Presentation Slide CE Pharm 111011

USES OF CAPILLARY
ELECTROPHORESIS FOR
PHARMACEUTICAL QUALITY
CONTROL IN JAPAN
1 Kumiko Sakai-Kato, Ph.D.

National Institute of Health Sciences
CE Pharm 2011, Florida, October 12, 2011

CE IN JAPANESE PHARMACOPOEIA
 Capillary electrophoresis procedures are

described in General Information of JP (Japanese
Pharmacopoeia).
 The pharmacopoeial texts can now be used

interchangeably in ICH regions as the result of
the Q4B process.
2
CE IN JAPANESE PHARMACOPOEIA
 General principles
 Apparatus
 1.Capillary Zone Electrophoresis
 2.Capillary Gel Electrophoresis
 3.Capillary Isoelectric Focusing
 4.Micellar Electrokinetic Chromatography

3
THE USE OF CAPILLARY ELECTROPHORESIS
IN JAPAN
 Survey : how capillary electrophoresis is used for

pharmaceutical quality control in pharmaceutical
companies in Japan
 Members of The Japan Pharmaceutical Manufacturers

Association (JPMA)
 21 Companies, 32 respondents
4
IN JAPAN
Target: Area Scale of business

Process ≥ 30,000 < 200
development of 10% 5%
drug < 1,000
Other
substances 9%
13%
Manufacturing 3%
< 30,000 < 2,000
12% Formulation 14% 14%
development
31%
Quality
< 10,000 < 5,000
control 29% 19%
41%
5
IN JAPAN
Status of use
≥ 30,000
< 30,000
in use
< 10,000
will be
< 5,000
introduced
< 2,000
not in use
< 1,000
<200
0 20 40 60 80 100 (%) 6
AREA IN USE
Other 4 Multiple answers
Manufacturing 2
Quality control 10
Formulation development 13
Process development of drug substances 3
0 5 10 15
e.g.) Physicochemical properties of drug substances,

specification, quality test (drug substances, drug products,
excipients), stability test, monitoring for manufacturing
method, shipping test
Nucleic acid drugs
4% Drugs by chemical
synthesis
27%
Biotechnological 7
products
69%
EXAMPLE:
GLYCOSYLATION ANALYSIS OF IGG
PA800
eCAP PVA type Coated Capillary
Flurorescent labelled with
G0
APTS(8-aminopyrene-1,3,6-trisulfonate)
G1A
G1B
G2
6 7 8 9 10 11 12 13
Time (min)
8
Courtesy of Dr. Nakashima (KAKETSUKEN)

Q. HAS CE BECOME PART OF THE
SPECIFICATION AND TEST METHOD ?
No
24%
Yes
62%
Under
consideration
14%
e.g.)
• Purity test (CE-SDS, c-IEF, glycosylation mapping)
• Identification test
• Process control of drug substances 9
ADVANTAGES AND DISADVANTAGES
OF CE IN DRUG DEVELOPMENT
Advantages
 The variety of separation modes in the method.
 Quantitative performance, sensitivity, repeatability,

automatization, short run time-compared to slab gel
electrophoresis
 Small sample volumes, small effluent, characteristics of

separation mode (e.g. ion analysis, charged compounds,
highly polar compounds)
-compared to LC
 The same software as for LC and GC
10
 Simultaneous analysis of various components

ADVANTAGES AND DISADVANTAGES
OF CE IN DRUG DEVELOPMENT
Disadvantages
 Not yet in common use, High cost
 Not repeatable (injection volume, eluent time, response,
quantification), Difficulties in fractionation and low sensitivity
–compared to LC
 Instability in performance (unexpected trouble, clogging of the
capillary tube, difficulty in system conditioning)
 Difficulty in the setting of analytical conditions
 Difficulty in peak characterization
 Discrepancy of analytical results between different companies’
instruments
11
 Matrix effect
THE USE OF MICROCHIP
ELECTROPHORESIS IN JAPAN
Status of use
Yes
Under
23%
considerat
No ion
74% 3%
Other(e.g. physicochemical properties) 4

Manufacturing 0
Quality control 1
Formulation development 3
CE-SDS
Process development of drug substances 0 Glycosylation mapping
12
0 1 2 3 4 5
GENERAL COMMENTS FROM USERS
 CE will become a more important method if it is
applied to more chemical synthesis drugs.
 Great skill is required to get data with good

repeatability.
13
REQUESTS TO MAKERS FROM USERS
 Devices to connect CE and MS
 Standardization of instrument specification

between CE makers.
 Improvements in injection repeatability,

automation of analytical optimization, and
miniaturization of equipment
 Improvement of sudden instability in results
 Improvement of difficulties in injecting samples

to equipment
 These improvements are necessary to enable an 14
effective system suitability test.

REQUESTS TO REGULATORS FROM USERS
 Standardization of method validation in purity test

of therapeutic antibodies
e.g.) - Accuracy of response factor for
fluorescently-labeled antibodies
- Robustness
 Standardization of injection method and washing

method
 Standardization of method of calculating isoelectric
point 15
CONCLUSION
 CE is an analytical method with many
advantages such as quantitative performance,
sensitivity, and short run time.
 However, there are some difficulties in the
setting of analytical conditions, and peak
characterization.
 By improving these difficulties, CE can be in
more common use as methods for
characterization, quality controls, and
specification.
16
ACKNOWLEDGEMENT
National Institute of Health Sciences (NIHS)
Dr. Kawanishi
Dr. Yamaguchi
Dr. Kawasaki
Dr. Okuda
Pharmaceutical and Medical Devices Agency (PMDA)

Dr. Sakai
KAKETSUKEN
Dr. Nakashima
CE Pharm 2011 Organizing Committee 17

Thank you for your
attention!
18

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USES OF CAPILLARY

1 Kumiko Sakai-Kato, Ph.D.

CE Pharm 2011, Florida, October 12, 2011

 Capillary electrophoresis procedures are

 The pharmacopoeial texts can now be used

 1.Capillary Zone Electrophoresis

 2.Capillary Gel Electrophoresis

 3.Capillary Isoelectric Focusing

 4.Micellar Electrokinetic Chromatography

 Survey : how capillary electrophoresis is used for

 Members of The Japan Pharmaceutical Manufacturers

Target: Area Scale of business

e.g.) Physicochemical properties of drug substances,

Courtesy of Dr. Nakashima (KAKETSUKEN)

 Quantitative performance, sensitivity, repeatability,

 Small sample volumes, small effluent, characteristics of

 Simultaneous analysis of various components

Other(e.g. physicochemical properties) 4

 Great skill is required to get data with good

 Standardization of instrument specification

 Improvements in injection repeatability,

 Improvement of sudden instability in results

 Improvement of difficulties in injecting samples

 These improvements are necessary to enable an 14

effective system suitability test.

 Standardization of method validation in purity test

 Standardization of injection method and washing

Pharmaceutical and Medical Devices Agency (PMDA)

CE Pharm 2011 Organizing Committee 17

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