cGMP Compliance

Pharmaceutical Market (’98) Market size

$300 billion Gross margins

80-95% Annual growth

10-12%

Challenge of Pharmaceutical Market High risk

10,000 discovery 10 preclinical development 5 human trials 1 approval

High cost $400-500 million Over 10-12 years

Korean Pharmaceutical Industry

품목당 평균 매출액 50 억원 / 연 의약품개발을 위한 투자비에 비해 외소 수출 주도형 산업으로의 전환 절실

World Market Composition

Region % of World Market

North America 34%

Europe 32%

Japan 19%

Latin America 7%

Asia Pacific 6%

선진국시장 진출 품질경쟁력 (Regulation)

미국 FDA 인증 필수 cGMP 규정에 의한 제조

판매제품 임상시험용 시제품

가격경쟁력 ( 개량의약품 )

cGMP Current Good Manufacturing

Practices 우수의약품 제조 및 품질관리 규정 International Conference on

Harmonization (ICH)

cGMP Regulations Act

Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301) 약사법 ( 법률 제 5529 호 )

Code of Federal Regulation (CFR) Current Good Manufacturing Practice for the Manufact

ure, Processing, Packing, or Holding of Drugs (21CFR-Parts 210&211)

약국 및 의약품 등의 제조 수입자와 판매업의 시설기준령 ( 대통령령 제 15732 호 )

약국 및 의약품 등의 제조 수입자와 판매업의 시설기준령 시행규칙 ( 보건복지부령 제 15732 호 )

Gudiance (Guideline) For the Submission of Chemistry, Manufacturing, a

nd Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody product for in vivo use (August 1996)

약국 및 의약품 등의 제조 수입자의 시설 및 기구와 제 3 자의 시설 및 기구이용 범위지정 (식품의약안정청고시 제 1998-10 호 )

Point to Consider

21CFR - Parts 210 & 211 Part 210

Status of cGMP regulations Applicability of cGMP regulations Definitions

Part 211

A. General provisionsB. Organization and personnelC. Building and facilitiesD. EquipmentE. Control of components and drug product

containers and closuresF. Production and process controlsG. Packaging and labeling controlH. Holding and distributionI. Laboratory controlJ. Records and reportsK. Returned and salvaged drug products

B. Organization and Personnel

조직 (Organization) 제조와 품질관리 분리

인력 (Personnel) 자격기준 및 인원 교육•훈련

C. Building and Facilities Facility design and layout

오염과 혼합 방비 청소 및 유지 용이 작업실의 적절한 크기와 구조 제조 시설•설비 확보 및 검증

Water system HVAC system Steam system

작업장 및 작업대의 분리 시험실과 시험시설의 확보

환경 monitoring program 시설유지 program Contractor control program

F. Production and Process Controls Equipment control Cleaning validation Cell bank Cell growth and harvesting Purification and downstream

processing Process controls and validation Reprocessing/disposition of materials

Equipment Control Design and placement Qualification program

(IQ/OQ/PQ) Identification and log books Maintenance and calibration

program

Cleaning Validation Equipment/line/area Cleaning principles

Residue/containment types Cleaning chemistry Cleaning technology

Ultrasonic Spray machines

Cleaning process strategies Dedicated vs multi-use Manual vs automatic CIP (Clean-in-place) vs COP (Clean-out of-place)

Analytical and sampling methods How to measure and quantify residues Where to look Sensitivity, specificity, recovery

Validation of cleaning procedures

Cell Bank Master cell bank (MCB) Working cell bank (WCB) End of Production cell (EPC)

Master Cell Bank (MCB) From a single colony or cell

Origin and history Methods, reagents and media used Date of creation Quantity of the cell bank In-process controls Storage conditions

Assure genetic stability Integrity Stability

Genotypic characterization DNA finger printing

Phenotypic characterization Nutrient requirement Isoenzyme analysis Growth Morphological characterization

Reproducibility of product production Virus contamination Sterility test and mycoplasma test

Working Cell Bank (WCB) Derived from MCB

Methods, reagents and media used Date of creation Quantity of the cell bank Number of cell doublings from MCB Storage conditions

Only used once Phenotypic characterization Restriction enzyme mapping Sterility test and mycoplasma test Reproducibility of product production

End of Production Cell (EPC) Consistency of growth Phenotypic or genotypic

makers Contamination

To confirm identity and purity Restriction enzyme analysis

Cell Growth and Harvesting Validation of aseptic techniques

Inoculation Transfer Harvesting

Medium Raw materials and composition Fermentation

Equipment preparation and sterilization

Stages of cell growth Selection of inoculum Scale-up for propagation Production batch size

All operating conditions & in-process controls Operating and control parameters

Fermentation time Cell doubling time Cell culture purity Cell viability Aeration Mixing pH CO2

Purification and Downstream Processing Detailed description and flow charts Rationale for the chosen methods Contamination Multi-use nature of areas and equipmen

t In-process bioburden and endotoxin limi

ts In-process storage condition Description of reprocessing

Process Controls and Validation In-process controls

Fermentation Harvesting Downstream processing

Validation studies Media sterilization Cell growth Harvesting process Purification process

Chemicals used for purification Column contaminants Residual host proteins

Clearance study Endotoxins Host cellular DNA Viruses

Inactivation of cells

Quality Control

Lab equipment qualification Design Qualification (DQ) Installation Qualfication(IQ) Operational Qualification(OQ) Performance (PQ)

Analytical Method Development Accuracy Precision Linearity Range Limit of detection (LOD) Limit of quantitation (LOQ) Sensitivity Robustness

Validation of analytical methods Bias Specificity Recovery Repeatability Intermediate precision Reproducibility Ruggedness

Materials control Specification and identity test Vendor control program Receipt, inspection, sampling,

lab testing Storage and handling Inventory control program

Characterization and Quantitation of Drug Product

Physicochemical properties Molecular weight/size Isofrom pattern Extinction coefficient Electrophoretic patterns Liqid chromatographic patterns Spectroscopic profiles

Structural characterization/ confirmation Amino acid sequence Amino acid composition Terminal amino acid sequence Peptide map Sulfhydryl group(s) and disulfide bridge

Biological activity in vivo and in vitro biological tests

Purity, impurity and contaminants Impurity profile Process-related impurities

Cell substrates: Host cell proteins, Host cellular DNA Cell culture Downstream processing

Product-related impurities Precursors Degradation products Aggregation products

Mandatory impurities Virus Host cellular DNA Pyrogen

Contaminants Chemicals and biochemical materials

Microbial protease Microorganisms Viruses Microplasma

Quantity (mass)

Quality Assurance (QA) Documentation control Education and training Validation support Internal audit FDA inspection