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
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.