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ちかこしんまつ
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1 より高い信頼性を実現するためにジェネリック医薬品開発のためのアジレントのソリューション 1

2 (BRIC) 2

3 QbD (Quality by Design) UHPLC : NMR / LC/MS LC ISET : LC LC MS MS Q-TF MS FTIR NMR CE SFC ICP-MS ICP-ES GC GC/MS NMR UV/UV-VIS LC LC MS LC FTIR LC FTIR

4 (HPLC) LC 12 Infinity LC UV 3 1 (ISET) (ICF) LC LC UHPLC HPLC LC LC/MS : Poroshell 12 ZRBAX High Definition (RRHD) 1.8 µm penlab CDS penlab penlab ECM Data Store GxP 21 CFR Part 11 4

5 DAD1 A, Sig=278\Exp 4 Agilent Poroshell EC-C mm, 2.7 µm mau 2 1 mau E API G min DAD1 A, Sig=278\Exp 3 Agilent Poroshell 12 EC C mm, 2.7 µm mau min 6.929E DAD1 A, Sig=278\EXP2 Agilent Poroshell 12 EC-C mm, 2.7 µm mau min 9.216E API API DAD1 A, Sig=278\EXP1 Agilent ZRBAX Eclipse Plus C mm, 5-µm EP Method G G 12.89E API G (EP) Agilent 129 Infinity LC ( 1) EP min 1.EP 1 mau DAD1 A, Sig=27, Exp 1, Agilent ZRBAX Eclipse Plus C18, mm, 5 µm DAD1 A, Sig=27, Exp 2, Agilent Poroshell 12EC C18, mm, 2.7 µm mau DAD1 A, Sig=27, Exp 3, Agilent ZRBAX Eclipse Plus C18, mm, 1.8 µm min min 6 ( 2) USP 35-NF USP<621> USP (>5 %) 25 cm 5 µm HPLC 1 cm 1.8 µm UHPLC ( USP ) 9 % 8 % mau min 2. USP 3 1. Higher throughput and cost reduction for salmeterol xinafoate analysis using the Agilent 129 Infinity LC System with ISET.Agilent publication EN. 2. Higher throughput and cost reduction for purity analysis of olanzapine tablets using the Agilent 129 Infinity LC System with ISET.Agilent publication EN. 3. Reducing analysis time and solvent consumption for isocratic USP assay methods with current and proposed USP guidelines using the Agilent 129 Infinity LC System.Agilent publication EN. 4. Reducing total analysis cost for generic drugs within USP <621> allowed limits.agilent publication EN. 5

6 QbD QbD QbD QbD 12 Infinity mm 3 mm / ChromSword Fusion AE QbD LC ph 6

7 QbD Agilent ISET Infinity LC ISET : 1 HPLC UHPLC LC ISET 129 Infinity LC Waters Alliance HPLC/UHPLC 11 LC 12 LC 129 Infinity LC with ISET 122 Infinity LC 126 Infinity LC 3. ISET QC 5. ISET Agilent 129 Infinity LC JAJP. 7

8 3 3 ( 12 Infinity LC + 71 USP <233> 16 ( ) USP 126 Infinity SFC (213 2 ) 126 Infinity Cary 63 FTIR DD2 NMR 12 Infinity LC 61 MS 62 TF MS 65 Q-TF MS 12 Infinity LC + 64 LC/MS 77 ICP-MS 7 ICP-ES As Hg 12 Infinity LC + 77 ICP-MS USP <467> 789 GC A / 789 GC /5977 GC/MS A 8

9 NH H CH3 CH3 NH H H H3C H3C CH3 CH3 NH NH H H H NH2 H3C CH3 NH H H H3C CH3 NH H3C CH3 H NH NH2 H H3C H H3C CH3 NH CH3 NH H H H NH2 H 3 C H 3 C H 3 C H 3 C NH NH H NH 2 H H mau 8 Impurity A Amoxicillin 6 4. Agilent 122 Infinity LC/UV ZRBAX SB-Aq 5 6 LC/MS analysis using Agilent 654 Q-TF with full MS scan followed by auto MS/MS Find and identify impurities by MFE and MFG based on the accurate mass MS and MS/MS data MSC facilitates the structure elucidation of the impurities 5. Agilent 12 Infinity LC Accurate Mass Q-TF MassHunter MSC 7 x x1 3 5 CH3 CH NH Impurity C Impurity B min Impurity D Impurity E LC/UV Agilent 12 Infinity LC/UV 4 Agilent 122 Infinity LC UV Agilent ZRBAX SB-Aq penlab CDS ChemStation Edition 7.1 % LC/MS/MS (API) ( 5) Accurate-Mass Q-TF LC/MS ( 6) ( m/z: ) G ( m/z: ) Molecular Structure Correlator (MSC) Counts vs Mass-to-Charge (m/z) 6. G MSC ( m/z: ) G ( m/z: ) 7 6. Analysis of amoxicillin and five impurities on the Agilent 122 Infinity LC System.Agilent publication EN. 7. Pharmaceutical Impurity Analysis Solutions.Agilent publication EN. 9

