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

                               

Dissolution Testing for Generic Drugs – Extended 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, 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).

For ER products, if a USP method is available then dissolution testing recommendations are based on the product formulation and number of strengths to be marketed. As presented in Decision-tree, if the USP method is adequately discriminating and the drug product is to be marketed in only one strength then dissolution data generated using only the USP method may be sufficient.

ER capsule product - Produce from a “common blend”

In the case of multiple-strength ER capsule drug products, the dissolution testing recommendations are based on the formulation design. If multiple strengths of an ER capsule product are produced from a “common blend” then dissolution data generated using only the USP method may be sufficient, provided that the USP method is adequately discriminating.

ER capsule /or Tablet product – Not produce from a “common blend”

For multiple strengths of an ER tablet drug product, and for multiple strengths of an ER capsule product which are not produced from a “common blend”, dissolution testing in addition to the USP method is recommended, in order to provide the FDA with sufficient information to determine the optimal and most discriminating dissolution method for the product. The additional dissolution testing should be conducted using at least three dissolution media, for example, pH 1.2, 4.5, and 6.8 buffers . Water may also be tested as a possible dissolution medium during the method optimization process. If the applicant proposes to use a dissolution method other than the USP method, then it should submit dissolution data generated on 12 units per strength for all strengths, for both the test (generic) and reference/Innovator products using both the USP method and the applicants newly developed method.

Delayed-release (DR) solid oral dosage forms

For delayed-release (DR) solid oral dosage forms, the dissolution testing should demonstrate that

(a) the product is stable under the acidic conditions of the stomach (for example pH 1.2); and

(b) release in the pH present in the intestine.

If a USP method is available, then dissolution should be conducted using that method. If there is no USP method, then for all the strengths of a DR product the Division of Bioequivalence (DBE) recommends that dissolution testing should be conducted under acidic conditions (pH 1.2) for 2 h followed by neutral medium (e.g., pH 6.8). In general, DR products should display acid resistance under the dissolution testing conditions. Currently, the DBE does not request additional multimedia dissolution testing for DR products demonstrating biphasic release.

As stated above, for some ER and DR drug products, a USP and/or FDA-recommended method is available, but not necessarily suitable for the generic test product. In this case, the DBE encourages the applicant to develop the most suitable and adequately discriminating dissolution to distinguish any changes that could affect the test product’s in vivo performance. In such a case, the Division of Bioequivalence (DBE) requests the submission of a dissolution method development report. In addition, it is recommended that the submission contain results of comparative test and reference dissolution profiles generated using the USP and/or the FDA-recommended method and the applicant’s proposed method. In this way, the appropriateness of the new proposed method can be carefully evaluated.

Decision-tree for ANDA sponsors for submitting dissolution testing data for an extended-release solid oral generic drug product.

Note:

Common blend: A batch of final blend that can be packed in different amounts providing various strengths of the capsule product.

Multimedia: lower pH, e.g. 1.2; medium pH, e.g. 4.5; higher pH, e.g. 6.8 and water