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Quality Regulation for Biological Products: Current and Future
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
Presentation OverviewPresentation 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
I. Current Regulation of Biological Products
What is Quality Regulation ?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
Overview of Quality Authority FunctionsOverview 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
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:
SafetyEfficacyQuality
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
GeographicalArea
RegulatoryAuthority
PharmacopeiaInternationalGuidelines &
Standards
Korea KFDA KP
EuropeanUnion
European agency forthe Evaluation of
Medicinal Products(EMEM)
EP
JapanMinistry of Health and
Welfare (MHW)JP
USA FDA USP
InternationalConference onHarmonization
(ICH)InternationalOrganization
forStandardization
(ISO)
Regulatory Capacity
A fully developed NRA has implemented all the functions in the below
GMP Distribution Regulate
Inspection inspection promotion
Own assess-ment
Assessmentother DRA
Decisionother DRA
Products
Produced incountry
Imported
Products
Product registrationPost-
marketingactivities
Authorizeclinicaltrials
( )
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 inspectionsDistributing references.
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
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
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)
The Process of Biological Products Licensure in the US
Approval Process in Europe: Overview
Determine Product Status
Select aRapporteurcountry (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
Overall relationship between NRA and Drug Manufacturer
Unapproved ProductsIND initial CMC Amendments Annual Reports Lot Release Process Changes BLA (CMC)
Inspections
Inspections
Reg
ulat
ory
Aut
hori
ty
RE
VIE
WR
EV
IEW
Compliance Action
Approved ProductsChanges to ProceduresAnnual ReportsAdverse ReactionsLicense UpdatesR
egul
ator
y A
ffai
rs
Legal
Quality Control
Marketing
Customers
Licensors
Manufacturing
Clinical
Supplier
Product Development
Licenses
Management
Quality Assurance
Biological Products Regulated By KFDA
Documents generated by:
• Discovery Patent applicationsHighly specialized chemistry
and biology reportsMethods for identifying lead
compound
Documents generated by:
• Preclinical Studies
PharmacodynamicsToxicology reportsPK studies (ADME)GLP compliance
documentation
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
DEFINITIONDEFINITION
Documents generated by:
• IND Preclinical results, manufacturing information, clinical protocols, investigator brochure, investigator qualifications
These must be adequate to avoid a clinical hold
Documents generated by:
• Clinical Development
Study protocol(s) Informed Consent FormsCase Report Forms Investigator BrochureGCP compliance
documentation
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
DEFINITIONDEFINITION
Documents generated by:
• NDA CMC (chemistry, manufacturing control) Human PK (pharmacokinetics),
bioavailability data Microbiology Statistical data Samples and labeling GMP documentation
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
DEFINITIONDEFINITION
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
II. Current Approach To Regulation of Biological Products
Regulation of Biological ProductsBased on Sound Science, Law, and Public Health Impact
Policy Compliance
SurveillanceResearchReview
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 focusedMore specific
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
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
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
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
III. Registration Process of Biologicals
Licence for Pharmaceutical manufacturerApplicant Via department
(Regional KFDA)
Transaction adminstration
KFDA
Fill-up of
application form
Release
Report
Facility inspection
Order
Receipt
Order & Review for
Facility inspection
Completion for
Facility inspection & Review
Proposal & Approval
Issue of certificate for Pharmaceutical manufacture
Applicant
Registration Process of NDA
Safety & Efficacy application
Specification and test methods application
Safety Evaluation Office
NITR
Central Pharmaceut
ical Affair Council
Evaluation Council In KFDA(If
necessary)
Review Result
Notification
Review Result
NotificationApplicant
NDA
Biologics Department
NDA Action
IND Application Process
PreIND Meeting Application IND Plan
PreIND Meeting
Notification of Application
EligiblityIND (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
IV. Law and Ordinances Related to Biologicals Approval
System of and ordinances
Pharmaceutical Affairs Law (PAL)
Pharmaceutical Enforcement Ordinance(PEO)
Pharmaceutical Enforcement Regulation(PER)
Notice, Guidance’…etc
Laws and Regulations concerned with Biologicals Approval
PAL PEO PER Notice…etc
Licence for Pharmaceutical manufacture Article 26 Article 22 KFDA Notice 2000-49
Product Licence
Article 26
Article
23, 24, 27,
27-2
,28,29,83
KFDA Notice 2000-49,
1997-67,
1999-6,
2001-9,
2001-35
Lot release Article 45 Article 62~70
Re-examination of
New drug
Re-evaluation of drug
PMS Adverse reaction
monitoring
GMP Inspection
Article 26-2 Article 30,31 KFDA Notice 1999-11
Article 26-3
Article 19,31 Article 11.40 KFDA Notice 1999-39
Article 64 Article 85~88
System to Regulate Biologicals
Licensing Process
1. 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.)
