1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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)

12. 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

13. 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

14. 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

15. F. NDA/BLA CMC Comparison: Conclusion