Postapproval Considerations

As a product proceeds through the registrational process and into commercial manufacturing, additional considerations with respect to biopharmaceutics arise. A product approval is based on the evidence that a drug is safe and effective when administered according to the product labeling. Upon review of a product insert or other reference literature, the reader would find an extensive discussion of the properties of the drug product, including details on the ingredients, dosage form, available strengths, and pharmacokinetic properties, in addition to indications and dosing information. Once a product is approved by a regulatory agency, any changes to the formulation, manufacturing process or site, or dosing regimen must be assessed for impact on the biopharmaceutical behavior. Regulatory guidances are available that discuss the requirements to support a postapproval manufacturing change, the extent of which depend on the scope of the change intended. For example, a minor change may require the sponsor to inform the regulatory agency prior to implementation, and a more significant change could require human PK data, submission of other supporting data, and agency review to assure that the changes do not impact the drug's performance in humans. Inherent in this assessment is the assumption that pharmacokinetic equivalence will be predictive of clinical equivalence.

Another major source of change in a postapproval environment is product enhancements or extensions, including different dosage forms (e.g., capsule to tablet or oral liquid), new strengths, modified-release (e.g., for less frequent dosing to improve patient compliance), or alternate routes of administration

(e.g., addition of an injectable dosage form for use as a loading dose or for emergency use, or long acting depot injection). The data requirements for these new products vary. A change to a new oral solid dosage form may require a demonstration of bioequivalence while a new route of administration may necessitate additional human safety, PK, and efficacy data. The biopharmaceutical profile of a particular drug is one of the important determinants in the design of the studies used to support approval of product enhancements. The reader is referred to the available regulatory documents to provide guidance for requirements for specific products and markets. Specific applications of in vitro-in vivo correlations in dosage form development are further discussed in Chaps. 11 (parenterals) and 12 (oral products).

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