Postapproval Change Evaluations

The EU published and later modified their guidelines for submission of variations to marketing applications. These guidelines list the type of changes that can be submitted as Type I (minor) variations, and contain the necessary information and documentation required to support the proposed change. A number of the defined Type I (minor) variations 

Under the current mutual recognition and centralized procedures, variations must be reviewed with, and approved by all concerned member states. The variation is provided under mutual recognition through the reference member state for the original application, and defined timelines exist for review and approval of the variation, based on whether it is a Type I or II submission. The timelines do not include the time required by the application holder to respond to any questions raised by any of the concerned member states. 

For variations submitted to the EU, it is necessary to utilize the same CTD format used for new applications, even if the original filing was prepared in an older, approved format (e.g.. Part II). This requirement has met resistance from a portion of the industry, in that it implies the need for conversion of existing registration documents to CTD format. European Union has not mandated such conversion rather they have strongly recommended that the conversion be performed. 

For all postapproval supplements/variations worldwide, the key for the company is to provide evidence that the change does not impact the quality (e.g., impurity profile. 

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Guidance for Industry Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes Chemistry, Manufacturing, and Controls In Vitro Release Testing and In Vivo Bioequivalence Documentation. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), May 1997. 

FDA. 1995. Guidance for industry. Immediate release solid oral dosage forms. Scale-up and postapproval changes Chemistry, manufacturing, and controls, in vitro dissolution testing, and in vivo bioequivalence documentation. Rockville, Md., USA Food and Drug Administration, Center for Drug Evaluation and Research. 

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