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1 Quantitative analysis by LBA (PK/Biomarker) 1

2 Seiji Mito (Mitsubishi Tanabe Pharma Corporation) Kousuke Iijima (Kyowa Hakko Kirin Co., Ltd.) Satomi, Sasahara (JCL Bioassay Corporation) Hiroyuki Shimizu (Toray Research Center, Inc.) Masako Soma (Daiichi Sankyo Co., Ltd.) Fumiaki Meguro (LSI Medience Corporation) Itadaki Yamaguchi (Sumika Chemical Analysis Service, Ltd.) Yoshinobu Yokota (Shin Nippon Biomedical Laboratories, Ltd.) 2

3 Biotechnology-based drugs, typified by antibody drugs, are currently being developed for various diseases. The ligand binding assay (LBA) is being used for the concentration measurement of these drugs. LBA is also commonly used to measure various biomarkers that serve as indices for drug efficacy and safety evaluations. In this regard, LBA was taken up as one of the topics in a JBF discussion group (DG) starting in Presentations were held in the fourth and fifth JBF symposium. As to this particular topic, the discussion was held with a focus on the quantitative analysis by LBA (PK/Biomarker). 3

4 In particular, this DG talked about sample preparations, LBA platforms, surrogate matrices, stability assessments, specificity, reference standards and critical reagents. This presentation gives an overview of contents discussed in the DG to help establish the standard procedures for the quantitative analysis by LBA (PK/Biomarker) and reliability of the assay. 4

5 May 2014: Member recruitment from DG supporters. 24 Jun 2014: Kick off meeting with 8 members. Jul Dec 2014: Monthly teleconferences and conversations. 20 Aug 2014: F2F meeting collaborated with DG Jan 2015: Summarizes and preparation poster presentation. 5

6 1. Sample preparation 2. LBA platform 3. Surrogate matrix 4. Stability evaluation 5. Specificity 6. Reference standard Critical reagent 6

7 1.1 Operating and inspecting pipette 1.2 Using low-protein binding tip and tube, and sample additives 7

8 Back ground Discussion points Operation Do you use both pipetting modes (forward or reverse mode)? How to select the pipetting mode and the volume range Inspection When to perform the test Test volume 8

9 Back ground Discussion points When to select a low-protein binding tip and tubes Do you use the same tip and tube in actual sample analysis? When to select to use sample additives Do you use the same additives in actual sample analysis? 9

10 10

11 Background Discussion points Commonly used Platforms Priority criteria of Platform selection Risk management of using a Platform supported by a single vendor What should be done when a validated assay have to be changed its platform. Will you continue to use an instrument with expired warranty terms? 11

12 1.1 Selection of a surrogate matrix 1.2 Analytical method validation and stability 12

13 Back ground Discussion points What is used as a surrogate matrix? How to select the surrogate matrix Risk management of using a surrogate matrix 13

14 Back ground Discussion points Analytical method validation Stability 14

15 4-1) Considerations for Validation Study Stability Evaluations 4-2) Importance of ISS 4-3) Stability evaluation for Biosimilar 15

16 Background Discussion points 4-1) Considerations for Validation Study Stability Evaluations Target-relevant stability samples (PK or biomarkers) Stability conditions and period Stability evaluation method using individual sample Stability evaluation method using SS*-spiked sample Different criteria for PK and biomarkers Handling against incidental criterion non-fulfillment 4-2) Importance of ISS 4-3) Stability Evaluation for Biosimilars *: Standard substance 16

17 17

18 Background Discussion points Related substances and selection When do you not perform the specificity? Setting of spiked concentration When a commercial kit is used, Is the specificity necessary? When a related substance exists in a matrix Judgment of necessity for additional specificity testing after a method validation is completed 18

19 6.1 Stability of purchased reference standard 6.2 Handling of lot changes 6.3 Expiration date of critical reagent 19

20 Background Discussion points Stability of purchased reference standard Handling of lot changes Reference standard Critical reagent Assay kit Expiration date of critical reagent 20

