Feb. 25, 2015 SCAS-BTT Bioanalysis Co., Ltd. Masahiro Taniguchibioanalysisforum.jp/images/2015_6thJBFS/43_Bioanalytical... · 2015. 3. 30. · from 2006 to 2015 *KFDA drove down drug

Feb. 25, 2015SCAS-BTT Bioanalysis Co., Ltd.

Masahiro Taniguchi

1

SCAS-BTT Bioanalysis Co., Ltd.

Pharmaceutical market in South Korea

Korean BMV Guideline

Different point between Japan and Korea

BE Study Process in Korea

Summary

2

2004 2007 2008 2011 2013

Analytical Department

GLP study initiation

Analytical-center built

Spin-off

SBBfounded

GLP certificated

H/W, Human

Biotoxtech(2000.8～)

Total analysis company（Pharmaceutical/Chemistry/IT/Environment etc.） SCAS

(1972.7～)

S/W, Human

3

BE studycertificated

GLPPeriodical inspection

4

It takes approximately 2 hours from Inchon International Airport to SBB.

Laboratory C Laboratory B

Laboratory A

Ground

▲

2F/3F/4F

5

Test Facility Management (1)

Archive Mgmt. Director (1) Facility Control DirectorStudy Director (3)

Standard Mgmt. Director (1*)

Instrument Mgmt. Director (1*)

Facility Control (4)

Computer Control (4)

Sample Mgmt. Director (1*)

Study Personnel (7) Including 3 employees from SCAS

* : Concurrent Position

: Consigned to Biotoxtech

QAU (2)

Classification Instrument Name Number Details

Measurement instrument

LC/MS/MS

3 Prominence/API5500 (AB SCIEX)

4 Prominence/API4000 (AB SCIEX)

1 Alliance2795/Micromass (Waters)

Microplate reader 1 Synergy MX (BioTek)

Storage

Deep Freezer4 Range：-80~-60℃ (OPERON)

2 Range：-90~-70℃ (SANYO)

Freezer4 Range：-25~-10℃ (OPERON, SANYO)

1 Range：-40~-20℃ (OPERON)

Refrigerator 1 Range：2～8℃ (SANYO)

Refrigerator & Freezer 3 Range：2～8℃, -25~-10℃ (SANYO)

RT Storage 3 Range：15～25℃ (Neuronfit)

Balance

Micro Balance 1 ME5 (Sartorius)

Semi-micro Balance1 CP224S (Sartorius)

1 LE225D (Sartorius)

BiohazardBiological Safety

Cabinet2 CHC-777A2-04 (CHC lab)

1 Labconco6

7

* : BTT Analysis Department( ) : Clinical Study

Unit: Number of protocol

2009* 2010* 2011 2012 2013 2014

MethodDevelopment

6 13 7 17 (1) 19 (2) 18 (5)

Method Validation

23 20 14 38 (6) 44 (7) 32 (11)

TK analysis 13 15 7 11 18 19

PK analysis 13 14 7 40 (5) 25 (3) 16 (12)

Sum 55 62 35 106 (12) 106 (12) 85 (28)

8

* : BTT Analysis Department( ) : Japanese Client

Unit: Number of protocol

2009* 2010* 2011 2012 2013 2014

MethodDevelopment

6 13 7 17 (7) 19 (2) 18

Method Validation

23 20 14 38 (9) 44 (7) 32 (5)

TK analysis 13 15 7 11 (1) 18 (4) 19 (4)

PK analysis 13 14 7 40 (10) 25 (4) 16 (8)

Sum 55 62 35 106 (27) 106 (17) 85 (17)






Summary

9

10

Pharmaceutical Market in South Korea

(MarketLine, Pharmaceutical in South Korea, 2012)

Approximately 10,000 million$ to 20,000 million$ from 2006 to 2015Up to 10% growth except 2010 from 2006 to 2015*KFDA drove down drug price on 2010

Japan KoreaMarket 93 $ Billion*1 10 to 20 $ Billion Population 125 million*2 50 million*3

Elderly Population 33 million (26%) *2 6.1 million (12%) *3

*1:厚生労働省「薬事工業生産動態統計」 2011年, *2: 総務省統計局 2014年8月， *3: KOSIS (2015.1)

11

Total CRO Industry Market in South Korea

300

120

Clinical CRO Non-Clinical CRO

$ million

(KoreaBio, 2014)

Non-Clinical: 120 million $ Global CRO: 67 million $Local CRO: 50 million $

Clinical: 300 million $ Global CRO: 200 million $Local CRO: 100 million $

Global CRO > Local CRO

Global CRO57%

Local CRO43%

Non-Clinical CRO

Global CRO67%

Local CRO33%

Clinical CRO

12

Total Clinical Trial Status in South Korea

Clinical Trial IIT(Investigator

InitiatedTrial)

GrandTotalTotal

Local(Korea)

