Dissolution Testing for Generic Drugs – Immediate Release Dosage Forms: An FDA Perspective

                                 

    

Dissolution is the process in which a substance forms a solution. Dissolution testing measures the extent and rate of solution formation from a dosage form, such as tablet, capsule, ointment, etc.

Dissolution testing has emerged as a very important tool in the generic pharmaceutical industry. It is very widely used in formulation development, in monitoring the manufacturing process and as a quality control test. It can also be used to predict the in vivo performance of certain products. Dissolution testing has been successfully used for development and approval of generic solid oral dosage forms. dissolution testing plays significant role in identifying the need for the bioequivalence (BE) studies related to Scale-Up and Post-Approval Changes (SUPAC).

 

Role of Dissolution Testing in Approval of Generic Drug Products

In vitro dissolution testing (dissolution) plays a critical role in the life cycle of a generic drug product. In developing a dissolution test for a generic product intended to be marketed in the USA, investigators should consider the official methods and standards published in the United States Pharmacopeia (USP).

The USP describes seven different dissolution apparatuses which can be used to develop an appropriate dissolution method based on the drug product characteristics. The dissolution method should be adequately discriminating to distinguish any changes that could affect the product’s in vivo performance . US-FDA asks investigators to conduct comparative dissolution testing using at least 12 dosage units each of test and reference products (Innovator Products). Dissolution data should be generated by sampling the dissolution medium at time points appropriate to characterize the dissolution profile. It is suggested that three to four or more dissolution time points (other than zero), equally spaced, be utilized for rapidly dissolving drugs.

Dissolution Testing Recommendations For Solid Oral Generic Drug Products

One of the first steps during the BE review of a potential new generic drug product is an assessment of whether the dissolution method proposed for the product is the appropriate one. The Division of Bioequivalence (DBE) recommends that for generic drug products, if a USP method is available for the product, then dissolution should be conducted using that method. If there is no USP method available, then the dissolution testing should be conducted using a method recommended by the FDA (FDA-recommended method). The FDA posts a list of its recommended dissolution methods (http://www.accessdata.fda.gov/scripts/cder/dissolution/).

It is worth noting that even if the USP method is used, the DBE asks generic applicants to submit to the Abbreviated New Drug Application (ANDA) comprehensive dissolution testing data. Thus, an applicant should characterize comparative dissolution testing using at least 12 dosage units each of test and reference products, whether it proposes to use a USP method, FDA-recommended method, or its own method. In cases where the applicant develops their own method, both data using their method as well as data from the FDA-recommended method should be submitted for comparison.

Decision tree for ANDA sponsors to select a dissolution method for their generic product (fig. 1)

                        

In cases where neither a USP and nor FDA-recommended method is available, an appropriate new dissolution method should be developed. The new dissolution method development report should be submitted to the ANDA, so that the Division of Bioequivalence (DBE) can evaluate the feasibility of the new method. The new dissolution method development report should include a pH solubility profile of the drug substance, dissolution profiles at different rotational speeds and dissolution media. Dissolution profiles should be generated using at least three dissolution media for example, pH 1.2, 4.5, and 6.8 buffers. Water may also be tested as an additional dissolution medium for method optimization. 

It may be difficult to achieve sink conditions for poorly water-soluble drugs; therefore, a suitable surfactant in an appropriate concentration can be used in the dissolution medium for these drug products.

·       Sink Condition: Sink condition is the ability of the dissolution media to dissolve at least 3 times the amount of drug present in the dosage form.