Being the first to gain the most is a fundamental principle in the generics business because several companies compete to create generics of successful products going off patent. For a generics company to maintain revenue growth in a market in which product prices continue to fall, it must secure a continuous flow of new products, with quality and speed to market being key drivers. Thus, generics companies must be highly skilled in product and process development (1), the generics business, and achieving bioequivalence—the most critical development area.
Most generics are oral solid dosage forms (e.g., tablets and capsules) that are composed of various excipients, each having a specific purpose (2). Although excipients are clinically inactive, they are pharmaceutically active and, therefore, can affect all aspects of drug product performance (3). For example, functional excipients such as stabilizers and dissolution modifiers contribute to the dissolution and bioavailability of drug products. Determining the original drug's excipient content and other formulation optimization steps can be facilitated using reverse engineering, which is the decoding of an innovator product's formulation parameters. Such parameters include the quantitative composition of the innovator product, the solid-state characterization of the active pharmaceutical ingredient (API), and the manufacturing process.
Although some information about an innovator drug product's API and excipient components can be found in common sources such as product information brochures, Physician's Desk Reference, or FDA's Web site (
http://www.fda.gov/), one can be more confident about the generic product's performance by developing a formula that is as qualitatively and quantitatively similar to the reference listed drug (RLD) as possible. Under US law, quantitative information about the excipients in oral dosage forms is not required to be revealed. In this context, reverse engineering of the innovator product's formulation is a scientifically sound and cost-effective strategy for accelerating generic product development. From a practical perspective, the chances of developing a bioequivalent product can be significantly increased by extending the concept of generic product sameness to formulation sameness with the RLD. Generic product sameness is defined in terms of pharmaceutical equivalence and bioequivalence. Formulation sameness with the RLD is defined in terms of equivalence of qualitative and quantitative formulas, solid state characteristics, and manufacturing process to the RLD (see Sidebar, "Generics terminology").
Though generics companies have used reverse engineering for quite some time, the topic is scarcely covered in the published literature. In this article, we discuss the importance of reverse engineering and propose a decision-making process for developing solid oral dosage forms. We suggest various components of reverse engineering and the tools needed to carry out the process. The method is based on information generated from a series of reverse engineering experiments on RLD products (4).
Components of reverse engineering
Decoding the quantitative formula.
Decoding an RLD's quantitative formula should begin with identifying which excipients most affect the formulation's performance in quality tests (i.e., stability or dissolution). These data will provide information about the resources required for reverse engineering versus the importance of the information derived. Resources (e.g., time and money) can be streamlined on the basis of these findings because sometimes traditional formulation optimization techniques may be more efficient than reverse engineering. In general, pH-adjusting agents, buffers, stabilizers (e.g., antioxidants and chelating agents), and dissolution modifiers (e.g., surface active agents) are the best candidates for reverse engineering.
The next step is to quantify an identified excipient in the tablet matrix, which is challenging because of possible interference from the other excipients. Hence, the excipient must first be separated from the tablet matrix using techniques such as differential solubility, filtration (with filters of a specific pore size or molecular weight cutoff), high-performance liquid chromatography (HPLC), high-performance thin-layer chromatography (HPTLC), and size-exclusion chromatography. One must select the separation technique based on the number of interfering components present and their physicochemical properties.