21 LBA (PK/Biomarker) 21

22 22

23 ligand binding assay (LBA) LBA 2013 JBF (DG) LBA 4 5 JBF LBA PK/Biomarker 23

24 DG LBA DG LBA PK/Biomarker 24

25 DG TC DG F2F

26 1. 2. LBA platform

28 28

29 LBA 29

31 Japan Bioanalysis Forum QC 8 31

32 Japan Bioanalysis Forum QC QC QC QC 揃 32

33 Japan Bioanalysis Forum

34 34

35 35

36 Japan Bioanalysis Forum CMC TK PK PK 36

37 TK PK PK 37

38 38

39 Japan Bioanalysis Forum Platform Platform Single vendor Platform 39

40 Japan Bioanalysis Forum LBA 40

41 Immuno PCR SPR TMB, pnpp Luminol, dioxetane Ruthenium Alexa Fluor, Europium DNA SPR Immuno PCR SPR 41

42 platform PK ELISA ECL ELISA ECL Biomarker ELISA 42

43 Single vendor LBA platform platform 43

44 platform 44

45 PK Biomarker 45

47 Japan Bioanalysis Forum 47

48 Japan Bioanalysis Forum

49 Japan Bioanalysis Forum. * * * 49

50 Japan Bioanalysis Forum 50

51 Japan Bioanalysis Forum 51

52 Japan Bioanalysis Forum 52

53 Japan Bioanalysis Forum. 53

54 Japan Bioanalysis Forum. n 5. 54

55 Japan Bioanalysis Forum MRD.. 55

56 Japan Bioanalysis Forum. QC.. ISS Incurred Sample Stability. ISS ISR. 56

57 4-1) 4-2) ISS 4-3) 57

58 Japan Bioanalysis Forum 4-1) PK, Biomarker PK Biomarker 4-2) ISS 4-3) 58

59 Japan Bioanalysis Forum LBA PK * Biomarker fit-for-purpose** PK Biomarker *: ( ) **: Fit-for-Purpose Method Development and Validation for Successful Biomarker Measurement ( AAPS Research paper, 2005 ) 59

60 / PK, Biomarker PK LQC* HQC** Extra QC n=3/ Biomarker PK LQC HQC CRO 5 7 PK Biomarker *: Low quality control, within 3 times of LLOQ (lower limit of qualification) **: High quality control, more than one-thirds of ULOQ (upper limit of qualification) 60

61 / PK, Biomarker PK Biomarker PK Biomarker Deep Freezer

62 %Initial* 20% *: %Initial = /

63 PK LQC, HQC, Extra QC 20% PK Biomarker LQC, HQC, Extra QC LQC, HQC Extra QC / 20% LQC HQC Extra QC* 20% 20% 20% *: BMV Extra QC % 50% 63

64 PK Biomarker PK 20% Biomarker PK 20% Biomarker 20% 25% Biomarker 64

65 65

66 LQC, HQC, Extra QC HQC n=3/ 3 LQC Extra QC HQC n=1 n=3 CV 20% 僅僅 66

67 ,3,6 2 1,3,6 3 HQC 15% % 20% %Initial 20% 67

68 PK Biomarker ISS* PK ISR** ISS Biomarker ISS PK ISS *: Incurred sample stability **: Incurred sample reanalysis 68

69 PK 1 69

70 70

71 Japan Bioanalysis Forum 71

72 Japan Bioanalysis Forum 72

73 IgG IFN IFN-α β 73

74 Japan Bioanalysis Forum a. b. COA 74

75 75

76 PK 76

77 77

78 78

79 79

81 Japan Bioanalysis Forum 81

82 Japan Bioanalysis Forum Q&A No.3 Q&A No.25 82

83 Japan Bioanalysis Forum 83

84 84

85 /PK 85

86 /PK QC QC QC QC 5 (LLOQ L M H ULOQ). 3 (L M H) 86

87 PK BM PK BM PK 87

88 QC,, ( ) QC 5 (LLOQ L M H ULOQ) 3 (L M H). 88

89 /PK QC (5 LL L M H UL) 89

90 / BM PK 90

91 Q&A No.25 QC 91

92 QC 10 92

FIBA In Memoriam

FIBA In Memoriam ICH 日本シンポジウム 2016 ( 第 35 回 ICH 即時報告会 ) 平成 28 年 12 月 14 日全電通ホール M10 生体試料中薬物濃度分析法バリデーション Bioanalytical Method Validation 石井明子 M10 ラポーター国立医薬品食品衛生研究所生物薬品部 International Council for Harmonisation of Technical