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

2. Janssen Research & Development 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. 2 Penicillin Monoclonal antibody

3. Janssen Research & Development B. NDA and BLA Comparison: a CTD M3 Overview 3 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

4. Janssen Research & Development C. NDA/BLA: Essentially Same Information – DS S11: Nomenclature –IUPAC/CAS name, INN/USAN, company code etc. S21: Manufacturers –Facilities involved in the manufacturing of the commercial API and establishment registration numbers S5: Reference standards –Detailed testing results of reference std/mat batch(es) S6: Container closure system –May need to consider container closure integrity for sterile API S72: Post-approval stability commitments –Regulatory commitments for post-approval stability monitoring studies 4 Green: Same Yellow: Similar Red: Different

5. Janssen Research & Development D. NDA/BLA: Essentially Similar Information S12/S13 Structure and Properties S12: Structures –Chemical structure, stereochemistry S13: Properties –Physical form, Melting point, Solubility –BCS class –Dissociation constant, –Partition coefficient –pKa –Hygroscopicity –Specific optical rotation, –Particle size –Polymorphism –Stereochemistry S12: Structures –primary structure (aa seq. + S-S bonds), CDR regions, glycosylation sites S13: Properties –Summary of bioactivity –Physicochemical properties (may just refer to S31) Primary structure Higher order structure Carbohydrate structure Microhetereogeneity NDABLA 5

6. Janssen Research & Development D. NDA/BLA: Essentially Similar Information S41 Specifications ID by UV/IR Appearance Assay Purity/Impurities by HPLC Optical rotation Residual moisture Heavy Metals Residual solvents Residue on ignition Particle size ID by DRID/Dot Blot Purity/Impurity by cSDS, SE-HPLC Size by SE-HPLC Charge by IEF/cIEF Bioactivity Protein concentration (Impurities (HCP, DNA, protein A)) Bioburden Endotoxins pH NDABLA 6

7. Janssen Research & Development D. NDA/BLA: Essentially Similar Information S42/S43 Analytical methods/validation ID tests (spectroscopy) Assay (chromatography) Organic impurities (chromatography) Inorganic impurities (specific tests) Residual solvents (chromatography) ID & bioactivity (product specific) Assay & characterization (electrophoresis + chromatography) Total protein (spectroscopy) Product impurities (electrophoresis + chromatography) Process impurities (rDNA, HCP, protein A) Microbiology (bioburden/endotoxins) NDA: USP Chapter 1 Chart 1BLA: USP Chapter 1 Chart 2 7

8. Janssen Research & Development D. NDA/BLA: Essentially Similar Information S44/S45 Batch analysis/Justification of specification S44: Batch analysis –GLP toxicology batches –Clinical batches –Validation batches –Registration stability batches –Impurity profile is key –Captures results for tests not in specs S45: Justification of specs –Based on all relevant batches –Consider impurity profile changes S44: Batch analysis –No toxicology batches –Clinical batches (current process) –Validation batches –Manufacturing process/scale is key –Captures results for tests not in specs S45: Justification of specs –Based on commercial process only and sometimes restricted to clinical experience –Consider comparability NDABLA 8

9. Janssen Research & Development D. NDA/BLA: Essentially Similar Information S7 Stability S71: Stability summary and conclusions –Covers final API only –Re-test based on extrapolation –Often without stat analysis S73: Stability data –3 registration stability batches at long-term, accelerated and stress conditions –Force degradation data (high/low pH, oxidation, light) –Stability data from process intermediates S71: Stability summary and conclusions –Covers final API and intermediate from end of upstream processes –Shelf-life based on extrapolation –Often with stat analysis S73: Stability data –Data from clinical and development batches –Data from process intermediate –No forced degradation data (usu. discussed in S31) NDABLA 9 The intermediate from end of upstream is the crude API equivalent.