MultiNational

2010 340 140 200 99 439

2011 398 209 189 105 503

2012 498 208 290 172 670

2013475

(▽4.6%)

227(△9.1%)

248(▽14.5%)

132(▽23.3%)

607(▽9.4%)

ClinicalTrial

Local(Korea) Multi-national

P1 P2 P3 Other Total P1 P2 P3 Other Total

2010 75 31 31 3 140 23 57 119 1 200

2011 130 37 41 1 209 19 60 107 3 189

2012 128 30 47 3 208 32 75 180 3 290

2013 130 38 58 1 227 25 65 154 4 248

Total Clinical Trial Status in Korea (2013) (KFDA,2014)

Clinical Trial Status in Korea (2013) (KFDA,2014)

13

Total Clinical Trial Status in South KoreaLocal Clinical Trial Status from 2010 to 2013(2013) (KFDA,2014)

Multi-national Clinical Trial Status from 2010 to 2013 (2013) (KFDA,2014)

57

119

1

60

107

3

75

180

3

65

154

4

2319

3225

0

20

40

60

80

100

120

140

160

180

200

Phase I Phase II Phase III Other

2010

2011

2012

2013

P I> P II, P IIIMany of BE studies (P1) were performed.

P III > P II > P IPI was conducted at native country.P II and P III were conducted in South Korea.

31 31

3

37 41

1

30

47

3

38

58

1

75

130 128 130

0

20

40

60

80

100

120

140

Phase I Phase II Phase III Other

2010

2011

2012

2013

14

Total Clinical Trial Status in South Korea

Chemical

BiomedicineHerbal

medicineTotal Generecombination Biologics Cell

TheraphyGene

Theraphy

2010 322 92 65 9 14 4 25

2011 378 107 76 16 11 4 18

2012 486 159 103 28 23 5 25

2013435

(▽10.4%)155

(▽2.5%)88

(▽14.5%)38

(△26.3%)26

(△11.5%)3

(▽40.0%)17

(▽32%)

Clinical Trial Status (Compound, 2013) (KFDA,2014)

Biomedicine has been actively developed in South Korea. (approximately 25%)






Summary

15

Establish& Revision No.

Date of approval

Contents Rest

11-1470129-000073-01

May 2003 Establish of BMV guideline Following FDA guidance

B1-2010-2-016 June 2010 Establish of Practical guide on BMV

Following FDA white paper

B1-2013-2-004 March 2013 Establish of sample analysis on bioanalysis

-

B1-2013-2-007 December 2013

Revision of BMV and fusion of BMV and sample analysis

on bioanalysis

Following EMA, MHLW, and FDA draft BMV

guideline

16


Korean BMV Guideline has been harmonized other guidance and guideline.

Korean BMV Guideline is for only low molecule.

17


MFDS Guideline (2013)Where data are obtained from different methods within and across studies or when data are obtained within study from different laboratories, applying the same method, comparison of those data is needed and a cross validation of applied analytical methods should be carried out. Acceptance criteria: For QC samples, the obtained mean accuracy by the different methods should be within 15% and may be wider, if justified. For study samples, the difference between the two values obtained should be within 20% of the mean for at least 67% of the repeats.

Cross validation

MHLW Guideline (2013)Similar to Korean guideline, but 20% for QCs is accepted.

EMA Guideline (2011)Similar to Korean and Japanese Guideline

FDA draft Guidance (2013)There are no criteria for cross validation.

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Analyte: Azelnidipine

Internal standard: Nicardipine

Matrix: Human plasma (Anti-Coagulant：Sodium heparin)

Sampling volume: 0.05 mL

Pretreatment: PPT (Protein precipitation)

Instrument: LC/MS/MS

Process of Transportation

Friday

(16:00)

-80oC to -60oC

Monday

(16:00)

From SCAS

To SBB

Sample nameTheoretical

concentration (ng/mL)

Observed concentration

(ng/mL)

Accuracy (%)

SD (ng/mL)

Mean (ng/mL)

Precision (%)

QC-L0.1044 104.4

0.0032 0.1080 3.0 0.1 0.1106 110.60.1090 109.0

QC-H38.08 95.2

2.13 39.94 5.3 40 42.27 105.7 39.47 98.7

Unkown-124.76 99.0

0.36 25.15 1.4 25 25.47 101.9 25.21 100.8

Unkown-2< 0.05 -

- - -< 0.05 < 0.05 -< 0.05 -

Unkown-30.2112 105.6

0.0042 0.2066 2.0 0.2 0.2057 102.9 0.2030 101.5

SBB data

Sample nameTheoretical

concentration (ng/m)

Observed concentration

(ng/mL)

Accuracy (%)

SD (ng/mL)

Mean (ng/mL)

Precision(%)

QC-L0.0853 85.3

0.00445 0.08963 5.0 0.1 0.0942 94.20.0894 89.4

QC-H36.7 91.8

0.80 36.77 2.2 40 36.0 90.037.6 94.0

Unkown-122.9 91.6

0.10 22.80 0.4 25 22.8 91.222.7 90.8

Unkown-2< 0.05 -

- - -< 0.05 < 0.05 -< 0.05 -

Unkown-30.182 91.0

0.0072 0.1867 3.9 0.2 0.183 91.50.195 97.5

SCAS data

19

The results met the Korean criteria for cross validation.

