Quality regulation for biological products current and future

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  • 1. Quality Regulation for Biological Products: Current and Future Sue Nie Park, Ph.D. Director, Division of Viral Products Center for Biologicals Evaluation Korea Food & Drug Administration
  • 2. Presentation Overview
    • I. Current Regulation of Biological Products
    • - Functions of Regulatory Authorities
    • - Relationship between Regulatory Authority and manufacturers to regulate quality of biological products
    • II. Current Approach To Regulation of Biological Products
    • III. Registration Process of Biologicals
    • IV. Law and Ordinances Related to Biological Approval
    • V. Control of Viral Products
    • VI. Challenges
    • VII. Scientific Researches
  • 3. I. Current Regulation of Biological Products
  • 4. What is Quality Regulation ?
    • Definition: Overall management system to secure high levels of safety and efficacy and quality of biological products
    • Scope: Investigational New Drug (IND)
    • Post Marketing Surveillance
  • 5. Overview of Quality Authority Functions
    • Registration (licensing) of products
    • Inspection and licensing of manufacturers
    • Inspection and licensing of distributors
    • Post-marketing suveillance
    • Regulation of claims that can be made for commercial promotion of products
    • Authorization of clinical trials
  • 6. Regulatory Agencies
    • Korea Food and Drug Administration (KFDA)
    • Food and Drug Administration (US FDA)
    • European Medicines Evaluation Agency (EMEA)
    • Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS)
      • What they’re looking for:
        • Safety
        • Efficacy
        • Quality
  • 7. Overview of Processes to Register Pharmaceuticals Worldwide
    • Regulatory Authorities use a combination of National Guidelines and Regulations together with established standards in National Pharmacopeias and International Guidelines and Standard to evaluate the efficacy, quality and safety of pharmaceuticals
  • 8. Regulatory Capacity
    • A fully developed NRA has implemented all the functions in the below
  • 9. National Control Laboratories (NCL)
    • The activities of an NCL are as follows:
    •          Laboratory testing
    •          Advice on clinical trials
    •          Protocol review
    •          Developing laboratory tests
    •          Basic research
    •          Review of post-marketing surveillance data
    •          Input into licensing decisions
    •          Assistance with inspections
    • Distributing references.
  • 10. A NRA can be effective only if it has:
    • A legal basis for all its functions in legislation & Regulations
    • Sufficient human & financial resourses
    • Access to appropriate scientific expertise
    • Access to a quality control laboratory
  • 11. Quality Regulation System Network Manufacturer NCL NRA RA * QA QC Production Final lot New drug approvals Changes to drugs Compliance with regulations Consequences of violations Do as a “gatekeeper” Inspection: regularly once every 2 years RA *: Regulatory Affair
  • 12. The Process of Biological Products Licensure in Korea Pre-clinical & clinical reports Specifications & Test methods KFDA Simultaneously or separately application Licensure Market Submit a post-marketing surveillance report to KFDA by 5 years after approval Pre-approval Post-approval According to “Provision for Inspection of Request on Specifications and Test Methods of Drugs (No. 2001-9, Feb 16 2001 revised)
  • 13. The Process of Biological Products Licensure in the US
  • 14. Approval Process in Europe: Overview Determine Product Status Select a Rapporteur country (if France, AFSSAPS)) Apply to other EU members** Non Therapeutic Effect Submit to AAFSSAPS Therapeutic Effect Centralized Procedure Mutual Recognition Procedure * Based on rapporteur country’s authorization In France: additional submission to Transparency Commission Apply to EMEA
  • 15. Overall relationship between NRA and Drug Manufacturer Unapproved Products IND initial CMC Amendments Annual Reports Lot Release Process Changes BLA (CMC) Inspections Inspections Regulatory Authority REVIEW REVIEW Compliance Action Approved Products Changes to Procedures Annual Reports Adverse Reactions License Updates Regulatory Affairs Legal Quality Control Marketing Customers Licensors Manufacturing Clinical Supplier Product Development Licenses Management Quality Assurance
  • 16. Biological Products Regulated By KFDA
  • 17. Documents generated by:
    • Discovery
    • Patent applications
    • Highly specialized chemistry and biology reports
    • Methods for identifying lead compound
  • 18. Documents generated by:
    • Preclinical Studies
    • Pharmacodynamics
    • Toxicology reports
    • PK studies (ADME)
    • GLP compliance documentation
  • 19. GLP / BPL
    • organization and personnel
    • testing facility & operation
    • test and control article characterization
    • protocol and conduct of the nonclinical laboratory study
    • records and reporting
    • equipment design
    DEFINITION
  • 20. Documents generated by:
    • IND
    • Preclinical results, manufacturing information, clinical protocols, investigator brochure, investigator qualifications
    • These must be adequate to avoid a clinical hold
  • 21. Documents generated by:
    • Clinical Development
    • Study protocol(s)
    • Informed Consent Forms
    • Case Report Forms
    • Investigator Brochure
    • GCP compliance documentation
  • 22. GCP / BPC
    • The definition in ICH Guidelines Glossary:
    • “ A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.”
