Quality Regulation for Biological Products: Current and Future

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 theyre 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
QA
QC
NRA
Inspection regularly once every 2 years
RA
Production
New drug approvals Changes to drugs Compliance
with regulations Consequences of violations Do as
a gatekeeper
NCL
Final lot
RA Regulatory Affair
12
The Process of Biological Products Licensure in
Korea
According to Provision for Inspection of Request
on Specifications and Test Methods of Drugs (No.
2001-9, Feb 16 2001 revised)
Pre-clinical clinical reports
Specifications Test methods
Simultaneously or separately application
Licensure
Market
KFDA
Pre-approval
Post-approval
Submit a post-marketing surveillance report to
KFDA by 5 years after approval
13
The Process of Biological Products Licensure in
the US
14
Approval Process in Europe Overview
Centralized Procedure
In France additional submission to Transparency
Commission
Apply to EMEA
Therapeutic Effect
Select a Rapporteur country (if France, AFSSAPS))
Determine Product Status
Mutual Recognition Procedure
Non Therapeutic Effect
Apply to other EU members
Based on rapporteur countrys authorization
Submit to AAFSSAPS
15
Overall relationship between NRA and Drug
Manufacturer
Quality Assurance
Unapproved Products IND initial CMC
Amendments Annual Reports Lot
Release Process Changes BLA
(CMC)
Management
Regulatory Authority
Regulatory Affairs
REVIEW
Licenses
Product Development
Supplier
Clinical
Inspections
Approved Products Changes to Procedures Annual
Reports Adverse Reactions License Updates
REVIEW
Manufacturing
Licensors
Customers
Inspections
Marketing
Quality Control
Compliance Action
Legal
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
DEFINITION

• organization and personnel
• testing facility operation
• test and control article characterization
• protocol and conduct of the nonclinical
  laboratory study
• records and reporting
• equipment design

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

• Study protocol(s)
• Informed Consent Forms
• Case Report Forms
• Investigator Brochure
• GCP compliance documentation

• Clinical Development

22
GCP / BPC
DEFINITION

• 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

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)
DEFINITION

• Core concept At no time in the manufacturing
  process can operations NOT be under absolute
  control --gt QA
• Documentation records
• Personnel qualifications
• Sanitation cleanliness
• Equipment verification
• Process validation
• Design controls
• Monitoring feedback

25
Documents generated by

• MedWatch, other pharmacovigilance
• Pharmacoeconomic studies
• Articles for scientific journals
• Materials for professional meetings (abstracts,
  posters)
• Promotional marketing pieces

• Post-marketing, Phase IV

26
II. Current Approach To Regulation of Biological
Products
27
Regulation of Biological ProductsBased on Sound
Science, Law, and Public Health Impact
Surveillance
Research
Review
Policy
Compliance
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 DevelopmentLeveraging

• 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
35
Applicant
Registration Process of NDA
Safety Efficacy application
Specification and test methods application
NITR
Safety Evaluation Office
Central Pharmaceutical Affair Council
Evaluation Council In KFDA
(If necessary)
Review Result Notification
Review Result Notification
Applicant
NDA
Biologics Department
NDA Action
36
PreIND Meeting Application
IND Application Process
IND Plan
PreIND Meeting
Notification of Application Eligiblity
IND (or its amendment) Application 1 2
Protocol
Was there a PreIND?
Review Initiation at PreIND Meeting level
No
Yes
IND (or its amendment) Approval
Trial Ongoing
Reporting of CT completion
NDA Application
IND Requisite Dossier
If necessary, forwarding to KCPAC
Final PL Approval
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, Guidanceetc
39
Laws and Regulations concerned with Biologicals
Approval
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
Approval
Crosscheck
QM
QM
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
Animal Tests

• 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

58
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59
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60
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61
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62
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63
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66
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69
Potency Standards / Reference Reagents for Viral
Vaccines
70
Proposed KNBS Set-up Project Phase I
71
Korean Standards for Vaccines Biologicals
72
Summary on Annual Activities (96-01)
1 Including 25 withdrawals 2 Including 2
withdrawals and 1 rejection
73
Research Activity 2001-2003

• 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

74
WHO Collaborative Study 2001-2003

• 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)

75
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.

76
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

77
VI. Challenges
78
KFDAs 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

79
Emerging New Technologies- BiomedicalResearch
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

80
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

81
The Future Challenges of NewTechnologies

• Quantitation
• Validation
• Robustness
• Standards
• Imagination and creativity in their application

82
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