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

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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