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Science Webinar Series
Microfluidic Electrophoresis Assays for
Rapid Characterization of Protein in
Research and Development
14 November, 2012
Brought to you by the Science/AAAS Custom Publishing Office
Participating Experts:
Joey Studts, Ph.D.
Boehringer Ingelheim Pharma GmbH & Co. KG
Biberach, Germany
Timothy Blanc
ImClone Systems
Branchburg, NJ
Bahram Fathollahi, Ph.D.
PerkinElmer
San Francisco, CA
Sponsored by:
Microfluidic Assays for High
Throughput Screening of Protein
Quality in Bioprocess
Development
Bahram Fathollahi
Microfluidics R&D
November 14, 2012
Science/AAAS Microfluidics Webinar
© 2009 PerkinElmer
What is a Microfluidic Device?
An integrated device with
controlled transport of sample and
reagents in microchannels to carry
out bio/chemical analysis
Advantages
 Miniaturization
 Fast analysis/high throughput
 Small sample volume
 Integration
 Automation
4
Microfluidic Chip Format and Fabrication
Planar Chip
 Single use
 Samples added to wells manually
Sipper Chip
 Reusable
 Samples introduced automatically
from microtiter plate
Sipper (autosampler)
Chip Fabrication
 Chips manufactured using photolithography
and wet etching technology
 Quartz and glass substrate
 Highly reproducible and precise control of
channel geometry
 Typical depth - 5 µm to 25 µm
 Typical width - 10 µm to 100s µm
5
Electrophoretic Separation in Microfluidic Chips
Buffer
Reservoirs
SAMPLE LOAD
AND
INJECTION
SEPARATION
DETECTION
B
C
D
A
Sample
Reservoir
Sample
Load
B
∆V
A
6
Waste
Reservoir
LIF
detection
Sample
Separation
Sample
Injection
∆V
∆V
∆V
Commercial Microfluidic Electrophoresis Platforms
LabChip |DX/GX/GXII
Bioanalyzer 2100
Higher Throughput
• RNA & DNA analysis
• Proteins
• N-Glycans (LabChip Only)
Experion
• Digital information
• Easy-to-use
• Time and cost savings
Planar chip format
7
Sipper chip format
Protein Characterization Assays on LabChip GX II
Multiple HT Screening Assays on a Single Microfluidic Platform
1) Microchip CE-SDS – 40 sec/sample
 Protein expression optimization
 Assess purity
 Reduced and non-reduced
 Titer
 Quantify impurities
 Product- and process-related
 Monitor fragmentation and Ab assembly
2) N-Glycan Profiling – 60 sec/sample
LabChip GX II
 Measure relative amounts of major N-linked glycans
3) Charge Variant Profiling – 68 to 90 sec/sample
 Identify and measure relative amounts of basic, main,
acidic variants
8
Microchip
Microchip CE-SDS Assay Workflow
Crude or purified
protein sample (2µL)
Add Sample Buffer
Heat denature ~15min
Reusable chip
Up to 400
samples
Prepare
Gel/DyeSolution and
Ladder
Add Reagents to
chip
Place Ladder and
Buffer on GXII
Identified
expected protein
peaks
Plate View
~ 40 sec per sample
E-gram
~ 75 min for 96-well plate
Protein
Analysis
Sizing, Conc.,
and
Purity
9
Gel View
Microchip CE-SDS vs. Conventional CE-SDS
Reducing
Non-reducing
HC Microchip CE-SDS
LC
30 seconds
Monomer
1250
In-process
sample
1000
750
HHL
Fluorescence
NGHC
LM
500
Aggregates (covalent)
HL
250
0
30
28
26
24
22