10 (API) ( ) NMR API DD2 NMR RF NMR NMR (T3) VnmrJ 21 CFR Part 11 1

11 NMR 1 ppb amorphous NMR NMR crystalline ppm 7. NMR 7 NMR monohydrate 8 dihydrate NMR 2 9/1 mixture: 9 % mono + 1 % dihydrate NMR ppm 8. NMR API 11

12 in vitro QbD (Quality by Design) / 78-DS 79-DS 21 CFR Part 11 ( ) UV 8453 UV-Vis UV Cary 6 UV-Vis UV ChemStation penlab ECM Cary WinUV 21 CFR Part 11 LC LC LC LC 12

13 8-1 L Agilent 78-DS 79-DS (USP Apparatus 1) Agilent 78-DS 79-DS (USP Apparatus 2) cgmp 28-DS (PVT) 28-DS Agilent 78-DS 79-DS (USP Apparatus 5) Agilent 78-DS 79-DS (USP Apparatus 6) - Agilent BI-DIS (USP Apparatus 3) Agilent Agilent 4 DS (USP Apparatus 7) - API (78-DS ) DS 9 Agilent Agilent Agilent 8. Dissolution Systems Source Book Edition.Agilent publication EN DS Mechanical Qualification System Brochure, Agilent publication EN. 13

14 LC/MS/MS 12 Infinity LC 129 Infinity LC HTC/HTS - 24 ( ) 64 LC/MS ifunnel MassHunter MS ptimizer Bond Elut SPE Captiva Bond Elut SPE Captiva ND Lipids MassHunter MassHunter LC/MS MassHunter Study Manager penlab ECM MassHunter MassHunter 14

15 Relative response x R 2 = Concentration (pg/ml) LC/MS/MS Agilent ptimizer MRM LC/MS/ MS Agilent 646 LC/MS Agilent 129 Infinity LC 1 1. Agilent 646 LC/MS/MS 1 1. Agilent LC/MS QC 1 L1 L2 L3 L4 L5 L6 L7 L8 L9 L1 HQC MQC LQC % CV (n = 3) % (a = 3) QC ( 1) MRM LC/MS Agilent 646 LC/MS LC/MS/MS LLQ ( 11 ) Counts x MRM ( ).1 Bupropion.528 min Acquisition time (min) Counts x MRM ( ) Risperidone.393 min Acquisition time (min) 11. LLQ (1.52 ng/ml) (IS) Development of an LC/MS/MS Assay for Atorvastatin in Human Plasma Using a 646 Triple Quadrupole LC/MS System.Agilent publication EN. 11. Development of an LC/MS/MS Method for Bupropion in Human Plasma Using a 646 Triple Quadrupole LC/MS System.Agilent publication EN. 15

16 GMP 12 Infinity LC 126 Infinity LC QC 122 Infinity LC UHPLC penlab GLP GMP 21 CFR Part 11 Cary 63 FTIR / Microlab 21 CFR 16

17 Wavenumber % Transmittance FTIR Agilent Cary 63 FTIR Web FTIR ( KBr ) Cary 63 FTIR ( DRIFT) 12 FT-IR 13 FT-IR DialPath DialPath Absorbance Wavenumber 13. DialPath 3 µm Agilent Cary 63 FTIR JAJP. 13. Quality verification of incoming liquid raw materials using the Agilent 55 DialPath FTIR spectrometer.agilent application note EN. 17

18 42 Flexscan FTIR (1.36 kg (3 )) Flexscan 21 CFR Part Infinity LC Agilent 129 Infinity (DAD) Max-Light UV 129 Infinity ( <.1 % < 1 ppm) penlab ECM Data Store penlab CDS GMP 21 CFR Part 11 18

Absorbance.26.22.18.14.1.6.2 17 16 15 14 13 12 Wavenumber 1 µg/cm 2.5 µg/cm 2 2.5 µg/cm 2 1.25 µg/cm 2? µg/cm 2 Absorbance (peak area).4.35.3.25.2.15.1.5 R 2 =.

