Generics Joining the 12-Month Stability Data Club, But 'When?' Is Big Question

Generic drug sponsors will need to submit six-month and 12-month stability data for their ANDAs under draft guidance being developed by the Office of Generic Drugs.

Currently, only three-month data is required, so drug makers will need to revise their development, production and testing schedules accordingly.

"You just start nine months earlier. … Eventually that will be the norm," Glen Smith, director of OGD's Division of Chemistry II, advised participants at the Generic Pharmaceutical Association's fall technical meeting. OGD expects to unveil soon the proposed draft, along with a request for public comment.

Unanswered Questions

Many issues remain to be decided as part of an implementation policy for new stability testing requirements for generic drugs. Among those identified at the GPhA technical meeting were:

• Will stability studies that are ongoing when the new guidance takes effect be grandfathered in so they can meet the current requirements?
• What is the definition of a pilot-scale batch?
• Will stability testing be required for product made from all sources of API when there are multiple suppliers?
• Will the guidance address post-approval supplement requirements?
• What is the timeline for implementing the new policy?

In response to a suggestion that sponsors be allowed to submit three-month data with the ANDA and longer-term data later during the review period, Smith admitted that OGD has not yet decided whether to require submission of the six-month and 12-month data with the ANDA.

That may not happen immediately, he said, but "the day will come when you're going to have to have 12 months [of stability data] when you file."

The day of stability reckoning will be particularly brutal since a large part of the business strategy for generic firms is racing their applications to FDA in order to win first-to-file status. Without clear advance notice on when they need to start the sprint, some firms will be in for a rude surprise when they reach the OGD finish line.

Short-term stability data comparing a generic drug's performance to that of its reference drug will not suffice. Comparability between the two products' stability at six months proves nothing in terms of the longer term outcome, Smith noted.

"We still want the 12 months [of data]. The question is, 'what is this material going to do at twice the time?'"

OGD currently does not have a formal published stability guidance. It relies on other guidances and questions are addressed on a case-by-case basis.

To provide consistency, OGD is proposing to use the International Conference on Harmonization Q1A standards that already have been adopted by the Office of New Drugs for NDAs (Also see "Revised Stability Testing Requirements For Generic Drugs" - Pink Sheet, 22 Nov, 2011.).

With this approach, "industry and OGD will have a single, consistent standard across the board, division to division, team to team, company to company," Smith explained.

Alternatives Will Be Considered

Although consistency is the goal, Smith did not rule out allowing firms to make their case through methods other than testing.

The new standard "doesn't mean that one cannot propose other ways of demonstrating the stability of your product in your application, from a risk-based approach, product development understanding, things looking at product development information, understanding what the causes of destability are," Smith said.

The bottom line, he maintained, "is the products have to be stable throughout the shelf life and we have to know that when we convey approval to the ANDA."

More Knowledge, Fewer FARs

Another benefit to the longer-term data, Smith pointed out, is they will give firms "increased knowledge of your drug product, which is consistent with the evolving QbD [quality by design] paradigm" that FDA is adopting to improve drug quality (Also see "FDA Officials Urge Generic Drug Industry to Adopt QbD to Improve Submissions" - Pink Sheet, 1 Jul, 2010.).

That knowledge can translate into savings for companies, according to Smith, who pointed out that it "should reduce the number of FARs [field alert reports] you receive for stability, which means all those resources you were spending to do failure investigations go away."

Since January, Smith reported, more than 20% have been for stability failure. These include out-of- specification for known degradants, OOS for unidentified degradants, OOS for total degradants, dissolution rate failures and reduced expiry dating.

From a quality standpoint, Smith said "the additional data will help to understand your product, to set reasonable specs so you don't have to worry about these things and also waste resources for doing investigations."

FARs go to FDA's field offices, he noted. As a result, "now they are in your plant looking at what's going on." If submitting the additional data avoids quality problems and FARs, then the change is worthwhile, he maintained.

The proposed guidance will be brief, according to Smith. But the implementation policy could be a lengthy document, he indicated as he responded to a multitude of questions by saying the answers are under discussion and the issues should be raised in comments on the guidance (Also see "Revised Stability Testing Requirements For Generic Drugs" - Pink Sheet, 22 Nov, 2011.).

While there continues to be uncertainty about the pending stability requirements, much of industry's concern about another recent requirement, submitting failed studies, appears unwarranted (Also see "Failed ANDA Bioequivalence Studies Haven’t Impacted Review Decisions, FDA Says" - Pink Sheet, 31 Oct, 2011.).

[Editor's note: This article appears courtesy of "The Pink Sheet," Elsevier Business Intelligence's source for pharmaceutical and biotech industry news. Register for a 30-day risk free trial.]