Comments from the AAPS In Vitro Release and Dissolution Testing focus group.
By Gregory Martin
Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs
Published in August 2015, this draft guidance has the potential to become a valuable asset for industry, providing clarity and specific guidance for the covered drug products. In September 2015, the In Vitro Release and Dissolution Testing (IVRDT) focus group conducted an in-depth review of the draft. According to the Biopharmaceutics Classification System (BCS), drug substances are separated into four categories based on their aqueous solubility and intestinal permeability. This guidance focuses on those drugs in BCS Class 1 and 3, which are classified as high solubility/high permeability and high solubility/low permeability, respectively. Due to their high solubility, these drugs are considered to pose relatively low risk for drug product performance for conventional oral dosage forms. The guidance proposes standard dissolution test conditions and specification acceptance criteria based on the assessment of the lower risk. There are a variety of potential options for dissolution method conditions (apparatus, agitation rate, medium, time points), resulting in a significant effort to select the conditions and evaluate many different combinations of the conditions. Proposing specification criteria has often involved significant negotiations as part of the regulatory submission process. With this guidance, the Food and Drug Administration (FDA) has reduced the expectations, and the effort required for these activities may also be significantly decreased.
For the eligibility, this guidance is scoped for immediate-release dosage forms intended to be swallowed, such as tablets and capsules, but not for chewable and orally disintegrating dosages. It is for BCS Class 1 or 3, with the drug substance highest dose soluble in 250 mL or less over the pH range of 1–6.8. It does not apply to narrow therapeutic index drugs or to rapid analgesic or rescue medications. For the standard dissolution test conditions, the draft guidance recommends that a fixed agitation speed, fixed volume, and fixed medium be used rather than ranges, which are found in the 1997 guidance. The overall impact of making specific recommendations rather than providing ranges can be to reduce the amount of work necessary to identify the final conditions. This guidance also defines a standard specification criterion, which is a benefit that requires fewer time points and data to be collected and less negotiation with FDA when the standard criterion is appropriate. A tighter requirement for BCS Class 3 (Q = 80% in 15 min.) is stated, which provides better assurance that the bioavailability of the drug is not limited by the dissolution, but that the rate-limiting step for drug absorption is gastric emptying. It is very interesting that replacement of dissolution testing with disintegration is addressed in this guidance. It is recommended that disintegration can be used in lieu of dissolution if the product has been shown to meet a specification of Q = 80% in 15 min. This approach is much less complicated than the current guidance.
No recommendations are provided for products that will not meet the recommended specifications. In those cases, presumably the scientists will revert to the 1997 guidance and continue according to the paradigm prior to the issuance of this new guidance. Would those be similar to the recommendation for Class 2 and 4 drug substances and presumably also for drug substances or drug products that do not fall within the scope of eligible products? Meanwhile, both the new draft guidance and the 1997 guidance are silent with respect to the analytical finish for the dissolution testing. The expectation is that the analytical finish will be suitable for its intended use (e.g., sufficiently specific, accurate, and precise over the range of interest). In addition, several concerns have been raised and further clarifications are expected from the agency, including why there is a requirement for the drug substance to be chemically stable for 24 h, how “normal” and “large” quantities of excipients in the dosage are defined, and what are the expectations for discriminatory ability. This guidance is expected to make significant impact when implemented.