Many people worldwide depend on drugs that have gone off-patent. According to analyses by the FDA, prices of generic drugs can be as low as 20% of the cost of a brand-name drug, and these significant price drops often occur when two or three generic versions of a drug come onto the market. In 2004, approximately two-thirds of all prescriptions in the US were for generic drugs. For most drugs, which are delivered orally, the verification of bioequivalence, a requirement for the approval of a generic drug, is usually achieved by the relatively simple process of measuring the blood plasma levels of test subjects. However, some types of drugs cannot be verified in this way. For example, nasal sprays and pharmaceutical creams currently require more complicated in vivo clinical tests to assure bioequivalence, which can make developing a generic version of such products difficult and prohibitively expensive.

This May, in an effort to alleviate this situation, the FDA issued the “Critical Path Opportunities for Generic Drugs” report, which describes particular obstacles to the development of certain generic drugs and makes recommendations for solutions. The Critical Path Initiative was established in 2004 in order to identify specific obstacles on the “critical path” that lies between discovering a therapeutic product and making that product marketable. Last year, the Critical Path Initiative published a Critical Path Opportunities report listing 76 specific scientific projects that could make critical path obstacles easier to negotiate for the general pharmaceutical industry (see IBO 3/31/06). According to Robert Lionberger, chemist in the Immediate Office of the Office of Generic Drugs (OGD) at the FDA, timelines and dedicated funding have not yet been established for collaborations related to the generic drugs report, but in the past the OGD has provided contracts to support research projects similar to those outlined in the report.

Among the analytical techniques highlighted in the report are particle sizing and rheometry. Each analytical issue is cited in relation to a particular type of drug product. Particle sizing’s use for studying nasal sprays in suspension is discussed. Rheometry’s potential for analyzing topical products such as antifungal creams is also examined. The report also calls for improvements in the methods used to characterize natural source drugs, which involve multiple analytical techniques. The solutions, involving analytical methods for generic drug testing, will be realized through the collaboration of instrument companies, generic pharmaceutical manufacturers and the research community.

Nasal sprays in solution can have their bioequivalence proven solely through in vitro tests, but nasal sprays in suspension frequently require clinical and pharmacokinetic studies. One of the critical path opportunities noted in the report is the development of methods that can sufficiently determine particle size and particle size distribution (PSD) and make in vivo studies unnecessary. There are a number of analytical challenges preventing this development. To begin with, not all particles in a given suspension are spherical—some may be highly irregular in shape—but most particle size measurements use size estimates that are spherically based, and are therefore not always accurate. Dr. Lionberger mentioned a general concern that particle size results can frequently be instrument specific-that is, different manufacturers’ particle sizing instruments may yield different results when testing the same suspension. There is also the challenge of being able to “quantitatively compare measurements made with different techniques,” as Dr. Lionberger explained. Microscopy, zeta potential analyzers and various laser diffraction methods, including Raman imaging microspectrometry, can also be used for particle sizing and PSD analysis, but each technique yields different answers. One potential solution to these problems is the establishment of particle sizing standards, an endeavor that could involve the National Institute of Standards and Technology. Another challenge of PSD measurements, specifically in the case of microscopy, is sample preparation: Dr. Lionberger pointed out that particle aggregation may occur when the solvent is evaporated from a suspension, which would yield incorrect PSD results.

Rheological measurements are a method of determining bioequivalence in topical creams used for dermatological products. As Dr. Lionberger explained, most topical products are semisolids; differing manufacturing methods or the use of different raw materials in formulating generic topical drugs can result in microstructural changes. These microstructural changes can have drastic effects on the rheological properties of a given product. Although Dr. Lionberger believes that rheometers currently on the market are capable of detecting these changes, “rheological techniques for characterizing [the microstructure of] topical dermatological products have not been widely used” in the pharmaceutical and academic communities. Rheometry has generally been used to measure the effect of aging, temperature and various ingredients on a topical product, as well as to quantify a topical product’s flow during processing or end-usage. One of the first solutions to this problem will be establishing rheometry’s capability to detect microstructural changes between different topical products. This would be a major step towards being able to use rheometry to demonstrate bioequivalence.

Another problem area that the report identifies is the development of analytical methods to identify the components of natural source drugs. According to Dr. Lionberger, in the context of drug products, the term natural source “is used to mean an active ingredient that is not fully synthetic.” Although the active ingredients for a number of natural source products have already been completely quantified, characterizing these active ingredients is considerably more complex than characterizing small-molecule drugs. Dr. Lionberger admitted that “for some complex natural source products, the exact components of the reference product that are responsible for its safety and efficacy have not been identified.” One example of such a drug is Premarin, a widely prescribed drug used to treat menopause symptoms and to prevent osteoporosis. However, Dr. Lionberger explained, the challenges in characterizing these complex natural source products “are very much product specific.” Using HPLC to provide two examples, he stated, “a peak in an HPLC method might contain multiple components of the drug product . . . another example would be that there are many small peaks in the HPLC method and it is not certain which peaks contribute to safety or efficacy.” In many cases, characterizing the components of a natural source drug requires a combination of techniques, and each technique has its own limitation for the product-specific application.

Although the next steps toward solutions for these challenges are not specified in the Critical Path Initiative’s report, similar documents in the past have motivated discussions and collaborations within the scientific and pharmaceutical communities, and this collaboration should help to bring more affordable drugs to the public.