ABSTRACT

Active pharmaceutical ingredients (APIs) are also known in regulatory and pharmacopeial parlance as “drug substances.” Additional terms frequently employed in commerce and the literature are bulk pharmaceutical compound, bulk actives, and “active ingredient.” All terms relate to the same “article.” New chemical entities (NCEs), also termed new molecular entities (NMEs), refer to drug substances that are first to enter the drug regulatory arena under the banner of a New Drug Application (NDA). The term “official substance” is defined in the United States Pharmacopeia (USP) as a drug substance, excipient (frequently termed inactive ingredient), dietary ingredient, other ingredient, or component of a finished device for which the monograph title includes no indication of the nature of the finished form [1]. Official substances are the subject of formal monographs in the USP or The National Formulary. Drug substance (API) monographs grace the USP exclusively. The other official articles noted are in other sections of the compendia. Not surprisingly, the end use of the API is to produce a drug product, which is the final

Introduction .............................................................................................................. 19 Sources of APIs ........................................................................................................20 Patent Restrictions and Exclusivity Granted to an NDA Sponsor ........................... 21 Comparison With Innovator API .............................................................................. 21

Chemical Structure ..............................................................................................22 Impurity Profile ...................................................................................................22 Physical Form ......................................................................................................23

Specifications ...........................................................................................................24 Drug Master File ......................................................................................................25 Regulatory Oversight of API Manufacturers ...........................................................26 Bulk Active Chemical, Post-Approval Changes (BACPAC) ...................................26 Technical Partnership Between the API Manufacturer and the Drug Product Manufacturer ............................................................................................................27 Identifying and Qualifying API Sources ..................................................................27 Conclusion ...............................................................................................................28 References ................................................................................................................29

form of the drug substance administered to patients. Drug products are the subjects of companion monographs to the API in the USP. The ultimate safety and efficacy of the finally administered drug product are dependent on the assurance of the consistency of the physical and chemical properties of the API. This chapter will focus on the plethora of issues involved with the API, which must be considered when developing a generic drug product. In particular, the point of establishing specifications for critical quality attributes of the API will assure that the generic drug product, employing the API material, will have consistent in vitro/in vivo characteristics, batch after batch. As part of the routine evaluation of the compendial status of an API, in addition to the USP, the European Pharmacopeia, Japanese Pharmacopeia, British Pharmacopeia, Indian Pharmacopeia, the World Health Organization, and other “recognized” compendia should be checked to verify the presence or absence of published “official monographs” for the API.