20
18
16
14
12
10
8
13
18
23
28
33
38
43
48
Time (seconds)
Conventional CE-SDS
10
Attributes
Assay
Instrument time
Microchip CE-SDS
Concentration
ProA HPLC
RP HPLC
2-5 min
~20 min
< 1 min
Assembly, covalent aggregation
nrCE-SDS
30-50 min
< 1 min
Fragmentation, Degree of N-glycosylation
rCE-SDS
30-50 min
< 1 min
X. Chen et al .Electrophoresis 2008, 29, 4993-5002
53
HT N-Glycan Profiling Sample Prep Workflow
LabChip GXII
Denature and Reduce mAb in Denaturing Buffer
Add Denatured Reduced mAb to Enzyme Plate
Denaturing plate
Heat (Denatured mAb + Enzyme) at 37 °C for ~1h
microchip
Transfer to Dye Plate
PNGase-F Plate
Heat Assay Plate at 55 °C for ~2h
G0F
Dilute with separation Buffer
Read 96-well plate on LabChip GXII ~1.5h
G1F’
Glycan Labeling Plate
G2F
11
G1F
G0
M5
Digested and Labeled N-Glycan Profile
G0F
G1’F
G1F
G2F
Man5
UNK
12
G0
G1
G2
UNK
UNK
Methods of Characterizing Charge Heterogeneity
Three methods of separation used in the biotherapeutics industry:
 Ion Exchange Chromatography (IEC)
 Extension of HPLC systems
 Proteins interact with charged resin, based on pI and hydrophobicity
 Capillary Zone Electrophoresis (CZE)
 Based on Capillary Electrophoresis (CE) systems
 Proteins migrate at different speeds, based on pI and hydrodynamic drag
 Isoelectric Focusing (icIEF)
 Based on imaged CE systems
 Proteins migrate to a particular position within a pH gradient, based on pI
HT Protein Charge
Variant Assay
Limitation of current methods: Lack of speed
Analysis Time
13
IEC
icIEF
CZE
Microchip-CZE
Per Sample
30 - 90 min
15 - 20 min
8 - 30 min
1 - 2 min
Per 96-Well Plate
48 - 144 hrs
24 - 32 hrs
16 - 48 hrs
1.8 - 2.9 hrs
Variant Detection
Conventional methods use absorbance at 280 nm
LabChip detects via LIF
 Dye must be conjugated to protein variants
 Dye must absorb & emit at wavelengths that are compatible with instrument optics
 Dye must conserve charge of protein variants
From icIEF analysis
Relative Amount (%)
Before Labeling
After Labeling
Charge profile does not change
Acidic
Variants
14
Main
Variant
Basic
Variants
Direct Comparison With Alternative Methods
HT
PCV
Microchip-CZE
60 sec
Basic
Main Isoform - 8.810
icIEF
15 min
Acidic
Conventional CZE
~10min
Basic
Acidic
8.948
9.044
8.712
8.585
0
8.00
15
8.20
8.40
8.60
Acidic
Basic
8.80
9.00
9.20
9.40
9.60
1.60
1.80
2.00
2.20
2.40
2.60
Minutes
2.80
3.00
3.20
3.40
Small-Scale High Throughput Process Development
Higher demand of product quality requires multi-factorial DOE studies in
upstream and downstream process development
Sample prep/
µscale purification
Clone
selection/cell
culture
optimization
BioTx workstation
Daughter Plate
Mother Plate
Screening high
number of cell
clones in smallscale bioreactors
16
Analytics for determination of
critical quality attributes
µscale chromatographic
purification
Daughter Plate
Daughter Plate
Informatics
Purity Assessment
N-Glycan profiling
Charge Variant
Process parameter
optimization
Optimization
and
Scale-up
Process
understanding
and decisions
Acknowledgements
Microfluidics R&D







