FDA’s Draft ANDA Stability Guidance Applies ICH Expectations to Generics

The Office of Generic Drugs (OGD) has released a new draft guidance indicating that Abbreviated New Drug Applications (ANDAs) and the Drug Master Files (DMFs) that support them will be expected to follow the stability recommendations provided in the ICH Q1A-E stability guidelines.

The content of the guidance is only two pages. A short introduction and a background section, which lists the ICH QA-E guidelines, are followed by a discussion section that tells the applicant how to apply the ICH stability recommendations in the drug substance and product context.

When following the ICH stability recommendations, the draft guidance states, the applicant should:

● Submit data from three pilot scale batches or two pilot batches and one small scale batch.  If the size of the pilot does not follow ICH recommendations, the applicant should provide a justification.

● At the time of submission, provide 6 months of data that include accelerated and long-term conditions.  FDA recommends following ICH with respect to utilization of intermediate conditions to support shelf-life.

● Use multiple lots of drug substance as appropriate.

● Manufacture and package the drug product using principles that are representative of the commercial process.

● Provide a fully packaged primary exhibit batch.

● Use three batches when bracketing and matrixing designs under ICH Q1D.

● Provide statistical analysis of the data as appropriate, in accordance with ICH Q1E, Appendix A.

Applicants deviating from the recommended procedures should justify the approach they are taking, OGD indicates.

The office had met with representatives of the Generic Pharmaceutical Association (GPhA) for input during the guidance drafting process and will be looking for further input from stakeholders during a comment period that will extend for three months following the draft’s publication in the Federal Register.

Draft Reflects Industry Input

At the GPhA/FDA CMC workshop in May, OGD Senior Review Chemist Raman Murali previewed the draft guidance and described the context and reasons for his office more formally adopting the ICH stability standards (IPQ “The News in Depth” September 10, 2012 – Murali’s full remarks are included in the story).

Murali explained how the move fits in with OGD’s overall effort to better align its ANDA standards with those for new drugs and internationally, in line with the new quality-by-design paradigm.

Also addressing the May workshop was a member of the GPhA stability subcommittee, Nicholas Cappuccino, who discussed his group’s  concerns and recommendations regarding the application of ICH Q1A (stability testing), Q1D (bracketing and matrixing) and Q1E (stability evaluation) to generic drug products (see also IPQ “The News in Depth” September 10, 2012).

Cappuccino participated on the ICH working group that wrote Q1A and, as such, has provided salient background information and expertise to the GPhA committee.

While some further refinements and clarifications may be needed in applying the innovator-oriented ICH standards to generics, he said, “from my point of view, we are not very far apart from where we need to be to bring this forward in a very cooperative way.”

The draft does allow for six months of stability data at the time of ANDA submission and provide for matrixing and bracketing, as urged by the GPhA subcommittee.

Other of the GPhA concerns, such as the implications of minor formulation changes from the innovator product, expiration dating, and where the packaging for the exhibit batch is performed, are not specifically addressed in the draft guidance.

The industry/regulator dialogue on the efforts underway to improve FDA’s generic drug review process, including those related to stability, will continue at the GPhA/FDA Fall Technical Conference in Bethesda, Maryland on October 1-3, which, like the spring workshop, is sold out.

The keynote address for the Fall conference will be given by the new OGD Director, Gregory Geba, who took over the helm in July (IPQ “The News in Depth” September 21, 2012). Geba will also be giving the “OGD Director’s Update” at the conclusion of the conference.

A significant portion of the meeting will be focused on GDUFA implementation issues, including their impact on industry and the regulatory process. Biosimilar technical issues (IPQ “Monthly Update July/August, 2012) and the industry/FDA collaboration on drug shortages (IPQ “The News in Depth” February 12, 2012) are among the other issues that will elicit FDA and industry discussion.

SEE RELATED STORIES:  IPQ has been closely tracking FDA’s broad-ranging efforts to create a more efficient and effective generic drug review process, including the initiative on stability.  Building on a foundation of QbD and user fees, the efforts are intended to address an expanded backlog of ANDAs and fulfill OGD’s commitments to industry under the Generic Drug User Fee Amendments (GDUFA).  The following series of stories is included in IPQ’s September Monthly Update:

FDA’s Generics Office is Revising its QbR Questions to Sharpen Focus on QbD and Control Strategy

The Role of QbD in ANDA Review Draws Comment from Generics Office Management

Changes to OGD’s API DMF Process Target Submission Quality and Review Streamlining

New FDA ANDA Stability Guidance Will Embody ICH Standards; GPhA Supportive With Some Adjustments

Initiatives to Strengthen FDA’s Generic Drug Review Process Include OGD Supplement and Peptide Teams

GDUFA Expectations for Fee Payment and Facility Registration Out for Comment; Public Meeting Scheduled

GPhA Weighs In On API and QbD Issues Needing Clarification for Generics; OGD Outlines Starting Material Expectations

New OGD Director Geba May Take the Helm of a Super Office; CDER Director Woodcock Sharpening Center’s Quality Focus


ANDA stability draft guidance document