FDA has expanded its risk-based approach to include ANDA chemistry reviews, focusing the most scrutiny on critical parts of the submission in the hopes of gaining a better handle on the high application volume seen in recent months.

It is one idea that potentially could ease the burden of formal application review goal dates, which begin Oct. 1, and a recent rush to file ahead of the implementation of new stability requirements.

But industry reminded FDA to make sure complex generic products, which could bear more risk, continue to be approved as quickly as possible.

FDA has developed an algorithm for immediate-release solid oral dosage form ANDAs that allows it to score a product’s critical quality attributes based on severity, probability and likelihood of detection.

Susan Rosencrance, acting deputy director of chemistry in the FDA Office of Generic Drugs, said the risk-based approach directs personnel to items that deserve the most attention.

“It allows us to better allocate our reviewer resources,” Rosencrance said during the Generic Pharmaceutical Association’s recent CMC Workshop. “Instead of exhausting our review resources across the board without any risk evaluation, this allows us to focus and target and ensures higher risk issues receive the appropriate level of expert scrutiny that they deserve.”

The risk-based approach has been a buzz-word around FDA for several years. As the agency implemented plans to deal with the globalization of the pharmaceutical industry, it decided a risk-based approach to facility inspections was necessary. The agency also is using a risk-based method for domestic compounding facility inspections ([A#00140512011]).

FDA decided it needed to rely more on the work of other trusted regulators like the European Medicines Agency so it could better target its inspections to facilities that needed more attention Also see "FDA Envisions Many Regulatory Coalitions Dealing With Globalization Issues" - Pink Sheet, 26 September, 2011..

Process Helped Deal With ANDA Volume

It seems like a natural progression to see a risk-based concept reach the ANDA review process.

Rosencrance said it was designed in part because ANDAs were arriving at much higher rates than estimated when the generic drug user fee program launched in October 2012.

ANDA volume increased dramatically in June. By June 20, the agency had received nearly 600 ANDAs, a surprising total for a single month.

The agency may not have many options to deal with the workload, but could call upon some new drug colleagues to help ([A#00140630007]).

Rosencrance said the agency expected about 700 ANDAs per year, but after the first year of GDUFA, there were about 200 more submissions than expected.

She said the chemistry review teams saw the difference in estimated and actual receipts and looked for a way to pick up the pace.

“Around last summer, in our chemistry program, we started to really ask ourselves, how are we going to meet this 10-month review cycle,” Rosencrance said. “We really did sort of a self-examination and asked ourselves how can we enhance what we do in chemistry, how can we enhance the efficiency and effectiveness of our quality assessment.”

Submission volume also exceeded the expectations used to determine hiring goals for GDUFA ([A#00140303008]).

Testing began on the risk algorithm in October 2013 on low- and medium-risk immediate release solid orals. By February, the method was expanded to include all immediate release solid orals.

Rosencrance also said the division decided to create algorithms for other dosage forms.

“We’ve been going through this throughout the spring, expanding and improving it as we go along,” she said. “Right now we’re presently undergoing an independent audit to acquire unbiased constructive feedback on what we’ve done.”

Once program testing began, the division was better able to keep pace with the new ANDA receipts, Rosencrance said.

“We have to make up that gap, so we [have to] increase our pace a little bit, but I think that we will because we’re going to continue to expand risk-based review,” she said. “Where we did use risk-based review, we’ve got it at a steady state now.”

The June rush, spurred by sponsors’ desire to get submissions to the agency before new stability requirements went into effect on June 20, may skew those figures.

ANDA and other submission levels through the first half of fiscal year 2014 exceeded those seen in the same period the previous fiscal year. Generic drug approvals in the first half of the year also mostly lagged the first half of FY 2013 ([A#00140421013]).

Industry: Ensure Resources Balanced

Industry wants to ensure adequate resources are applied to more complex products while using the risk-based quality assessment idea.

Dan Snider, VP of Morgantown RD for Mylan Pharmaceuticals Inc., said in slides presented at the CMC workshop that FDA should work with industry to ensure the algorithm details are clear and give guidance on risk rankings that are “based on the molecule and independent of the manufacturing process.”

Snider also pointed out that resources need to be balanced so complex drugs are approved in a timely and predictable fashion despite an increased risk ranking.

“Complex products and their associated risk should not delay access to affordable generic drug products,” Snider said in the slides.

FDA would like to create a team-based review system to assess product quality, where a team would deal with the original NDA and then transfer it to a generics team to deal with the ANDAs when they arrive. The agency hopes the idea will increase review consistency and streamline the process ([A#14140604004]).

Risk-Based Quality Assessment Growing Among ANDA Chemistry Reviews

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