David G. Donne, Ph.D. and Thomas J. DiFeo, Ph.D. Regulatory CMC BLA and NDA Submissions: Differences and Correlations from Regulatory and Scientific Perspectives – Drug Product David G. Donne, Ph.D. and Thomas J. DiFeo, Ph.D. Janssen Research & Development, LLC Welsh and McKean Roads Spring House, PA, USA

A. NDA and BLA: CMC Basics NDA – New drug application The NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. (5-year data exclusivity for new chemical entities) ANDA for generics (Waxman-Hatch Act, 1984) BLA – Biologic license application The Biologics License Application (BLA) is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce (12- year data exclusivity for biologics). ABLA for biosimilars (BPCI Act, 2009) Focus here will be on monoclonal antibodies Common CMC Requirements Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to assure the drug's identity, strength, quality, and purity. Penicillin Monoclonal antibody

B. NDA and BLA Comparison: a CTD M3 Overview 32S Drug substance S11, S12, S13 S21, S22, S23, S24, S25, S26 S31, S32 S41, S42, S42, S44, S45 S5 S6 S71, S72, S73 32P Drug product P1 P21, P22, P23, P24, P25, P26 P31, P32, P33, P34, P35 P4 P51, P52, P53, P54, P55, P56 P6 P7 P81, P82, P83 32A Appendices A1: Facilities and Equipment A2: Adventitious Agents and Safety Evaluation Non-viral agents Viral agents A3: Novel excipients 32R Regional DP batch records Comparability protocol and method validation package Medical devices DS batch records Green: Same; Yellow: similar; Red: Different

C. NDA/BLA: Essentially Same Information – DP (1) P1: Description and Composition of the Drug Product NCE/mAb: description and composition (function and QS), diluents, CCS mAb: description for delivery devices (sometimes for NDA too) P21: Components of the drug product A regulatory section with only summary information P25: Microbiological attributes Microbiological attributes (bioburden, endotoxins, sterility) Container closure integrity to prevent microbial contamination NDA for sterile products has the same requirements P26: Compatibility (reconstituted products only) Compatibility of reconstituted products with diluents and dosage devices In-use stability data to support hold times in USPI Green: Same Yellow: Similar Red: Different

C. NDA/BLA: Essentially Same Information – DP (2) P31: Manufacturers Facilities involved in the manufacturing of the commercial API and establishment registration numbers P32: Batch formulas List of components (quantity/batch) Quality standards and Overages P4: Control of Excipients Similar requirements for NDA/BLA P6: Reference Standards/Materials Usually cross references to S5 P82: Post-approval stability commitments Regulatory commitments for post-approval stability monitoring studies (on-going registration batches, validation batches, annual batches) Green: Same Yellow: Similar Red: Different

C. NDA/BLA: Essentially Same Information: Appendix and Regional 32A2: Non-viral adventitious agents safety information BSE/TSE Bacteria/fungi Mycoplasma 32A3: Novel Excipients Details provided here (summary in P4) 32R: Regional Information Executed batch records (DP) Comparability protocol for post-approval changes Method validation package

D. NDA/BLA: Essentially Similar Information P23 DP Manufacturing process development Solid dosage forms Injectables Process DOE Developed at smaller scale Sterilization and/or aseptic processing for injectables only P23 Manufacturing process development Injectables only Platform approach for fill and finish Developed at commercial scale Sterilization and/or aseptic process for all biologics

D. NDA/BLA: Essentially Similar Information P33/34/P35 Manufacturing process dev/controls P33 Manufacturing process description Flowchart Description (granulation, tablet compression, etc.) P34 Controls of critical steps/intermediates IPCs/CPPs Sterilization for injectables P35 Process validation ProVal Commitment for solids (data not requried) ProVal for injectables Media fill P33 Manufacturing process description Flowchart Description (sterile fill and finish) Equipment for injectables (32A1) P34 Controls of critical steps/intermediates IPCs CPPs Sterilization P35 Process validation ProVal for injectables (detailed data required) Media fill

D. NDA/BLA: Essentially Similar Information P5 Control of the drug product (1) P51/52/53 specifications, analytical procedures and validations Additional tests for DP Content uniformity Additional tests for injectables Sterility Particulate matter Turbidity Endotoxins Often same release and stability specs P51/52/53 specifications, analytical procedures and validations Additional tests for DP Content uniformity Additional tests for injectables Sterility Particulate matter (visible/subvisble) Turbidity Additional tests for biologics Osmolality Often different release and stability specs

D. NDA/BLA: Essentially Similar Information P5 Control of the drug product (2) P54 Batch analysis Development, clinical, validation, stability batches P55 Impurities Additional DP impurities P56 Justification of specifications Based on all relevant batches Often no statistical analysis P54 Batch analysis Phase 3 clinical and validation batches P55 Impurities Additional DP impurities Product related Process related P56 Justification of specifications Based on clinical/validation batches only Statistical analysis performed

D. NDA/BLA: Essentially Similar Information Container closure system/delivery device P24 Container closure system Selection and development Validation Design control if device (may be placed in 32R) P7 Container closure system Primary: description/specs Functional 2nd CCS Sometimes a delivery device (additional info in P24/32R) P24 Container closure system Selection and development Validation (+ shipping validation) Design control if device (may be placed in 32R) P7 Container closure system Primary: description/specs Functional 2nd CCS Often a delivery device (additional info in P24/32R)

D. NDA/BLA: Essentially Similar Information P81/P83 Stability summary and data P81 Stability summary and conclusions Shelf-life extrapolated for solid dosage forms Statistical analysis required if long-term or accelerated stability data change/variability over time P83 Stability data From 3 registration batches P81 Stability summary and conclusions Shelf-life limited to real- time data for injectables (may be extrapolated less than solids) Statistical analysis required if long-term or accelerated stability data change/variability over time P83 Stability data From phase3 clinical/validation batches Additional characterization data on stability beyond specs presented

E. NDA/BLA: Essentially Different Information P22 Formulation development Formulation history Rational for formulation selection Physicochemical and biological properties - dissolution Dissolution method development Dissolution profiles of formulations Also focus on dissolution method development Formulation development Formulation history Formulation selection Physicochemical and biological properties - comparability Biological aspects Biophysical aspects Biochemical aspects Focus on DP May also contain DS comparability info

E. NDA/BLA: Essentially Different Information 32A/R Appendices and Regional 32A1 Facilities and equipment Not applicable 32A2 Adventitious agents - viral 32R Regional Medical devices can be placed here DS batch records not needed 32A1 Facilities and equipment Required for biologics 32A2 Adventitious agents - viral Viral clearance validation of viruses specific to the cell line used (6-log safety margin) 32R Regional Medical devices can be placed here DS batch records needed

F. NDA/BLA CMC Comparison: Conclusion