가이드라인등록번호 B1-2016-2-018 의약품품질위해평가가이드라인 2016. 12.

제 개정이력 연번제 개정번호승인일자주요내용 1 2016.12. 제정 2 3

목차 1. 서론 1 2. 품질위해관리 1 3. 품질위해평가절차 6 4. 품질위해평가방법및관련기법 9 5. 위해평가에영향을주는인자 14 6. 정성적평가방법및정량적평가방법을이용한위해평가 23 7. 정성적평가방법및정량적평가방법을이용한위해평가사례 25 8. 위해평가체크리스트 33 9. 참고 35

1. 서론 2. 품질위해관리 (Quality Risk Management) 1) ICH Q8 Pharmaceutical Development, Q9 Quality Risk Management, Q10 Pharmaceutical Quality System 2) 설계기반품질고도화 (QbD) 도입대비를위한품질심사안내서 (2014), 우수의약품개발가이드라인 (2015), 의약품품질위해관리가이드라인 (2015) - 1 -

위해평가 (Risk Assessment) 위해통제 (Risk Control) 위해검토 (Risk Review) - 2 -

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(Risk Identification).,,.?... (Risk Analysis). (harm) (severity) (provability). (harm) (, detectability). (Risk Evaluation). 3.,.,.,,... (High)", "(Medium)", " (Low)". - 4 -

2.3. (Risk Control) (Risk Control).... 1,? 2.? 3. (benefits), (risks), (resources)? 4.? (Risk Reduction). (harm) (severity) (probability). (detectability)... (Risk Acceptance). (Residual risk),..,.,. - 5 -

2.4. (Risk Communication) (Risk Communication).,,.,,. 2.5. (Risk Review) (Risk Review)...,,... 3. 품질위해평가절차,.,,,,,,,,, ( ). - 6 -

,,,,,,,.,,,,,,,, ( )., 3 (,,, ). - 7 -

,. (,, ) (, 5 ).,.,... - 8 -

4. 품질위해평가방법및관련기법 4.1.. (Material Attributes) (Process parameter) (Critical Quality Attributes).,.., (: (DoE) ).,. 4.2. [ 1]. [ 1] - Fault tree analysis (FTA) -, - (fault tree) - 9 -

Hazard operability analysis (HAZOP) Hazards analysis and critical control points (HACCP) Preliminary hazard analysis (PHA) - (And, Or ) - - - - Guide-words (No, More, Other than, Part of) - Guide-words, -,, -,,,,,, - 12 7,, -, -,, - PHA 1), 2) - 10 -

Failure modes effects analysis /Failure modes effects criticality analysis (FMEA/FMECA) Basic facilitation tool, 3), 4),,,,, - - - FMEA/FMECA MIL-HDBK-1629 QS 9000 Sheet,, / - (risk assessment). -,. basic facilitation tool Flowcharts, Process Mapping, Check Sheets, Fishbone or Ishikawa Diagram, 5 Why Analysis, Histogram, Pareto Analysis, Control Charts - 11 -

Quality Function Deployment (QFD) - - QFD (House of Quality, HOQ) (). [ 2] FMEA () - 12 -

[ 3] QFD (; House of Quality) () - 13 -

5. 위해평가에영향을주는인자 (Critical Quality Attributes; CQA) (Critical Process Parameter; CPP). 5.1. (Critical Quality Attribute; CQA) (, CQA),,,,. CQA,,,, CQA. CQA. CQA. CQA,. CQA, CQA. [ 2] [ 3].. - 14 -

[ 2] () (Description) (Identification) (Assay) (Impurities) (Physicochemical properties) (Particle size) (Polymorphic forms) (Water Contents) (,, ) HPLC/UV, HPLC/MS, GC/MS HPLC ph,, XRD, DSC Karl Fischer. IR...,,.,.., - 15 -

(Inorganic impurities) / (Microbiological quality),,, [ 3] () ( ) (Coated tablet, uncoated tablet and hard capsules) (Dissolution) (Disintegration) / (Hardness/Friability) (Uniformity of dosage units) (Water content) (Microbial limits)....... - 16 -

(Oral liquids) (Uniformity of dosage units) ph (Microbial limits) (Antimicrobial preservative content) (Antioxidant preservative content) (Extractables) (Alcohol content) (Dissolution) (Particle size distribution) (Redispersibility) (Rheological properties) (Reconstitution time) (Water content).......... (/)... - 17 -

(Parenteral Drug Products) (Uniformity of dosage units) ph (Sterility) / (Endotoxins/Pyrogens) (Particulate matter) (Water content) (Antimicrobial preservative content) (Antioxidant preservative content) (Extractables) (Functionality testing of delivery systems) (Osmolarity) (Particle size distribution) (Redispersibility) (Reconstitution time).........,..... - 18 -

5.2. (Critical Prcess Parameter; CPP) (, CPP)..,,,. CQA. CQA., (Risk assessment). (Process parameters) (Quality attributes) [ 4]. [ 4] PP QA - 19 -

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5.3. (CQA) (CPP) (risk) (severity), (probability), (detectability).. CQA. CPP, CPP. CQA. 1 ( ) 2 (Quality TPP, QTPP) 3 / / 4 CQA CPP. 1 CPP CQA (Risk assessment) 2 / / /(Design of Experiment, DoE)/(Quality Risk Management, QRM) 3 CPP 4 CQA CPP. CQA CPP - 22 -

.. 6. 정성적평가방법및정량적평가방법을이용한위해평가 - 23 -

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7. 정성적평가방법및정량적평가방법을이용한위해평가사례 [ 1] FMEA QFD,. 7.1. FMEA 1-25 -

심각도 점수 발생도 점수 검출도 점수 R P N 위해수준 일탈 1 1/10000 1 각단위공정전 1 4 0 높음 재시험시통과 2 1/1000 2 각단위공정중 2 2 0 < 4 0 중간 서브배치 / 배치부적합 3 1/100 3 제조공정중 3 < 2 0 낮음 제조공정중단 4 1/10 4 완제품시험 4 회수 5 > 1/10 5 사용자에의해발견 5-26 -

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7.2. QFD 2-31 -

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8. 위해평가체크리스트 - 33 -

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9. 참고 - 35 -

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본가이드라인은 2016 년도식품의약품안전처의연구개발사업 ( 효율적의약품품질평가를 위한시험계획법및위해평가기술개발연구, 16172 의약안 156) 의결과를활용하였습니다.