1. Drugs / Biologics Research & Development, Approval Process & Related Regulations
Chung Keel Lee, Ph.D.
Special Advisor to the Minister, MFDS
Advisor, WHO
Adjunct / Invited Professor, KU / EWU
President, ISPE Korea
July 18, 2013

2. A. Regulatory Aspect

3. Introduction The manufacture and distribution
of drugs / biologics for human use
are regulated under the following
statutory authorities
The Public Health
Service Act
(42 U.S.C.262)
The Federal Food,
Drug and Cosmetic Act
(21U.S.C.321)
Drugs
Biologics
Biologics

4. Laws, Regulations and Guidances
United States Codes(USC)
The Public Health Service Act
The Federal, Food, Drug & Cosmetic Act
Code of Federal Regulations(CFR)
Current Good Manufacturing Practice for Finished Pharmaceuticals
Good Laboratory Practice for Nonclinical Laboratory Studies
Guidances
Points to Consider in the Characterization of Cell Lines
Guidance for Human Somatic Cell Therapy and Gene Therapy
Sterile Drug Products produced by Aseptic Processing
Guideline on General Principles of Process Validation

5. Code of Federal Regulations (CFR)
ex). CGMP → 21 CFR 211
Title : Broad Areas
ex) 3 : The President
21 : Food & Drugs
40 : Protection of Environment
Chapter : Issuing Agent
ex) Title 21 : Food & Drugs
Chapter I : FDA, DOHHS
Chapter II : DEA, DOJ
Part : Specific Regulatory Areas
ex). CGMP for Drugs → 21 CFR 211
GLP for Drugs → 21 CFR 58
Section :
ex). 21CFR

6. CFR Revised Annually Volume : Title 21 has 9 volumes
Title 1 ~ 16 January 1
Title 17 ~27 April 1
Title 28 ~41 July 1
Title 42 ~50 October 1
Volume : Title 21 has 9 volumes
1~99, 100~169, 170~199, 200~299, 300~499, 500~599, 600~799, 800~1299, 1300~end
Federal Register (FR) : daily publication
ex). 65 FR 52018, Aug. 28, 2000

7. Major regulations applicable to Drug & Food development and production in 21CFR
Title
Chapter
Parts
Subchapter
Title 21
Food and Drug
Revised April 1 I
FDA
1~99
General
100~199
Food for Human Consumption
200~299
Drugs: General
300~499
Drugs for Human Use
500~599
Animal Drugs, Feeds & Related Products
600~680
Biologics
700~799
Cosmetics
800~898
Medical Devices
900
Mammography Quality Standards Act
1000~1050
Radiological Health
(Reserved)
1210~1299
Regulations under certain Other Acts II
1300~1399
Drug Enforcement Administration,
Department of Justice
III
1400~1499
Office of National Drug Control Policy A. B. C. D. E. F. G. H. I. J. K. L.

8. Drug(IND) Application
Major regulations applicable to Drugs & Biologics development and production in 21CFR
Title
Volume
Chapter
Parts
Issuing Agency
Title 21
Food and Drug
Revised April 1 1 I
1~99
Food and Drug Administration,
Department of Health and Human Services 2
100~169 3
170~199 4
200~299 5
300~499 6
500~599 7
600~799 8
800~1299 9 II
1300~1399
Drug Enforcement Administration,
Department of Justice
III
1400~1499
Office of National Drug Control Policy
GLP 58
CGMP
210,211
Investigational New
Drug(IND) Application
312
NDA/ANDA
314
Biological Products
600~680
BLA
601

9. Major CGMPS Drug/Biologics: 21CFR 210 & 211
Blood & Blood Components: 21CFR 606
Human Food: 21CFR 110
Medical Device: 21CFR 820
Cellular & Tissue-based Products: 21CFR 1271

10. Some Guidances Applicable to Drugs & Biologics Development and Production
Points to Consider in the Characterization of Cell lines Used to Produce Biologicals,FDA
Points to Consider in the Production and Testing of New Drugs and Biologics by Recombinant DNA Technology,FDA
Guidances for Research Involving Recombinant DNA Molecules,NIH
Guideline on Sterile Drug Products Produced by Aseptic Processing, FDA
Guideline on General Principles of Process Validation, FDA

11. Stages Involved in Regulating Drug / Biological Products
Safety review
by NRA
Phase 1
Phase 2
Phase 3 * **
*** * **
***
Preclinical R&D
Notice of claimed investigational exemption
for a new drug(IND application)
Clinical research and development
: Phase 1,2,3
Developmental stage
NDA / Licensing stage
Post-market stage

12. Preclinical R&D Exploratory study for new drugs / biologics
Common sense science
Production of drugs / biologics for human trials
Current Good Manufacturing Practice (CGMP)
Quality control testing of the products for human trials
CGMP
Nonclinical laboratory safety tests
Good Laboratory Practice (GLP)
In Vivo testing
In Vitro testing

13. Investigational New Drug Application
File with NRA to get permit for human trials
Details of the manufacture of drugs / biologics
Protocol of the proposed clinical study
Institutional review board (IRB)
Informed consent form
Reports of preclinical testing
Quality control testing of the product
Nonclinical laboratory safety test
Safety review by NRA