- 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)
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)
- 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)
V. Control of Viral Products
August 2003
Division of Viral ProductsCenter for Biologics Evaluation
Korea Food and Drug Administration
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.
Legal Authority
• Pharmaceutical Affairs Law (PAL)• Pharmaceutical Enforcement Ordinance
(PEO)• Pharmaceutical Enforcement Regulation
(PER)• KFDA Notice/Guidance/Rules…
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Organization & Responsibilities
MMR
VZV
OPV
IPV
InterferonClonorchis sinensis agnParagonimus westermani agn
Influenza JE
HFRS
Hep A Hep B (plasma)
HIV/HepB agn/aby test
QM
Crosscheck
QM
Approval
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
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
Live Attenuated Viral Vaccines
• Poliomyelitis vaccine (oral)• Measles vaccine• Rubella vaccine• MMR vaccine• Varicella vaccine• Small pox vaccine
(reintroduced 2002~)
Diagnostic Reagents
• Anti-HIV-1/2 antibody
• HBsAg
• HBsAb
• HBeAg
• Rotavirus
• Malaria
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
Test Items for Lot Release: Inactivated Vaccines or Antigens, 2003
Type of assay InfluenzaHA/Split
J E HFRS(Hantaan)
HepatitisA
HepatitisB (plasma)
IPV Cs &Pw
Test period (days) 35 47 68 46 61 35 36Sterility O O O O O O OPotency O O O O O O OIdentity Δ Δ Δ Δ Δ ΔAbnormal Toxicity O O O O O O OInactivation O O OThiomersal Δ Δ Δ Δ ΔTotal Protein O O O O O OFormaldehyde Δ Δ Δ Δ ΔpH Δ Δ Δ Δ ΔFinal Container Δ Δ Δ Δ Δ Δ ΔAluminium Δ Δ Δ2-phenoxyethanol Δ ΔPyrogen/Endotoxin O O OResidual Ether ΔEgg albumin O
No. of test item 13 (7) 10 (5) 11 (5) 11 (5) 8 (4) 9 (5) 6(3)O: Required for official release testing; Δ : Exempted (if first 3 lots are satisfied) or replaced by othertest(s)
Test Items for Lot Release : Live Attenuated Vaccines, 2003Type of assay OPV Measles Rubella MMR Varicella J E
Test period (days) 35 28 28 28 28 35
Sterility O O O O O O
Virus Content O O O O O O
Identity Δ O O O O
Abnormal toxicity O O
Thermostability O
pH ΔFinal container Δ Δ Δ Δ Δ ΔResidual moisture Δ Δ Δ Δ Δ
No. of test item 5 (3) 5 (3) 5 (3) 4 (2) 5 (3) 8 (5)O: Required for official release testing; Δ: Exempted or replaced
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
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
Tra
ckin
g......................
KFDA LIMS Work FlowKFDA LIMS Work Flow
Potency Standards / Reference Reagents for Viral Vaccines
Vaccines Sources Comment
Hepatitis B vaccine (plasma)
Manufacturer’s in house reference
Hepatitis A vaccine "
Influenza HA & Split NIBSC
JE (inactivated) Korea National Biological Standard 2001 (Established)
HFRSAsan Institute for life science (WHO collaborating center for viral reference)
IPVManufacturer’s in house reference
Measles vaccine "
Mumps vaccine "
Varicella vaccine Korea National Biological Standard 2002 (Established)
OPVManufacturer’s in house reference
Proposed KNBS Set-up Project Phase I Year Reference Materials for Biologicals
2001
- Tetanus toxoid- JE vaccine, inactivated- Interferon alpha, recombinant- Factor VIII
2002
- Pertussis vaccine- Varicella vaccine - EPO, Anti-thrombin III- Anti-JEV
- HAV RNA, HCV RNA - BVDV- Retrovirus- HPV DNA
2003
- Diphteria toxoid Rubella vaccine- Erythropoietin, recombinant - HbsAg- HPV VLPs
- HBV DNA - HEV, Factor IX- SV40 - Anti-HBsAg
2004
- Anti-tetanus toxoid, B19- Mumps vaccine - G-CSF, recombinant- Snake Antivenom (viper)
- IL-1 protein- Measles - Anti-HIV
Activity 1996 1997 1998 1999 2000 2001CMC Review 9 35 23 29 34 52*1
Lot Release 493 482 400 374 406 349*2
Summary on Annual Activities (’96-’01)
*1 Including 25 withdrawals*2 Including 2 withdrawals and 1 rejection
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
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
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.
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
VI. Challenges
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
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
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
The Future Challenges of NewTechnologies
Quantitation Validation Robustness Standards Imagination and creativity in their application