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PP10-77: Risk-Based Quality Assessment of Generic Narrow Therapeutic Index Drugs

Poster Presenter

      Mai Tu

      • Drug Product Reviewer, OLDP, OPQ, CDER
      • FDA
        United States


The objective of this study is to highlight key areas where tight control strategies should be implemented by the manufacturers to consistently and reproducibly manufacture generic quality narrow therapeutic index (NTI) drugs using generic Tacrolimus capsules as an example.


For this poster presentation, we describe the underlining principles for quality assessment of proposed generic products of NTI drugs. Additionally, we discuss case studies to demonstrate how FDA reviewers assess proposed generic products of narrow therapeutic index drugs.


Tacrolimus Capsules (0.5 mg, 1 mg, and 5 mg) is an immunosuppressive drug indicated for the prevention of organ rejection in patients receiving kidney, liver, or heart transplants. Tacrolimus drug substance (DS) in Tacrolimus Capsules is formulated and stabilized in its amorphous form. The stabilization of the amorphous DS and content uniformity of the finished product are of paramount importance for the bio-performance of Tacrolimus Capsules. The high-risk areas that require tight controls are highlighted below- • Formulation ? Drug load ? Type and use level of excipient(s) for the stabilization of amorphous DS • Manufacturing process ? Conversion of crystalline DS to amorphous DS ? Process aid – organic solvents used ? Order of addition ? Particle size and distribution control ? In-process control of blend and content uniformity ? In-process hold time ? Encapsulation fill weight control ? Package size (fill count) • Release and stability testing ? Content uniformity ? Suitable instrumentation method to detect potential DS crystallization ? Dissolution method with discriminatory power to detect potential DS crystallization ? In-use stability evaluation The risk-based approach to quality assessment of Tacrolimus Capsules applications has led to more consistent and robust quality products across different generic applications. Similar approach may be used for the assessment of other NTI drugs.


Risk-based quality assessment of generic NTI drugs emphasizes on the tight control strategies required to ensure NTI drugs that possess high degree of content uniformity and robust chemical and physical stability. Risk mitigation strategy should focus on upstream product development, i.e., formulation and manufacturing process understanding. Furthermore, effective communication between the applicants and FDA is helpful in the timely resolution of technical issues leading to faster regulatory approval. Additional authors of the poster abstract are: Jin Xu, Wilmarie Medina-Ramos, and Geoffrey Wu Office of Lifecycle Drug Products, Office of Pharmaceutical Quality, CDER/FDA Disclaimer: This presentation reflects the views of the authors and should not be construed to represent the views or policies of the FDA. The authors have no declarations of interest to report.