    • Multilingual site:
    • http://pharmacos.eudra.org/F2/eudralex/vol-1.home.htm
    DEFINITION
  • 23. Documents generated by:
    • NDA
    • CMC (chemistry, manufacturing control)
    • Human PK (pharmacokinetics), bioavailability data
    • Microbiology
    • Statistical data
    • Samples and labeling
    • GMP documentation
  • 24. GMP / BPF (bonnes pratiques de fabrication)
    • Core concept: At no time in the manufacturing process can operations NOT be under absolute control --> QA
      • Documentation & records
      • Personnel qualifications
      • Sanitation & cleanliness
      • Equipment verification
      • Process validation
      • Design controls
      • Monitoring & feedback
    DEFINITION
  • 25. Documents generated by:
    • Post-marketing, Phase IV
    • MedWatch, other pharmacovigilance
    • Pharmacoeconomic studies
    • Articles for scientific journals
    • Materials for professional meetings (abstracts, posters)
    • Promotional marketing pieces
  • 26. II. Current Approach To Regulation of Biological Products
  • 27. Regulation of Biological Products Based on Sound Science, Law, and Public Health Impact Policy Compliance Surveillance Research Review
  • 28. KFDA Policy Development
    • Legislative Laws
    • KFDA Regulation - public rule
    • KFDA Guidance - public notice and comment
    • - Communicate KFDA current thinking on topic
    • - Often provides acceptable approaches
    • - However, alternate and acceptable approaches may also be used
    • - Option to submit draft guidance to KFDA for consideration
    More focused More specific
  • 29. Policy Development
    • Transparent Process & Opportunity to Comment Meetings
    • - Public Hearings
    • - KFDA focuses specific products, specific concerns
    • - Scientific Meetings/ Workshops specific topic
    • Scientific Research
    • International component (e.g., ICH, WHO)
    • Policy is revised as appropriate
    • - Regulation and Rules - always open for comment
  • 30. Product Development and Regulation
    • GOAL: Balanced, flexible, responsive regulatory approach
    • – Assure the safety and rights of subjects
    • – Protect the public health
    • – Not impede technological innovation & product development
    • Influences
    • – Available scientific knowledge, pre clinical, clinical knowledge & experience
    • – Crises/ tragic events
    • Timing to develop policy, especially written policy
    • Appropriate Risk Assessment
  • 31. Five Areas of Regulatory Concern
    • Preventing transmission of communicable disease
    • Safe processing and handling
    • Clinical safety and effectiveness, where appropriate
    • Promotional claims
    • Monitoring of industry
  • 32. Standards Development “Leveraging”
    • Standards Organizations
    • – Non governmental organizations (NGO)
    • – Serve as facilitators to develop standards
    • Identify Standard to be Developed
    • – Participation by interested parties
    • – Transparent Process
    • – Agreement on “standard” reached by consensus
    • Option for KFDA to participate in development of standards
    • Option for KFDA to adopt
  • 33. III. Registration Process of Biologicals
  • 34. Licence for Pharmaceutical manufacturer Receipt Order & Review for Facility inspection Completion for Facility inspection & Review Proposal & Approval Issue of certificate for Pharmaceutical manufacture Report Facility inspection Order Fill-up of application form Release Transaction adminstration KFDA Via department (Regional KFDA) Applicant
  • 35. Applicant Registration Process of NDA Safety & Efficacy application Specification and test methods application Safety Evaluation Office NITR Central Pharmaceutical Affair Council Evaluation Council In KFDA (If necessary) Review Result Notification Review Result Notification Applicant NDA Biologics Department NDA Action
  • 36. IND Application Process PreIND Meeting Application IND Plan PreIND Meeting Notification of Application Eligiblity IND (or its amendment) Application 1 2 Was there a PreIND? Review Initiation at PreIND Meeting level Protocol No IND (or its amendment) Approval Yes Trial Ongoing Reporting of CT completion NDA Application Final PL Approval If necessary, forwarding to KCPAC IND Requisite Dossier
  • 37. IV. Law and Ordinances Related to Biologicals Approval
  • 38. System of and ordinances Pharmaceutical Affairs Law (PAL) Pharmaceutical Enforcement Ordinance(PEO) Pharmaceutical Enforcement Regulation(PER) Notice, Guidance’…etc
  • 39. Laws and Regulations concerned with Biologicals Approval Article 85~88 Article 64 KFDA Notice 1999-39 Article 11.40 Article 19,31 Article 26-3 KFDA Notice 1999-11 Article 30,31 Article 26-2 Re-examination of New drug Re-evaluation of drug PMS Adverse reaction monitoring GMP Inspection Article 62~70 Article 45 Lot release KFDA Notice 2000-49, 1997-67, 1999-6, 2001-9, 2001-35 Article 23, 24, 27, 27-2 ,28,29,83 Article 26 Product Licence KFDA Notice 2000-49 Article 22 Article 26 Licence for Pharmaceutical manufacture Notice…etc PER PEO PAL
  • 40. System to Regulate Biologicals
  • 41. Licensing Process
  • 42.
