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Dissolution Specification Setting Procedure as per FDA Guidance

In vitro dissolution specifications are established to ensure batch-to-batch consistency and to signal potential problems with in vivo bioavailability. For NDAs, the dissolution specifications should be based on acceptable clinical, pivotal bioavailability, and/or bioequivalence batches. For ANDAs/AADAs, the dissolution specifications should be based on the performance of acceptable bioequivalence batches of the drug product.

In the case of a generic drug product, the dissolution specifications are generally the same as the reference listed drug (RLD). The specifications are confirmed by testing the dissolution performance of the generic drug product from an acceptable bioequivalence study.

If the dissolution of the generic product is substantially different compared to that of the reference listed drug and the in vivo data remain acceptable, a different dissolution specification for the generic product may be set. Once a dissolution specification is set, the drug product should comply with that specification throughout its shelf life.

The International Conference on Harmonisation (ICH) Q1A guideline (Stability Testing of New Drug Substances and Drug Products) has recommended that for an NDA, three batches (two pilot and one smaller scale) be placed into stability testing. These batches also may be used to set dissolution specifications when a suitable bioequivalence relationship exists between these batches and both the pivotal clinical trial batch and the drug product intended for the market.

Three catagories of dissolution test specifications for immediate release drug products are described in the guidance.

Single-point specifications

  • As a routine quality control test. (For highly soluble and rapidly dissolving drug products.)

Two-point specifications

  • For characterizing the quality of the drug product.
  • As a routine quality control test for certain types of drug products (e.g., slow dissolving or poorly water soluble drug product like carbamazepine).

Dissolution profile comparison

  • For accepting product sameness under SUPAC-related changes.
  • To waive bioequivalence requirements for lower strengths of a dosage form.
  • To support waivers for other bioequivalence requirements.

In the future, a two-time point approach may be useful, both to characterize a drug product and to serve as quality control specification.

Approaches for Setting Dissolution Specifications for Generic Products

The approaches for setting dissolution specifications for generic products fall into three categories, depending on whether an official compendial test for the drug product exists and on the nature of the dissolution test employed for the reference listed drug. All approved new drug products should meet current USP dissolution test requirements, if they exist. The three categories are:

1. USP Drug Product Dissolution Test Available

In this instance, the quality control dissolution test is the test described in the USP. The Division of Bioequivalence, Office of Generic Drugs, also recommends taking a dissolution profile at 15-minute intervals or less using the USP method for test and reference products (12 units each). The Division of Bioequivalence may also recommend submitting additional dissolution data when scientifically justified. Examples of this include (1) cases in which USP does not specify a dissolution test for all active drug substances of a combination product and (2) cases in which USP specifies use of disintegration apparatus.

2. USP Drug Product Dissolution Test Not Available; Dissolution Test for Reference Listed NDA Drug Product Publicly Available

In this instance, a dissolution profile at 15-minute intervals of test and reference products (12 units each) using the method approved for the reference listed product is recommended. The Division of Bioequivalence may also request submission of additional dissolution testing data as a condition of approval, when scientifically justified.

3. USP Drug Product Dissolution Test Not Available; Dissolution Test for Reference Listed NDA Drug Product Not Publicly Available

In this instance, comparative dissolution testing using test and reference products under a variety of test conditions is recommended. The test conditions may include different dissolution media (pH 1 to 6.8), addition of surfactant, and use of apparatus 1 and 2 with varying agitation. In all cases, profiles should be generated as previously recommended. The dissolution specifications are set based on the available bioequivalence and other data.

Special Cases

1. Two-Point Dissolution Test

For poorly water soluble drug products (e.g., carbamazapine), dissolution testing at more than one time point for routine quality control is recommended to ensure in vivo product performance. Alternatively, a dissolution profile may be used for purposes of quality control.

2. Two-Tiered Dissolution Test

To more accurately reflect the physiologic conditions of the gastrointestinal tract, two-tiered dissolution testing in simulated gastric fluid (SGF) with and without pepsin or simulated intestinal fluid (SIF) with and without pancreatin may be employed to assess batch-to-batch product quality provided the bioequivalence is maintained.

Recent examples involving soft and hard gelatin capsules show a decrease in the dissolution profile over time either in SGF or in SIF without enzymes. This has been attributed to pellicle formation. When the dissolution of aged or slower releasing capsules was carried out in the presence of an enzyme (pepsin in SGF or pancreatin in SIF), a significant increase in the dissolution was observed. In this setting, multiple dissolution media may be necessary to adequately assess product quality.


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