Regulatory Open Forum

Change in the drug substance source…The manufacture of a batch of drug product using the post-modification drug substance is not always required. However, when, as a result of the change, the drug substance equivalence cannot be established, and the drug substance physical properties can affect manufacturability or performance of the drug product, application holders must assess the drug product made with the post-modification drug substance before distributing the drug product. In such cases a batch of drug product should be manufactured to fully evaluate the effect of a change in drug substance manufacturing. In vitro testing (e.g., dissolution, in vitro release) demonstrating the equivalence of the drug product made from the post-modification drug substance to the drug product made from the pre-modification drug substance

 When the drug product is available in multiple strengths (including different formulations), a batch of only one strength may be manufactured. The strength chosen for evaluation should be the strength most sensitive to changes in the drug substance's physical properties. If there is no evidence of one strength being more sensitive than another, the lowest strength should be used for low-dose drug products; the highest strength should be used for all other products. A scientific rationale for the strength chosen should be provided in the submission to FDA. In the case of complex dosage forms with multiple strengths, such as modified release products, one batch per strength may be needed.