10. Janssen Research & Development E. NDA/BLA: Essentially Different Information S22 Manufacturing process description Chemical synthesis process Chemical Synthesis/purification scheme (reaction scheme) Starting from chemical starting materials and reagents –Chemical reactions as major steps –Crystallization as preferred purification technique –Crude API can be obtained –Pure drug substance is final API Protein expression process Protein expression and purification flowchart Starting from cell banks and cell growth media –Cell growth and protein expression as major steps –Purification conditions should not denature the protein –Process intermediate from end of upstream processes equivalent to crude API –Drug substance presented as formulated bulk NDABLA 10 Ibuprofen

11. Janssen Research & Development E. NDA/BLA: Essentially Different Information S23 Control of materials Chemical starting material (SM) marks the beginning of GMP control and major of concern of HA’s SM often commercially available SM specifications and impurity carry-out will affect API quality –Impurities (esp. genotoxic) –Trace heavy metal carry-over Reagents (equivalent to media) –Many reagents are compendial Analytical methods for SM Cell substrate (cell line + gene constructs) developed in-house –Source, history and generation of cell substrate described in detail –Genetic stability of cell substrate critically important –Potential virus carry-over addressed elsewhere Cell banks (generation, storage, shipping and testing) as SM Growth media for cell growth –Minimize animal derived components –Many components are compendial Analytical methods for cell banks NDABLA 11

12. Janssen Research & Development E. NDA/BLA: Essentially Different Information S24 Control of critical steps/intermediates Criticality analysis –Synthesis: Fate of impurities (generation, elimination, reduction, and spiking experiments) Critical intermediates –Specifications –Process Selection and justification of in-process controls (IPC) – few IPCs Selection and justification of critical process parameters (CPP) – few CPPs –Selection of CQAs (qualitative aspect) Analytical methods/validation Selection and justification of in-process controls (IPC) –Critical intermediates Crude proteins captured from end of upstream processes –Process controls Selection and justification of in-process controls (IPC) – many IPCs Selection and justification of critical process parameters (CPP) – many CPPs Process monitoring tests (PMT) –Selection of CQAs Analytical methods/validation NDABLA 12

13. Janssen Research & Development E. NDA/BLA: Essentially Different Information S25 Process validation and/or evaluation Solid dosage forms –Validation commitment (data not required) Sterile API –Sterilization validations Filter studies Filter validation studies Aseptic process justification Process simulation test Container closure integrity testing Manufacturing Scale –Process Validation (detailed data required) –Critical Process Parameter Ranges –Process Evaluation Reduced Scale –Viral Clearance validation of viruses specific to the cell line used Manufacturing and Reduced Scales –Chromatography Resin Lifetime –Intermediate Hold –Reprocessing –Qualification of a Granular Form of Hybridoma Medium –Characterization of Cell Substrate and Process Consistency Analytical methods and validations NDABLA 13

14. Janssen Research & Development E. NDA/BLA: Essentially Different Information S26 Manufacturing process development Different chemical syntheses Changes to other aspects of processes –Scales –IPCs –Process parameters Manufacturing process changes –Upstream Cell line/media Scale/site –Downstream Process/scale/site Comparability studies –Biochemical & Biophysical Equivalence –Degradation Profile Comparison –Biological Assays –May also be place in P2 together with DP comparability NDABLA 14

15. Janssen Research & Development E. NDA/BLA: Essentially Different Information S31 Characterization Structure and other characteristics –Structure by EA, UV, IR, NMR, MS, XRD –Other properties (hygroscopicity, thermal properties) Polymorphism and form selection –Only one polymorph is selected for the formulation Focus is on the major form Structure –Primary structure –Carbohydrate structure –Higher order structure Microheterogeneity –Multiple forms are present in DS (mass, charge, glycosylation, term-L) –Consistency of DS/DP Biological function Impurities/degradants and degradation pathways NDA – physicochemical char.BLA – biophysicochemcal, biological char. 15 Multiple molecular variants are in the mAb drug substance.

16. Janssen Research & Development E. NDA/BLA: Essentially Different Information S32 Impurities Organic impurities –Specified/unspecified –Actual/potential –Synthesis/degradation Inorganic impurities Tox qualification of impurities –List tox studies and qual levels Genotoxicological concerns –DEREK screening –AMES/CA tests –If +, control below TTC Product related impurities –Equivalent to synthesis impurities in NDA Process related impurities –Equivalent to degradants in NDA High-level summary only. Detailed cross reference d to S31 Immunogenicity not a topic for CMC No specified levels set for individual impurities NDABLA 16

17. Janssen Research & Development F. NDA/BLA CMC Comparison: Conclusion 17