Tobias Wheeler
Lucy Sun
Rajendra Singh
Mai Ho
Hui Xu
Melissa Takahashi
Roger Dettloff
Marketing & App Support






Rick Bunch
Krystyna Hohenauer
Nate Cosper
Seth Cohen
Linda Gary
Marsha Paul
Chip and Reagent Fabrication




Joan McAuliffe
Ken Summers
Trang Le
Khushroo Gandhi
Software
 Advit Bhatt
 Dan Camporese
 Renil Das
17
Thank you!
14 November 2012
Microfluidic Electrophoresis Assays for
Rapid Characterization of Protein in
Research and Development
Process Science Germany, 2012
Project Timelines
Focus on Critical Bottlenecks in Development
Overall Project Timeline
Exploratory
Research
Preclinical
Development
Clinical
Dev.
Development
Phase I,II
Bottleneck to Clinic
Cell line
Process
Development/
optimization
non GMP
scale up,
Tox material
GMP
Pilot Plant
Ph I - Scale up
• Fast track development by applying
“platform technologies”
• Material supply: 1 g - 2 kg
Phase IIb/ III
Registration
Market
Supply
• Critical bottleneck is time to the
clinic
• Reduce time to clinic to shorten
time to market
• Often is data on the critical path in
development
• Early process understanding critical
to efficiency and safety
More data  Better Decisions  Efficient Development  Better Products
19
BI-PurEx: Lean Development Strategy
Understanding the product & the process
Cell Line Development
Process Development
USD & DSD
Scale-up
USD & DSD
Pilot Scale
GMP
Product & Process are critical
•
•
•
•
•
Cell line development is on critical path
Rate limiting step is cell growth, very little material with which to
gain knowledge
Choosing the correct cell line for each product is most critical
Impacts product quality, functionality, expression levels,
comparability…
Early knowledge and correct decisions will have an significant
impact on efforts and timeline throughout the development process.
25
Product Understanding
Glyco Patterns
4A
6A
7
2
S:/BPQC/QC/QCAS/LG7/FOB/Caliper Datenabgleich/T1-HEX-110-09.opj/13.01.2011 Zug
/ Em420 nm
Ex330 nm
HPLC: 20 min/run
MS: >> 20 min/run
8
4
1
20
30
3
40
5 6
50
60
70
• Initial challenges in Glycosylation
Retention Time [min]
• Mainly controlled by cell line decision
• Purification normally has very little impact on glycans
• Impacts comparability and functionality of molecule
• Critical to get early knowledge and impact cell line development decisions!
26
Product Understanding
High Throughput Glyco Analysis
20
18
% CGU (Caliper Glucose Units)
16
14
12
10
8
6
4
2
0
Man5
T9 Std. 5 T9-HEX2-101-T9-HEX2-101-T9-HEX2-101-T9-HEX2-101-T9-HEX2-101-T9-HEX2-101-T9-HEX2-101-T9-HEX2-101-T9-HEX2-101Standard
Clone 1
Clone 2
Clone 3
Clone 4
Clone 5
Clone 6
Clone 7
Clone 8
Clone 9
mg/mL
01
02
03
04
05
06
07
08
10
7,48
4
6,3
6,15
8,39
3,24
3,1
4,28
4,83
3,07
NGA2
3,09
1,94
1,23
0,92
6,65
1,73
1,16
1,19
2,54
2,31
NGA2F
16,95
14,71
17,45
0,37
0,73
12,03
9,15
12,17
14,2
11,52
NA2G1F
3,66
1,79
1,89
0
0,73
1,54
0,73
1,21
1,55
1,61
NA2
0,06
0,1
0
0
0
0
0,07
0,08
0,04
0,15
NA2F
0,24
0,26
0,14
0,37
0,22
0,17
0,1
0,17
0,17
0,26
• Using Microfluidic Assay – all pools are analyzed for glycan map prior
to cell line decision.
27
Product Understanding
High Throughput Glyco Analysis
HT- Microfluidic Assay
• High Throughput
• Very reproducible
• Comparable to standard
Methods.
DS01
[5mg/mL]
Inj. 1
Inj. 2
Inj. 3
Mean
SD
VK
Std.
Method
Man5
4,05
4,27
4,24
4,19
0,12
2,85
4,52
NGA2
2,93
2,89
2,83
2,88
0,05
1,75
2,73
NGA2F
59,61
57,5
59,1
58,79
1,10
1,87
60,48
NA2G1F
14,2
13,8
13,82
13,94
0,23
1,62
20,6
NA2F
1,7
1,83
1,43
1,65
12,34
12,3
1,9
28
Product Understanding
Product Based Impurities
Electorpherogram from reduced mAb sample
Standard
97.1 % Purity
Clone 1
94.1 % Purity
Clone 2
94.6 % Purity
Clone 3
95.1 % Purity
Clone 4
94.3 % Purity
Clone 5
94.2% Purity
• Product purity influenced by purification process development
• Microfluidic Assay helps point out critical impurities to focus later
development efforts and to track in cell line decisions.
29
Product Understanding
Product Purity – Charge Heterogeneity