20


MFDS Guideline (2013)An analytical instrument should be an appropriate operation and maintenance, a specific SOP should be used. System suitability should be assessed prior to analysis of validation samples and study samples. Apparatus conditioning and instrument performance should be determined using spiked samples independent of the study calibrators, QCs, or study samples.

System suitability

MHLW Guideline (2013)Analytical instruments used in bioanalysis should be well maintained and properly serviced. In order to ensure optimum performance of the instrument used for bioanalysis, it is advisable to confirm the system suitability prior to each run, in addition to periodical check. However, confirmation of the system suitability is not mandatory in bioanalysis, because the validity of analysis is routinely checked by evaluation of calibration curves and QC samples in each analytical run.

EMA Guideline (2011)Not addressed.

FDA draft Guidance (2013)Similar to Korean

21


MFDS Guideline (2013)It is recommended that calibration standards and QCs should be prepared from separate stock solutions. However, standards and QCs can be prepared from the same spiking stock solution, provided the stability and accuracy of the stock solution have been verified. A single source of blank matrix may also be used, provided absence of matrix effects on extraction recovery and detection has been verified.

QC samples preparation

MHLW Guideline (2013)Not addressed.

EMA Guideline (2011)Not addressed.

FDA draft Guidance (2013)Similar to Korean

22


Action of each topics by SBB

Topics Action

Cross validation Korean criteria (Mean accuracy within 15% for QC) is followed in Korea.

System suitability An LLOQ sample are separately prepared and pretreated on each analytical batch and repeatedly injected 5 times prior to each run. System suitability is estimated from peak area ratio and retention times of an analyte and IS. The precision of peak area ratio and retention times of an analyte and IS should be 10% or less as acceptance criteria in the SBB SOP.

QC samples preparation Calibration standards and QC samples are prepared from separate stock solutions.






Summary

23

Japan Korea

Calibration

QC

Study sample

24

Sampling 100 L

Sampling 100 L

Plasma (100 L) Std WS 10 L IS WS 10 L

Without sampling


Sampling 100 L


Sampling 100 L

IS WS 10 L

Sampling 100 L

Plasma (980 L) Std WS 20 L Solv. (10 L) IS WS 10 L

Solv. (10 L) IS WS 10 L

Korean BMV GuidelineDifferent points between Japan and Korea Preparation procedure of calibration standards

25


Different points between Japan and Korea Preparation procedure of calibration standards

Japan Korea

Merit Small amount of biologicalmatrix is required on freshly prepared prior to use. Calibration standards are

similarly processed with a study sample.

Remaining calibration standards are stored in a freezer and reused in a sample analysis. Calibration standards are similarly

processed with QC samples.

Demerit Different preparation procedure of QC samples. Calibration standards are

prepared at every analytical batch in a sample analysis.

Different procedure of a study sample. Large amount of biological matrix

is required on freshly prepared prior to use in a validation study.






Summary

26

27

BE study process in Korea

Standard Mgmt. Director

Archive Mgmt. Director

Facility Control Director

Instrument Mgmt. Director

Sample Mgmt. Director


Chief Executive Officer (CEO)

PI*2

(Study Director)

Study Personnel

Test Facility Management QAU

Analytical CRO

Korean Authority(MFDS*1)

Sponsor (Pharmaceutical Company)

*1: Ministry of Food and Drag Safety (from 2013.4)*2: Principal Investigator

28


Sponsor (Pharmaceutical Company)








PI*2

(Study Director)

Study Personnel


Analytical CRO



29


Sponsor (Pharmaceutical Company)CRO









PI*2

(Study Director)

Study Personnel


Analytical CRO


30

Summary

Considering the population (elderly population) pharmaceutical market of Korea is adequate size although that of Japan is larger.

Multinational pharmaceutical companies have developed more drugs than Korean local pharmaceutical companies.

Drug development of biomedicine is up to approximately 25% and is expected to be growth in the future.

Drug development has been performed by a reliable bioanalytical method according to BMV guideline in Korea, which is drug developing country.

The BMV guideline of Korea has been followed the FDA draft guidance, although that is harmonized to Japan, US, Europe.

Bioequivalence study has been once stop service for a pharmaceutical company in Korea.

31

SCAS-BTT Bioanalysis Co., Ltd.http://www.scas-btt.com

Documents

Feb. 25, 2015 SCAS-BTT Bioanalysis Co., Ltd. Masahiro Taniguchibioanalysisforum.jp/images/2015_6thJBFS/43_Bioanalytical... · 2015. 3. 30. · from 2006 to 2015 *KFDA drove down drug