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

The designation of drug substance starting materials and the information that will need to be provided on them in Drug Master Files are among the issues on which members of the Generic Pharmaceutical Association (GPhA) are asking for further clarification from FDA’s generics office as it moves forward in upgrading its review processes with the support of quality-by-design (QbD) principles and user fee resourcing.

In a presentation on the GPhA API subcommittee’s current areas of concern at the GPhA/FDA CMC workshop in late May, Endo/Qualitest Generic R&D VP Tony Amann pointed to starting materials as one of the areas viewed as needing further OGD clarification.

He pointed out that ICH Q7 defines starting materials as “raw materials, intermediates or APIs that are incorporated as a significant structural fragment into the molecule.”

However, Amann maintained, additional clarity on this definition is required from OGD as there is “inconsistency from reviewer to reviewer on what is an acceptable starting material.”

The API subcommittee spokesman pointed, in particular, to the need for clarification on what is meant by “‘significant’ as there is a lot of debate on this aspect,” as well as on the specific information that should be contained in the DMF on the starting material “if needed.”

The issues around starting materials have been particularly prominent in the industry/regulator API dialogue in Europe over the past few years.

The heparin contamination events of 2008 further strengthened European regulator concern with starting material definitions and control (IPQ “The News in Depth” March 21, 2012).

Industry, on the other hand – particularly on the drug chemical side – has been cautioning that an overemphasis by regulators on starting materials short changes the greater impurity threats that enter later in the drug substance and finished dosage manufacturing contexts and create roadblocks to API processing upgrades (IPQ “The News in Depth” March 20, 2012).

OGD Discusses Starting Material Expectations

Reflecting the importance of the starting material issues, OGD DMF Review Team member Deborah Johnson shared the agency’s current thinking about them at the GPhA/FDA workshop.

In her presentation, Johnson addressed: ● the basic definitions and properties of starting materials ● what the agency is looking for in its regulatory review ● common DMF issues with starting materials ● an illustrative case study, and ● suggestions for improving submissions (see box below).

[More on Johnson’s remarks and on the other issues that GPhA views as warranting clarification from FDA is provided for subscribers here.  Nonsubscribers can purchase the story for $195 by contacting Jonathan Trethowan (  For subscription/license information, click here.]

See related stories:

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

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

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

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

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

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