Qualitative analysis no longer enough
• Impact on safety and efficacy
MP
Critical to Comparability
• Impacted by cell line
• Impacted by fermentation process
• Impacted by purification process
BPG
APG
High throughput method required to look
at all samples
WCX
7.417
19.120
MP
iCE
MP
14.00
14.50
15.00
15.50
16.00
17.00
17.50
18.00
Minutes
18.50
19.00
19.50
20.50
21.00
21.50
22.00
2
6.90
7.00
7.10
7.20
7.40
7.50
7.763
7.555
7.30
7.842
7.655
7.304
20.00
7.178
7.030
20.913
16.50
BPG
19.760
18.279
17.766
16.555
16.136
13.50
APG
BPG
APG
7.60
7.70
7.80
7.90
Minutes
30
Product Understanding
Product Purity – Charge Heterogeneity
7.20
7.50
Minutes
7.60
7.70
13.00
14.00
15.00
16.00
17.00
18.00
Minutes
7.90
Clone Z
Clone X
19.00
20.00
8.00
Main Peak - 7.417
6.85
6.90
6.95
7.00
7.05
7.15
7.20
7.25
7.30
21.00
7.35
7.40
7.45
7.50
Minutes
7.55
7.60
Basic Peak 4 - 7.841
Basic Peak 3 - 7.759
Basic Peak 2 - 7.635
Basic Peak 1 - 7.554
Acidic Peak 3 - 7.304
Acidic Peak 2 - 7.180
7.10
Ability to detect 
differences to
reference material.
basic Peakgroup - 19.772
acidic Peakgroup - 18.332
WCX
7.80
Acidic Peak 1 - 7.035
Basic Peak 2 - 7.633
Basic Peak 1 - 7.543
7.40
7.30
 Ability to detect
differences between
clones
iCE
7.65
7.70
7.75
7.80
7.85
7.90
WCX
22.00
13.00
14.00
15.00
16.00
17.00
18.00
19.00
7.95
R&D 1
Clone Z
basic Peakgroup - 19.821
7.10
Sensitivity very high
R&D 1
Clone Z
Mainpeak - 19.212
7.00
R&D 1
Clone Z
acidic Peakgroup - 18.324
6.90
Clone Z
Clone X
Mainpeak - 19.235
.80
Acidic Peak 3 - 7.308
Acidic Peak 2 - 7.191
Acidic Peak 1 - 7.036
iCE
Main Peak - 7.409
Clone Z
Clone X
20.00
Minutes
21.00
22.00
23.00
24.00
31
Process Understanding
RAPPTor®
Rapid Automated Protein Purification Technology
Separate but
Seamless
Tecan 150 – HTScreeningTool
Tecan 200 - HTAnalytical Tool
Fully automated purification screening platform
From resin and plate preparation to step elution
Screen 96 variables and generate of up to 500 sample per day
Fully automated sample preparation and analytical assays
Automated homogeneous assays to screen critical output parameters
32
Process Understanding
High-Throughput Parallel Chromatography
robustness study (11 runs)
initial screening (96 runs)
Filterplate run
4
4
RoboColumn runs
9
72
33
Serial Column runs
288
0
100
200
300
time (h)
 gaining process knowledge earlier
 in a shorter timeframe
 with less material demand
• Microfluidic Assay allows analysis of impurities profile for each of the
samples generated.
33
Process Understanding
Critical Impurities
Sample Name
•
•
•
•
% Purity Type
Standard
0,22
Unknown
AT Prod Pool
0,88
Unknown
DF Prod Pool
0,87
Unknown
AEX Prod Pool
0,88
Unknown
CEX Prod Pool
0,76
Unknown
Bulk Prod Pool
0,79
Unknown
Assay set-up not complex, carried out within development lab
Data delivered within hours, not days
Can take next step to test fractionation of individual process steps
IMPACTon real time decsions!
34
Process Understanding
Determination of aggregates
Acquity UPLC H-Class:
• Shorten analysis time by
factor of 2.5
Size exclusion chromatography
Molecular weight standard
• Increase resolution through
smaller particle diameter
• Lower injection volumes
• Low carry over
• Applicable to WCX, RP….
~ 8 min
ACQUITY UPLC BEH200 SEC,
4.6 x 150 mm, 1.7 μm,4 µL
~ 20 min
HPLC TSK G3000 SWXL,
7.8 x 300 mm, 5 µm, 20 µL
35
Process Understanding
Analytical Throughput: Method portfolio
UPLC- SEC
96-well UV
detection
Lab Chip GXII
CHO HCP AlphaScreenTM
(768 data points overnight)
Excitation 680 nm
Emission 615 nm
1O
2
Streptavidin
-coated
Donor bead
Host cell
proteins
Anti-CHO HCP
conjugated
acceptor bead
Automated ELISA
iCE280
Analytical techniques with increased throughput. Understand
impact of each step on product quality and contaminant removal.
36
Boehringer Ingelheim Biopharma
Process Science
Thanks to many colleagues at Boehringer Ingelheim especially:
to H. Kaufmann, D. Ambrosious
to, J. Stolzenberger, S. Combe, O. Haas, S. Müller, D. Dieterle
