Category: Formulation and Quality
Purpose: The FDA’s final guidance on “Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (BCS)” (December 2017) describes the possibility of waivers of conducting pharmacokinetic (PK) bioequivalence (BE) studies for BCS 3 drugs (high solubility and low permeability) in addition to BCS 1 drugs if certain formulation similarity criteria are met. The purpose of the present study is to investigate the formulation similarity found in the generic (test) product formulations of approved Abbreviated New Drug Applications (ANDAs) of selected BCS 3 candidate drug products by comparing test and reference product formulations qualitatively and quantitatively.
Methods: The collective data for a total of 57 approved ANDAs were examined for six BCS 3 candidate drug substances with high solubility and different permeability ranges (17 to 60%) delivered via immediate-release dosage forms (tablets and capsules). The PK parameters (AUC0-t, AUC0-i and Cmax) were collected for a total of 97 BE studies, including 57 fasting and 40 fed BE studies. The distribution of the Test/Reference (T/R) ratios and 90% confidence intervals (CIs) of the test/reference geometric mean ratios for AUC0-t, AUC0-i and Cmax were evaluated. In addition, the formulation compositions from both generic (test) and reference drug products were compared qualitatively (Q1) and quantitatively (Q2) in each ANDA submission. The sameness, similarities, and differences of the generic drug formulations to their corresponding reference products were categorized into four groups: Q1/Q2 same (individual excipient difference between test and reference products stays within ±5%), Q1 same/Q2 similar (criteria defined by BCS Waiver Guidance for Industry), Q1 same/Q2 different, and Q1/Q2 different. The excipients used in these BCS 3 candidate drug formulations were analyzed based upon the function, frequency of use, and percent of total weight (%w/w).
Results: The formulations of these 57 ANDAs showed that 15.8% (9/57) generic drug products were Q1/Q2 same, 3.51% (2/57) Q1 same/Q2 similar, 17.5% (10/57) Q1 same/Q2 different, and 63.2% (36/57) Q1/Q2 different compared to their corresponding reference drug product formulations. A total of 27 different excipients with various amount which listed in the current FDA-approved immediate-release solid oral dosage forms were used to formulate 57 generic drug products in ANDAs. The excipients identified in Q1/Q2 different formulations were mostly disintegrant, diluent (or filler), and binder. The top five common excipients were Magnesium Stearate, Microcrystalline Cellulose, Povidone, Croscarmellose, and Sodium Starch Glycolate. There were no novel excipients or atypically large amounts of commonly used excipients in these ANDAs. The T/R ratios and 90% CIs of T/R geometric mean ratios for AUC0-t, AUC0-i, and Cmax met bioequivalence criteria (80-125%) under fasting and fed conditions in all 97 BE studies from these 57 approved ANDAs.
Conclusion: The clear majority (80%) of ANDAs surveyed employed formulations that are not eligible for BCS 3 waivers according to FDA’s current guidance. This indicates a potential barrier to more extensive use of BCS 3 waivers in ANDAs. Although in this survey all the non-Q1/Q2 formulations contained passing BE studies, FDA’s data on the PK study results for these non-Q1/Q2 formulations are biased because failing studies do not always need to be submitted to FDA. Future work will focus on identifying what conclusions about the twenty-seven different excipients used to formulate generic drug products for these six BCS 3 drug substances can be drawn from the observation that they were used in passing BE studies. This will involve deeper consideration of the metabolism and transport of these BCS 3 drug substances. The goal of future work is to combine data-driven and mechanistic approaches to better identify the excipient space where non-Q1/Q2 BCS 3 products will be bioequivalent to their reference products.
Ping Ren– Silver Spring, Maryland
Wen Cheng Yang– Silver Spring, Maryland
Yan Wang– Staff Fellow, United States Food and Drug Administration, Silver Spring, Maryland
Markham Luke– Director, DTP/ORS/OGD/CDER and Supervisory Physician, U.S. Food and Drug Administration, Silver Spring, Maryland
Xiaohui Jiang– Silver Spring, Maryland
Yi Zhang– Silver Spring, Maryland