The generic drug market has become increasingly competitive. The need for cheaper drugs in the American marketplace has driven the abbreviated new drug application (ANDA) submissions to staggering numbers, which in turn has lead to increasingly longer US Food and Drug Administration review and approval times. Section 3.2.S.2 of the Common Technical Document (CTD) is reviewed as part of the ANDA application and is intended to convey to the reviewer and field investigators all manufacturing process information, critical controls, and risk management related to the active pharmaceutical ingredient (API). In many instances, the ANDA applicant references a drug master file (DMF) that contains the API information. It is important to identify a high-quality API supplier, especially with regard to understanding the impact of starting material designation on the ANDA review time.
Presently, API starting material designation continues to be a troublesome issue. Historically, API suppliers (DMF holders) have relied on the 1987 Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacturers of Drug Substances, International Conference on Harmonisation (ICH) Q7A (good manufacturing practice starting material), and recommendations from 2004 and 2006 working groups for help in defining a starting material for the API manufacturing process (1). The draft ICH Q11: Development and Manufacture of Drug Substances provides recommendations with respect to API process controls and starting material considerations (2). The API supplier's decision of how far back in the synthesis to go before designating the regulatory starting material is impacted by the cost of current good manufacturing practice (CGMP) compliance, publishing proprietary information, and the necessity of reporting any future changes to the process that might involve outsourcing. FDA uses a risk-based approach to determine where CGMPs should commence and defines the regulatory starting material accordingly (3). Increasingly, DMF holders define a key intermediate as the starting material and outsource the synthesis without due consideration to quality. In some cases, multiple suppliers of the outsourced starting material are provided, each with either a DMF or technical dossier requiring review. Inspections of these facilities or problems with the synthetic route for outsourced materials may significantly delay the ANDA review.
Furthermore, FDA does not formally approve DMFs. Technically only recommendations are made to the DMF holder. In the meantime, the ANDA applicant is notified that the DMF is currently under review. It follows that the lack of a timely response by the DMF holder or poor quality of the response increases the overall ANDA review time. Therefore, it is strongly recommended that the ANDA applicant make a judicious choice of the API supplier. High quality suppliers should be identified prior to commencing drug product development. Critical material attributes of the API need to be considered as part of the overall quality target product profile (QTPP) of the intended drug product.The Office of Generic Drugs' current thinking on the appropriate designation of API starting materials incorporate the recommendations described in detail in the following sections.