Boehringer Ingelheim, Bibearch, Germany
Thanks for your attention!!!
37
The Use Of Microfluidics Technology in
the Pharmaceutical Industry:
MicroChip Electrophoresis as a High
Throughput Process Analytical Platform
to support the Development of
Therapeutic Monoclonal Antibodies
Tim Blanc and Qinwei Zhou
ImClone Systems. Branchburg, NJ 08876
Company Confidential
Copyright © 2010 ImClone LLC
Introduction
Rapid analytical separations is an important application stemming from the development of Microfluidics.
One such separation technique is MicroChip Electrophoresis (MCE). MCE can be performed in several
modes to provide valuable insights to the relationship between bioprocess parameters and the quality
attributes of biopharmaceutical products.
Recombinant Monoclonal antibodies commonly exist as heterogeneous mixtures of product variants. Several
factors contribute to product variants, one such factor is glycosylation. Using Glycosylation as the example, It
is important to understand what the relationship is between process parameters and glycan distribution
expressed on the antibody. An effective Quality by Design (QbD) approach uses design of experiments
(DOE) to determine the most important process parameters, termed Critical Process Parameters (CPPs).
However the number of samples required for the experimental design can be high. Testing this number of
sample to gain the most thorough process understanding is time and cost prohibitive by standard methods.
Discussed will the regulatory and biopharmaceutical issues that have accelerated the need for rapid
analytical separation. Then, will be discussed application on MCE that have been developed to address those
needs.
Company Confidential
Copyright © 2010 ImClone LLC
39
The New Quality Paradigm
• ICH Q8 (R2)
Pharmaceutical Development
• ICH Q9
Quality Risk Management
• ICH Q10
Pharmaceutical Quality Systems
• ICH Q11
Development and Manufacture of
Drug Substance
ICH Q11: “Risk management, and scientific knowledge are used more
extensively to identify and understand process parameters
and unit operations that impact critical quality attributes
(CQA’s) and develop appropriate control strategies applicable
over the lifecycle of the drug substance
Company Confidential
Copyright © 2010 ImClone LLC
40
Quality Risk Management:
Linking Process Knowledge, Product Knowledge and Quality Systems
Product
Knowledge
Critical
Quality
Attributes
Process
Knowledge
Critical
Process
Parameters
Quality
Risk
Management
Control
Strategy
Quality
Systems
Ref.- Quality Attributes of Recombinant Thereapeutic Proteins: An Assessment of Impact on Safety and Efficacy as part of a Quality by Design Development Approach
Eon-Duval, A. et.al BIOTECHNOL. PROG., 2012, Vol.00, No. 00
Company Confidential
Copyright © 2010 ImClone LLC
41
Good Business too
Phase I
IND
Phase II
Phase III
BLA
Tox & PK Studies
Process Development and Scale-up (Changes)
Comparability Studies- Linking Commerical scale product
back to original material use in Tox. & PK Studies
Assure QCA’s are maintained within acceptable ranges (QTPP), Quality
Target Product Profile, throughout Process Development. Maintain link
to Tox. & PK studies.
Company Confidential
Copyright © 2010 ImClone LLC
42
Heterogeneity of Monoclonal Antibodies
Therapeutic Mab Product Contents
Product Variants
Process Related Impurities
Trace amounts (ppb-ppm)
• Residual Host Cell DNA,
• Residual Host Cell Protein,
• Residual Protein-A.
ProductRelated Impurities
1-5%
• Antibody Fragments,
• Aggregates
Product Variants
Post-Translational Modifications:
• Glycan Variants,
• C-Terminal Truncation,
• Deamidation, etc.
Critical Quality Attributes (CQA’s)
Company Confidential
Copyright © 2010 ImClone LLC
43
Heterogeneity of Monoclonal Antibodies
Therapeutic Mab Product Contents
Product Variants
Multiple Sources give rise to Product Variants
Company Confidential
Copyright © 2010 ImClone LLC
44
Critical Process Paramenters (CPP)