14. Clinical Research & Development (IND) (Human Clinical Trials)
Phase 1
Safety
Phase 2
Efficacy/Safety
Phase 3
Safety/Efficacy
Periodic reports to NRA during IND
Progress of the clinical trials
Adverse reactions observed

15. License / NDA Application
Biologics License Application (BLA)
New Drug Application (NDA)
License / NDA application submission
A complete description of facilities, personnel, manufacturing &
testing methods & record keeping procedures
The results of laboratory testing of the product
A summary of the clinical data
The proposed labeling for the product
Product samples
Pre-licensing / NDA inspection

16. Post-Market Surveillance
Lot to lot release by NRA for biologics
Representative sample test
Review the manufacturer’s test results
Inspection of biologic / drug manufacturer
At least once every two years
To check if the manufacturer follows the approved manufacturing & testing procedures
Monitoring of adverse reactions associated with products
Changes to be reported
Sanctions
Administrative sanctions
Legal sanctions

17. B. Technical Aspect

18. What is Vaccine?
A suspension of killed or attenuated microorganisms(bacteria, viruses, or rickettsiae), or of antigenic protein derived from them, administered for the prevention, amelioration, or treatment of infectious diseases

19. How to produce Vaccine?         Add virus cell Cell culture
centrifugation
virus
(production
seed)
cell   
Filtering / Dialysis
Chromatography
Cell culture
Inoculation
Harvest
Bulk
Purification 
Add
Bulking agent
Adjuvant
Stabilizer    
Preservative
Packaging
Labeling
Inspection
Filling
Formulation

20. Two broad categories of Vaccine
Live
Live vaccines
Able to replicate in the host
Attenuated in pathogenicity
Killed vaccines
Unable to replicate in the host
Inactivated by….
ex) formalin, -radiation, heating
Killed

21. Live vs. Killed vaccine Production Step
Disease-causing microorganism
Attenuated
strain
Wild
strain
Grow
Grow
Harvest
Harvest
Inactivate
Attenuated, live vaccine
Inactivated, killed vaccine

22. Killed (Inactivated)vaccine
Advantage
Non-infectivity of the immunogen
Relative product stability
Disadvantage
Requires large quantities of the immunogen
Complete inactivation needed
Needs high purity of final product
Needs multiple vaccinations
Potentially limited immune response

23. Live(Attenuated) vaccine
Advantage
Relative ease of production
Small amounts of immunogens are required
Only single inoculation is needed in most cases
Induction of appropriate immune response
Disadvantage
Potential for reversion to virulence
Limited shelf life
Potential interference by co-infection with a naturally
occurring wild type virus

24. Two different approaches to manufacture viral vaccines
Classical approach
Non-classical approach
(using modern biotechnology)

25. Classical approach Attenuation in cell culture
Variants from other species
Reassorted genomes
Temperature-selected mutants

26. Non-classical approach (New Biotechnology)
Attenuation by genetic manupulation
Recombinant DNA
Synthetic peptides
Anti-idiotype vaccines(mimic the form of antigen)
DNA vaccines
Combination vaccines
Conjugate vaccines

27. Major Test Articles 1.Cell lines 3.Products 2.Virus Seed  General
 Quality control
 Bulk vaccine
 Final container
2.Virus Seed
 Identity
 Extraneous organism-free

28. Major Test Articles 1. Cell Lines
 General
Passage History
Growth Characteristics in vitro
 Quality control
Tumorigenicity
Karyology
Mycoplasma
Bacteria & Fungus
Tests for the presence of
viruses
- Test in Cell Cultures
- Electron Microscopy
- Test in Animals
- Retroviruses

29. Major Test Articles 2. Virus Seed
Identity
Freedom from
Extraneous Organisms

30. Major Test Articles 3. Products
 Bulk Vaccine
Sterility
Mycoplasma
Tissue Culture Safety
Animal Safety
Mycobacterium tuberculosis
Egg Safety
Infectivity
Residual Live Virus
 Final Container
General Safety
Residual Moisture
Potency
Sterility
Identity
Stability

31. Four Basic Elements of CGMP: “4Ms”
Qualification
Adequate training
Buildings
Facilities
Equipment
Tools
Men
Machinery
“4Ms”
Materials
Methods
Products
Reagents
Components
Containers & Closures
Labels
Manufacturing
Control
Validation
Documentation

32. Organization & Personnel
Qualification
Training
Personnel Responsibilities

33. Materials Receipt Sampling Testing Release Retesting Cell Banking
Viral Seeds
Untested Components,
Drug product containers
& Closures

34. Building/Facilities/Equipment
Building Design
HVAC System
Water For Injection System
Clean Steam System
Washing & Toilet Facilities
Laminar Flow Hoods.
HEPA
filter

35. Manufacturing/Control
Production
Sampling & Testing
Environmental Monitoring
Packaging & Labeling
Validation
Documentation
Storage
Drug Products
- Under appropriate conditions
Quarantine
Quality Control(QC)
- The oldest stock product
is distributed first
A system to readily determine
the distribution of drug
Release

36. Thank you~*^^*