    • Evaluation of both facilities and products for licensing
    • ○ Authority gives and approval for biologics after document review and facility audit including GMP inspection
    • - The Pharmaceutical Affairs Act (PAL) : Law 6511,2001.8.14
    •   ․ Article 26(License, etc. for Manufacturing Industry)
    •   ․ Article 26-2(Re-examination of New Medicines)
    •   ․ Article 27(Conditional License)
    •   ․ Article 64(Report and Inspection, etc.)
  • 43.
    • - Enforcement Regulations of the Pharmaceutical
    • Affair Act (PER)
    • ․ Article 21(Restriction of License Related to Medicines, etc. Imposed on Manufacturer or Importer)
    •   ․ Article 22(Application of Manufacturing License for Medicines, etc.)
    •   ․ Article 23(Application for Manufacture or Import of Specific Items)
    •   ․ Article 27(Screening of Safety and Efficacy)
    •   ․ Article 28(Standards for Clinical Trial)
    •   ․ Article 29(Approval of Protocol, etc.)
    •   ․ Article 30(Re-examination of New Medicines, etc.)
    •   ․ Article 31(Application for Re-examination of new Medicines, etc.)
    •   ․ Article 32(Application for Conditional License, etc.)
    •   ․ Article 33(Observance of Conditions)
    •   ․ Article 34(License and Register of License)
    •   ․ Attachment 4(The Standards for Manufacture and Quality Management of Drugs)
    •   ․ Attachment 4.4(Guideline on Standards for Manufacture and Quality Management)
  • 44.
    • 3. Written guidelines for submission of the file
    • ○ Authority prepares guidelines for document requirements for biologics license application.
    • - The Pharmaceutical Affairs Act
    •   ․ Article 26(License, etc. for Manufacturing Industry)
    •   ․ Article 26-2(Re-examination of New Medicines)
    •   ․ Article 27(Conditional License)
    •   ․ Article 64(Report and Inspection, etc.)
    • - Enforcement Regulations of the Pharmaceutical Affair Act
    •   ․ Article 22(Application of Manufacturing License for Medicines, etc.)
    •   ․ Article 23(Application for Manufacture or Import of Specific Items)
    •   ․ Article 27(Screening of Safety and Efficacy)
    •   ․ Article 29(Approval of Protocol, etc.)
    •   ․ Article 31(Application for Re-examination of new Medicines, etc.)
    •   ․ Article 32(Application for Conditional License, etc.)
    •   ․ Attachment 4(The Standards for Manufacture and Quality Management of Drugs)
  • 45.
    • - Guidelines on review of application form approval of manufacturing and import of drugs, etc. (notification of KFDA)
    • - Regulation on evaluation of safety and efficacy of drugs, etc. (notification of KFDA)
    • - Guideline on standards for re-examination for new drugs, etc. (notification of KFDA)
    • - Guideline on Korean Good Clinical Practice (notification of KFDA)
    • - Guideline on approval and clinical trials for gene therapy (notification of KFDA)
    • - Regulation about examination in the letter of request for specification and test methods of drugs etc. (notification of KFDA)
    • - Guideline on stability testing (notification of KFDA)
    • - Guideline on bioequivalence testing (notification of KFDA)
  • 46. V. Control of Viral Products August 2003 Division of Viral Products Center for Biologics Evaluation Korea Food and Drug Administration
  • 47. Mission
    • Division of Viral Products
      • is a National Control Laboratory for certifying viral products including viral vaccines and diagnostic reagents for viral diseases.