CPPs are independent process parameters most likely to affect the
quality attributes of a product or intermediate

CPPs are determined by analytical testing, scientific judgment and on
research, scale‐up or manufacturing experience

CPPs are controlled and monitored to confirm that the impurity profile is
comparable to or better than historical data from development and
manufacturing.

Quality attributes related to CPPs include:
• Product Variants Distribution (Glycosylation is a major contributor)
• Product-Related Impurities
• Process-Related Impurities
Company Confidential
Copyright © 2010 ImClone LLC
45
Glycosylation
Company Confidential
Copyright © 2010 ImClone LLC
46
Implications of Glycosylation Variants
• The greatest source of Mab Product Variants is Glycosylation
• Glycosylation is very closely tied to process parameters
• Aspects of glycosylation will frequently be CQA’s
Glycan Structural Characteristic
Implication
Fucose:
Effector Function (e.g. ADCC)
Sialic Acids (NANA, NGNA)
PK modulation (up or down)
NGNA
Immunogenicity
α-Galactose
Immunogenicity
Company Confidential
Copyright © 2010 ImClone LLC
47
MCE and Product Variants

Sample prep designed in microtiter plate format with immobilized
enzyme to reduce sample prep from 2 days to ½ day (Glycans).

Rapid electrophoretic separation on Microchip with sensitive laserinduced fluorescence detection. (<60 seconds per sample)

Analytical separations in under 60 seconds for determinations of:
• Size Heterogeneity
• Charge Heterogeneity
• Glycosylation Heterogeneity

Throughput and Accuracy for thorough QbD testing, CPP determination
and Successful Control Strategy efforts
Company Confidential
Copyright © 2010 ImClone LLC
48
High Throughput Platform for PAT
Charge
Size
Glycosylation
MCE-CZE
Charge-Based
Evaluation
MCE-SDS
Size-Based
Evaluation
MCE N-Linked
Glycan Analysis
Relative Distribution
Of Product Variants
% APG
% NPG
% BPD
% Purity (NR)
% Aggregate
% Fragment
% Purity (Red.)
% Non-Reducible
% Aglyc HC
% G0 F
% G1F
% G2F
% α-Gal
% Fucosylated
% Sialylated (NGNA)
Data is all numerical for statistical comparison
Company Confidential
Copyright © 2010 ImClone LLC
49
MCE Platform: Size Heterogeneity
MCE-SDS < 60 SECONDS per Samples
CE-SDS ≈ 60 Minutes Samples
Company Confidential
Copyright © 2010 ImClone LLC
50
MCE Platform For QbD: Charge Heterogeneity
MCE < 60 SECONDS per Samples
IEC >60 MINUTES per Sample
Company Confidential
Copyright © 2010 ImClone LLC
51
MCE Platform: Glycan Heterogeneity
MCE < 60 SECONDS per Samples
HPLC ≈ 60 Minutes Samples
Company Confidential
Copyright © 2010 ImClone LLC
52
Conclusions
• Rapid Analysis time and easily automated.
• Allows more samples tested and better insight to Impact
of process parameters.
• CPP’s determined and detailed process understanding.
• Effective Control Strategy.
• Relevant Drug Substance Specification (JOS).
Company Confidential
Copyright © 2010 ImClone LLC
53
Science Webinar Series
AMicrofluidic
DVANCINGElectrophoresis
EPIGENETICS:Assays for
Characterization
of Protein
NRapid
OVEL DRUG
DISCOVERY STRATEGIES
FOR in
ResearchTARGETS
and Development
EPIGENETIC
1417
November,
October, 2012
Brought to you by the Science/AAAS Custom Publishing Office
Participating Experts:
Joey Studts, Ph.D.
Boehringer Ingelheim Pharma
GmbH & Co. KG
Biberach, Germany
Timothy Blanc
ImClone Systems
Branchburg, NJ
Bahram Fathollahi, Ph.D.
PerkinElmer
San Francisco, CA
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Microfluidic Electrophoresis Assays for
Rapid Characterization of Protein in
Research and Development
14 November, 2012
Brought to you by the Science/AAAS Custom Publishing Office
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For related information on this webinar topic, go to:
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