances in technology and manufacturing, "we needed to bring on more expertise so we were prepared to handle these newer products that were coming in."

Some of these issues will be addressed with CMC's move to FDA's new White Oak, Md. campus. The division was expected to begin moving the week of Oct. 18, she noted.

When CMC review moves to the new location, all chemists who review new drugs will be housed in one area. Previously, the 19 different chemistry teams were co-located with 15 different clinical divisions within CDER.

Under the old layout, co-location of chemists with clinical review sometimes resulted in a need for an analytical chemist by a particular division, "and there really wasn't an analytical chemist in that division. There was no exchange of chemists, there was no borrowing," Winkle said.

The new setup "will give us a better opportunity for flexibility within our office [and] give us an opportunity for being able to move our chemists around."

"If we get an application in where we do need the services of a different type of chemist, we will have those available. We will also look at more team reviews."

As part of the new review structure, FDA will begin using a Quality Overall Summary, which would be a summary that is added to the beginning of the application. The exact type of information that should be included in the summary - as well as exactly how the summary will be used in the review process - is still being determined.

The agency also will implement a Quality by Design (QbD) procedure, which will involve submission of pharmaceutical development data earlier in the application process.

"What we're anticipating in the new application process...is that we will get pharmaceutical development data upfront so that we will know that the company is understanding the product and the process, and that they have the capability of making changes to that process without involving the FDA," Winkle said.

"We very much understand it's going to take awhile for industry to come around to want to do that," she added, noting there is still discussion of "what kind of data we'll be looking for in the agency to ensure that that knowledge exists." Nonetheless, "this will now become a review based on the knowledge that exists in the industry."

FDA also is working to finalize the dispute resolution guidance that was introduced with the "cGMPs for the 21st Century" initiative.

"I think that will come out in the next few months, maybe next month, because we just signed off on it the other day," Winkle said.

The draft guidance was released in September 2003 (¹ (Also see "FDA Drug GMP Dispute Resolution Guidance Allows 10 Days For Objections" - Pink Sheet, 8 Sep, 2003.), p. 11). It describes the steps pharmaceutical firms should take to address concerns that arise during the inspection process.

- Bridget Behling