      • is responsible for assuring that safe and effective viral products are available to the public.
  • 48. Legal Authority
    • Pharmaceutical Affairs Law (PAL)
    • Pharmaceutical Enforcement Ordinance (PEO)
    • Pharmaceutical Enforcement Regulation (PER)
    • KFDA Notice/Guidance/Rules…
  • 49. Organization & Responsibilities QM Crosscheck QM Approval Hep B (plasma) HIV/HepB agn/aby test Hep A JE HFRS Influenza OPV IPV Interferon Clonorchis sinensis agn Paragonimus westermani agn MMR VZV
  • 50. Activities
    • Review of minimum requirements for viral products (specifications, standards and test methods for viral vaccines and diagnostic reagents for viral diseases)
    • Organization of Advisory Meeting of Central Pharmaceutical Council Subcommittee as a part of legislative procedure for enactment or amendment of minimum requirements for viral products
    • Legislative procedure for enactment or amendment of minimum requirements for viral products
    • Lot release testing of viral vaccines & related activities (facilities, equipments, maintenance, validation, SOP, training, etc)
    • Research & collaboration for improvement of test methods and quality control standards for viral products
  • 51. Inactivated Viral Vaccines or Antigens
    • Influenza vaccine
    • Japanese encephalitis vaccine
    • Hemorrhagic fever with renal syndrome (HFRS) vaccine
    • Hepatitis A vaccine
    • Hepatitis B vaccine
    • Poliomyelitis vaccine
    • Clonorchis sinensis antigen
    • Paragonimus westermani antigen
  • 52. Live Attenuated Viral Vaccines
    • Poliomyelitis vaccine (oral)
    • Measles vaccine
    • Rubella vaccine
    • MMR vaccine
    • Varicella vaccine
    • Small pox vaccine (reintroduced 2002~)
  • 53. Diagnostic Reagents
    • Anti-HIV-1/2 antibody
    • HBsAg
    • HBsAb
    • HBeAg
    • Rotavirus
    • Malaria
  • 54. Flowchart of Official Lot Release
    • Consumer Protection Office
    • Sampling
    • Certification
    • Center for Biologics Evaluation
    • : QC
      • Review of summary batch protocol
      • Laboratory testing
    • Center for Biologics Evaluation
    • : QA
      • Review of documentation
      • Review of test results
  • 55. Test Items for Lot Release : Inactivated Vaccines or Antigens, 2003
  • 56. Test Items for Lot Release : Live Attenuated Vaccines, 2003
  • 57.
    • Test for Inactivation: JE and HFRS (Hantaan) vaccines
    • Test for Abnormal Toxicity: All inactivated vaccines & OPV
    • Mouse Immunogenecity Test: Hepatitis A & B vaccines
    • (substituted in vitro methods)
    • Serum Neutralizing Antibody Titration: JE, HFRS
    Animal Tests
  • 58. Sample Logging pH Assay Identification Automatic/Manual Result Entry
    • 1. Sample logging
      • Evaluation analysis
      • Research
    • 2. Results entered
      • Automatic
      • Manual
    • 4. Reporting
      • Certificates
      • Statistics
      • Lab Information
    • 3. Approval
      • Automatic
      • Manual
    Tracking...................... KFDA LIMS Work Flow
  • 59. Potency Standards / Reference Reagents for Viral Vaccines Manufacturer’s in house reference IPV Asan Institute for life science (WHO collaborating center for viral reference) HFRS 2001 (Established) Korea National Biological Standard JE (inactivated) NIBSC Influenza HA & Split " Hepatitis A vaccine Manufacturer’s in house reference Hepatitis B vaccine (plasma) Comment Sources Manufacturer’s in house reference Korea National Biological Standard " " OPV 2002 (Established) Varicella vaccine Mumps vaccine Measles vaccine Vaccines
  • 60. Proposed KNBS Set-up Project Phase I
    • Anti-tetanus toxoid, B19
    • Mumps vaccine - G-CSF, recombinant
    • Snake Antivenom (viper)
    • Diphteria toxoid Rubella vaccine
    • Erythropoietin, recombinant
    • HbsAg
    • HPV VLPs
    • Pertussis vaccine
    • Varicella vaccine
    • EPO, Anti-thrombin III
    • Anti-JEV
    • Tetanus toxoid
    • JE vaccine, inactivated
    • Interferon alpha, recombinant
    • Factor VIII
    Reference Materials for Biologicals
    • IL-1 protein
    • Measles
    • Anti-HIV
    • HBV DNA
    • HEV, Factor IX
    • SV40
    • Anti-HBsAg
    • HAV RNA, HCV RNA
    • BVDV
    • Retrovirus
    • HPV DNA
    2004 2003 2002 2001 Year
  • 61. Summary on Annual Activities (’96-’01) *1 Including 25 withdrawals *2 Including 2 withdrawals and 1 rejection
  • 62.
