cGMP Compliance

김 찬 화

고려대학교 생명과학대학

Pharmaceutical Market (’04)

• Market size– $450 billion (’04)

• Gross margins– 80-95%

• Annual growth– 10-12%

Forecast slow sales growth to 2010

*Source: Traditional estimates for Compound Annual Growth Rates (CAGR)

CAGR of 9% is Out of Reach

We predict a CAGR of 5.3%

Challenge of Pharmaceutical Market

• High risk– 10,000 discovery– 10 preclinical development– 5 human trials– 1 approval

• High cost– $500-800 million– Over 10-12 years

Korean Pharmaceutical Industry

• 품목당 평균 매출액 50억원/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 제5529호)

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

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

– 약국 및 의약품 등의 제조 수입자와 판매업의

시설기준령 (대통령령 제15732호)

– 약국 및 의약품 등의 제조 수입자와 판매업의

시설기준령 시행규칙(보건복지가족부령 제15732호)

• Guidance (Guideline)– For the Submission of Chemistry, Manufacturing, and

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 제3자의 시설 및 기구이용 범위지정 (식품의약안정청고시 제1998-10호)

• Point to Consider

21CFR - Parts 210 & 211• Part 210

– Status of cGMP regulations– Applicability of cGMP regulations– Definitions

Part 211A. 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 equipment• In-process bioburden and endotoxin limits• 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

Type of Analytical Procedure

IdentificationImpurity testing

AssayQuantitative Limit Tests

Accuracy No Yes No Yes

Precision

Repeatability No Yes No Yes

Interm. Prec. No Yes No Yes

Specificity Yes Yes Yes Yes

LOD No No Yes No

LOQ No Yes No No

Linearity No Yes No Yes

Range No Yes No Yes

ICH Validation Characteristics vs. Type of Analytical Procedure

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

– Isoform 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

– 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