Purpose: Analytical methods are critical component of the control strategy in Abbreviated New Drug Applications (ANDAs) that ensures the quality of drug substances and products. Adequately developed and validated (or verified) analytical methods serve as tools in detecting any deviations and shifts in the manufacturing process and during storage of a drug substance and product over the proposed shelf life of the product. To demonstrate this capability a complete data package of method development and validation/verification details as per the compendia and regulatory guidelines are included in the applications submitted to the Agency. The data packages should contain sufficient information to demonstrate that analytical methods are suitable and adequate for their intended purposes, including in-process control, release, and/or stability testing of drug substances and products. This study focuses on frequently observed deficiencies on the analytical methods for assay, related substances, and dissolution, etc. in new Abbreviated New Drug Applications (ANDA). This presentation would provide an insight to the applicants to prepare quality ANDA submissions for the analytical methodologies and facilitate the assessment of the data package provided in the applications to the agency.
Methods: Assessment of analytical methods in ANDAs includes method development, method validation/verification, and transfer, etc. Several recently submitted ANDAs were reviewed based upon pertinent regulations, FDA guidance documents, ICH guidelines, USP general chapters/monographs, scientific principles, and development knowledge/data.
Results: Common deficiencies related to analytical methods will be discussed in three headers in this presentation:
Method validation of non-compendia methods, the common deficiencies includes non-compliance with ICH Q1A(R2) guidelines when performing stress studies, in particular ICH Q1B, lack of mass balance in forced degradation studies or justification for lack of mass balance, excessive y-intercept in linearity studies, and insufficient concentration ranges used in determining the ranges of accuracy and linearity studies, etc.
Method verification of compendia methods, the common deficiencies include lack of equivalency study between in-house and compendia methods where applicable, failure to cover the test of specificity, and improper designation of in-house method as compendia method.
On technology transfer of non-compendia methods, the common deficiencies include significant differences observed on levels of residual solvents without adequate justification, as well as lacking of data set to demonstrate the receiving lab’s capability in related compounds evaluation, etc.
Conclusion: These common deficiencies though not all inclusive, provides a window on how the methods data package is assessed and the guidance’s followed. Sponsor could use this information in preparing and presenting the data package to the agency and avoid the common deficiencies and in turn may facilitate the assessment process and the approval of the drug applications.