    • Korean Standards for Biologicals: Preparation/Potency/Stability
      • JE vaccine (inactivated)
      • Varicella vaccine
      • HBsAg
    • Development/Standardization of assay methods
      • RNA PCR: JEV, HCV, BVDV, Rotavirus
      • PERT assay: Retrovirus
      • VN: inactivated JE vaccine
    • Customer support
      • Guidelines for preparation of the specifications and test methods of diagnostic kits
      • Quality management of Korean standards for biologicals
    Research Activity 2001-2003
  • 63.
    • Anti-Hepatitis C Virus Antibody WHO International Standard (2001)
    • Hepatitis B Virus Surface Antigen WHO International Standard (2002)
    • First Human Papillomavirus DNA WHO International Standard(2002-2003)
    • First Anti-Japanese Encephalitis Virus Antibody International Standard (2002-2003)
    WHO Collaborative Study 2001-2003
  • 64. Publications 2003
    • Byoung-Guk Kim, Hye-Sung Jeong, Sun-Young Baek, Jin-Ho Shin, Seok-Ho Lee, Yong-Seok Jeong and Sue-Nie Park. Real-time quantitative detection of HCV RNA using MagNA Pure LC and LightCycler System . J. Virol. Methods (Submitted in June/2003).
    • Hye-Sung Jeong, Jin-Ho Shin, Young-Nam Park, Jung-Yun Choi, Young-Lim Kim, Byoung-Guk Kim, Seung-Rel Ryu, Sun-Young Baek, Seok-Ho Lee and Sue-Nie Park. Development of Real-Time RT-PCR for Evaluation of JEV Clearance During Purification of HPV type 16 L1 Virus-Like Particles . Biologicals 31(3):223-229. 2003.
    • Seung-Rel Ryu, Jin-Ho Shin, Sun-Young Baek, Jae-Ok Kim, Kyung-Il Min, Bok-Soon Min, Byoung-Guk Kim, Do-Keun Kim, Mi-Kyung Park, Mi-Jin Ahn, Kyung-Sook Chae, Hye-Sung Jeong, Seok-Ho Lee and Sue-Nie Park. Evaluation of Limit of Detection and Range of Quantitation of RT-PCR, Real-Time RT-PCR and RT-PCR-ELISA for the Detection of BVDV Contamination in Biologics Derived from Cell Cultures . J. Bacteriol. Virol . 33(2):161-168. 2003.
  • 65. Future Prospect of Center for Biologics Evaluation
    • Standardization
        • National Biological Standards
        • Regional Biological Standards
        • International Biological Standards
    • International Collaboration
        • Global Training Network
        • KOICA
        • WHO Collaborative Study
  • 66. VI. Challenges
  • 67. KFDA’s Public Health Challenges
    • Vaccine Safety and Availability
    • Blood Safety and Availability
    • Emerging Infectious Diseases, e.g.) SARS
    • Gene Therapy
    • Xenotransplantation
    • Encounter Bio-terrorism
    • New Technologies
  • 68. Emerging New Technologies- Biomedical Research and Technology
    • Proteomics
    • Genomics
    • Mass Spectroscopy
    • Nuclear Magnetic Resonance
    • Spectroscopy
    • Plasma Resonance Spectroscopy
    • PCR methods, e.g. MAPREC, PERT, Real-time PCR with TAQ-MAN
  • 69. Application
    • Product Quality
    • - Complex Biological Product Characterization
    • - Release Testing
    • - Manufacturing process monitoring
    • - Adventitious Agent Detection and Quantitation
    • - Transitioning from Animal/Human Testing to Analytical, In Vitro, or Biochemical Testing
    • Biological Assessments
    • - Mechanisms of Immunity or Immuno-modulation
    • - Biological Responses
    • - Mechanisms of Disease Pathogenesis
    • - Mechanisms of Product Toxicity
  • 70. The Future Challenges of New Technologies
    • Quantitation
    • Validation
    • Robustness
    • Standards
    • Imagination and creativity in their application