Common Deficiencies of in vitro Binding Bioequivalence (BE) Studies Submitted in Abbreviated New Drug Applications (ANDAs)
- 229 Downloads
There are several drug products that bind phosphate or bile acid in the gastrointestinal (GI) tract to exert their therapeutic efficacy. In vitro binding studies are used to assess bioequivalence (BE) of these products. The objective of this study is to identify the common deficiencies in Abbreviated New Drug Applications (ANDAs) for these products. Deficiencies were compiled from ANDAs containing in vitro binding BE studies. The deficiencies were classified into eight categories: Pre-Study Method Validation, During-Study Sample Analysis, Study Design, Study Procedure, Dissolution/Disintegration, Analytical Site Inspection, Data Submission, and Formulations. Within each category, additional subcategories were defined to characterize the deficiencies. A total of 712 deficiencies from 95 ANDAs for 11 drug products were identified and included in the analysis. The four categories with the most deficiencies were During-Study Sample Analysis (27.8%), Pre-Study Method Validation (17.3%), Data Submission (16.7%), and Study Design (15.7%). For the During-Study Sample Analysis category, failure to submit complete raw data or analytical runs ranked as the top deficiency (32.8%). For the Study Design category, using an unacceptable alternate study design (26.8%) was the most common deficiency. Within this category, other commonly occurring deficiencies included incorrect/insufficient number of absorbent concentrations, failure to pre-treat drug product with acid, insufficient number of replicates in study, incorrect calculation of k1 and k2 values, incorrect dosage form or pooled samples used in the study, and incorrect pH of study medium. The review and approval of these products may be accelerated if these common deficiencies are addressed in the original ANDA submissions.
KEY WORDSbioequivalence common deficiency generic drugs in vitro binding study
- 1.Federal Regulations Title 21. https://www.access.data.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm.
- 2.FDA. FDA product-specific recommendations for generic drug development. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm.
- 3.Samy R, Faustino PJ, Adams W, Yu L, Khan MA, Yang Y. Development and validation of an ion chromatography method for the determination of phosphate-binding of lanthanum carbonate. J Pharm Biomed Anal. April 6, 2010;51(5):1108–12.Google Scholar
- 4.FDA. Sevelamer carbonate tablets BE recommendation. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm089620.pdf. revised 2015.
- 5.FDA. Cholestyramine oral powder suspension BE recommendation. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273910.pdf. Revised June, 2015.
- 6.Swearingen RA, Chen X, Petersen JS, Riley KS, Wang D, Zhorov E. Determination of the binding parameter constants of Renagel capsules and tablets utilizing the Langmuir approximation at various pH by ion chromatography. J Pharm Biomed Anal. 2002;29(1–2):195–201. https://doi.org/10.1016/S0731-7085(02)00007-9.CrossRefPubMedGoogle Scholar
- 10.FDA. Handling and retention of BA and BE testing samples. https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126836.pdf.
- 11.FDA. In vitro binding bioequivalence study summary tables and SAS transport formatted tables for dataset submission. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM364105.pdf.