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

A. Regulatory Aspect

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

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

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 211.44

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

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.

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

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

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

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

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

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

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

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

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

B. Technical Aspect

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Organization & Personnel Qualification Training Personnel Responsibilities

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

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

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

Thank you~*^^*