20/21 September 2022
The Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) has published a Draft Guidance for Industry entitled "Questions and Answers on Quality Related Controlled Correspondence". The document provides FDA's current thinking on quality-related scientific and regulatory topics that appear frequently in controlled correspondence submissions. It contains, besides other topics, questions and answers related to bracketing and matrixing.
According to the ICH Q1A(R2) Glossary , bracketing is defined as "the design of a stability schedule such that only samples on the extremes of certain design factors, e.g., strength, package size, are tested at all time points as in a full design." Matrixing is "the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested."
Point 1 of the new Q&A document addresses the following question: "Is it acceptable to use a bracketing approach for the manufacture of the exhibit batches of a generic drug product with multiple strengths produced from common bulk granulations (or blends)? Do all of these exhibit batches need to be put into the stability program?"
According to the FDA's answer, "a bracketing approach is acceptable for a drug product with multiple strengths, as long as the active and inactive ingredients are in the same proportion between the different strengths (i.e., the strengths are dose proportional)."
In this context, the FDA refers to the FDA guidance for industry "ANDAs: Stability Testing of Drug Substances and Products Questions and Answers" (May 2014). According to this guidance, "for abbreviated new drug applications (ANDAs), three separate intermediate bulk granulations (or blends) should be manufactured. One batch of bulk granulation (or blend) should be used to manufacture all the strengths proposed. The other two bulk granulations (or blends) can be used to manufacture only the lowest and the highest strengths. Three bulk granulations (or blends) should be used to manufacture the strength(s) tested in the bioequivalence (BE) studies."
On the sub-question of submitting stability data, the FDA states: "Stability data should be provided for three batches of the highest strength and three batches of the lowest strength, and three batches of the strength(s) tested in the BE studies if the strength used in the BE study was not the highest or lowest strength. Release data should be provided for all the batches that were manufactured."