In a recent addition to USP 37 General Notices and Requirements (link), USP clearly describes that:
“Compliance with any of the [dissolution] tests does not assure bioequivalence or bioavailability”.
The reality is that dissolution testing has been introduced as an alternative to bioequivalence (BE) or bioavailability (BA) evaluations based on the principle that the dissolution is one of the most critical parameters for the assessment of BE/BA. Drug dissolution tests are, therefore, required to be conducted using physiologically relevant experimental conditions such as 37 ºC temperature, aqueous buffers within physiological pH range, moderate stirring etc.
There has been tremendous effort made in predicting BE and BA (e.g. predicting plasma drug concentration) using testers and methods commonly suggested in the compendia. Dissolution tests have been recommended for bio-waivers i.e. using them in lieu of BE/BA. In addition, it is a common practice and requirement that prior to a test becoming a compendial method the product development step must use, or at least be tried, testers and methods to establish their relevance to BE/BA data. Eventually, the selected dissolution method would become the pharmacopeial test commonly known as QC-test or tool.
The underlying assumption for conducting the test remains that the test monitors potential in vivo dissolution, hence BE/BA. USP Chapter <1092> highlights and stresses that method development exercises should be relevant to in vivo performance describing “The procedure should be appropriately discriminating, capable of distinguishing significant changes in a composition or manufacturing process that might be expected to affect in vivo performance.” Numerous guidance documents, including those from the FDA, stress the dissolution and BE/BA link. Some of the examples to this effect from the FDA guidance’s are reported at the bottom of this post as an appendix.
Therefore, the recent addition to the USP, as noted above, does not make sense.
On the other hand, if for reasons unclear yet, the compendial dissolution test is not considered linked to BE/BA but still be considered as a QC-test then compendium should clearly describe which quality attribute of the product the test is linked to and how this (revised use) has been validated.
Until, a clear and validated link between compendial dissolution tests and product (tablet/capsule) quality attribute is not re-defined and/or re-established, the requirement of such testing for compendial purposes should be discontinued, or put on hold, avoiding a significant and unnecessary burden on the industry.
Appendix:
“In vitro dissolution specifications are established to ensure batch-to-batch consistency and to signal potential problems with in vivo bioavailability.”
“If the dissolution characteristics of the drug product change with time, whether or not the specifications should be altered will depend on demonstrating bioequivalence of the changed product to the original biobatch or pivotal batch. To ensure continuous batch-to-batch equivalence of the product after scale-up and postapproval changes in the marketplace, dissolution profiles should remain comparable to those of the approved biobatch or pivotal clinical trial batch(es).”
“The goal is to develop product specifications that will ensure bioequivalence of future batches prepared within the limits of acceptable dissolution specifications.”
“The in vitro test serves as a tool to distinguish between acceptable and unacceptable drug products. Acceptable products are bioequivalent, in terms of in vivo performance, whereas unacceptable products are not.”
“Confirmation by in vivo studies may be needed for validation of an in vitro system.”
Source: US FDA Guidance for Industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms (link).