19 Absorbance Wavenumber 1 µg/cm 2.5 µg/cm µg/cm µg/cm 2? µg/cm 2 Absorbance (peak area) R 2 = Acetominophen (ugcm 2 ) Flexscan FTIR Flexscan FTIR FTIR 14 FTIR LQ UHPLC mau LD LQ.5 ng/µl.2 ng/µl Rinse 1. 1 ml 2. 1 ml 3. 1 ml 4. 1 ml 5. 1 ml ng/µl ~ LD ml MeH 5 Agilent 129 Infinity DAD (6 mm ) 15 min 129 infinity LC 15 6 mm Highly Sensitive UV Analysis with the Agilent 129 Infinity LC System for Fast and Reliable Cleaning Validation.Part 1:Measurement of calibration curves, determination of LD and LQ and method validation using a DAD equipped with standard or high sensitivity flow cell.agilent publication EN. 15. Highly Sensitive UV Analysis with the Agilent 129 Infinity LC Systemfor Fast and Reliable Cleaning Validation.Part 2:Monitoring of a cleaning validation procedure using a DAD equipped with standard or high sensitivity flow cell.agilent publication EN. 16. Highly Sensitive UV Analysis with the Agilent 129 Infinity LC System for Fast and Reliable Cleaning Validation.Part 3: Determination of residual active pharmaceutical impurities from a previous production batch using a DAD with standard or high sensitivity flow cell.agilent publication EN. 19

20 cgmp GLP (AIQ) AIQ Agilent Enterprise Edition LC GC MS 21 CFR Part 11 EU Annex 11 EU GMP (PIC/S) 21 CFR Part 211 Agilent Compliance Engine (ACE) 1, 2

21 (Q) 1 Agilent CrossLab Agilent Enterprise Edition 5 % 2 % CrossLab Enterprise RI CrossLab Remote Advisor Laboratory Business Intelligence 17. Maximize Laboratory Productivity:Compliance Using an Integrated Service Solution.Agilent publication EN. 18. Hidden Costs and Undiscovered pportunities in Analytical Instrument Qualification.Agilent publication EN. 19. Analytical Instrument Qualification and System Validation.Agilent publication EN. 21

22 カラム消耗品ソフトウェアカラムおよび消耗品アジレントは GC および LC カラムサンプル前処理製品などさまざまな消耗品を取り揃えていますアジレントのすべてのカラムおよび消耗品は IS 91 規格を満たしているため最大限の機器性能と再現性のある結果が保証されますアジレントは幅広い分析ニーズを満たしラボの開発環境全体にわたる最大限の拡張性により医薬品ライフサイクルをサポートするさまざまなカラムと世界規模のサービスおよびサポートにより LC 業界をリードしています例えば Poroshell 12 カラムは分析時間を大幅に削減し RRHD カラムは溶媒の選択と流量に関する最大の柔軟性を備えていますアジレントは革新的なウルトライナート GC カラムなど GC カラム製品も最も幅広く提供しています Bond Elut および Captiva などのサンプル前処理製品は今日の市場で最も多様なフォーマットとソリューションを提供しますアジレントの包括的な汎用消耗品シリーズにはバイアルシリンジガスフィルタ流量計漏れ検出器フィッティングツールスタンダードなどが含まれますそのすべてがアジレントの機器設計チームにより設計または選択され厳しい要求仕様に基づいて製造されさまざまな条件下でテストされていますソフトウェアおよびインフォマティクス penlab 電子ラボノート (ELN) penlab クロマトグラフィーデータシステム (CDS) アジレントの penlab ソフトウェアスイートは実験計画データ取り込みおよび分析情報管理などデータのライフサイクル全体に対応します penlab はマルチベンダーの相互運用性をサポートしアプリケーション機器データを統合してラボの効率を向上させるオープンシステムアーキテクチャに基づいています Agilent penlab 製品シリーズには情報の取り込み解析および共有に役立つ penlab クロマトグラフィーデータシステム (CDS) penlab 電子ラボノート (ELN) penlab エンタープライズコンテンツマネージャ (ECM) または DataStore が含まれていますお客様のソリューションを完成させるために Agilent penlab は全体的な使用性の向上と RI の増加を目的に設計されたサービスとサポートを提供しています 22 MSC facilitates the structure elucidation of the impurities Find and identify impurities by MFE and MFG based on the accurate mass MS and MS/MS data 科学データの管理 LC/MS analysis using Agilent 654 Q-TF with full MS scan followed by auto MS/MS MSC facilitates the structure elucidation of the impurities Find and identify impurities by MFE and MFG based on the accurate mass MS and MS/MS data データの取り込みおよび解析 LC/MS analysis using Agilent 654 Q-TF with full MS scan followed by auto MS/MS 実験計画 penlab エンタープライズコンテンツマネージャ (ECM)

23 ジェネリック医薬品開発のためのアジレントのソリューション 23

24 Agilent Technologies. Inc. 212 Printed in Japan, ct 19, JAJP 24

Agilent OpenLAB CDS ChemStation OpenLAB CDS ChemStation Lab Advisor Secure Workstation Data Store OpenLAB ECM OpenLAB C A P T U R E A N A L Y Z E S H

Agilent OpenLAB CDS ChemStation Rev. C.01.07 Agilent OpenLAB CDS ChemStation OpenLAB CDS ChemStation Lab Advisor Secure Workstation Data Store OpenLAB ECM OpenLAB C A P T U R E A N A L Y Z E S H A R E