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Imagination at work.
Fredrik Sundberg Nov. 23, 2017Wien
Global Trends and Health Authority Acceptance of SPR
GE © 2017 – All Rights Reserved
Outline
• Global industry trends, health authority acceptance and view on SPR
• Biacore applications for process development and manufacturing QC
• Regulatory expectations for SPR-based assays and recommended validation strategies
• Safety• Efficacy• Manufacturability
GE © 2017 – All Rights Reserved
Growing biologics market...
Advancements in knowledge and understanding
• Product (structure/function, modification and stability/formulation)
• Bioprocessing (platform and scale-up)
• Analytical technology (state-of-the-art)
Biosimilars growth and opportunity
• Regulatory pathway and guidelines
Novel and more complex drugs
• Bi-specifics, ADCs, etc.
Data courtesy of USFDA
“Industry biologics transformation and globalization”
GE © 2017 – All Rights Reserved
Process understanding for control CQAs = Critical Quality Attributes
Analyze
Analyze
Upstream conditionsCell line, cell cloneO2, CO2, N, glucose, lactose, temp, timeComposition of cell culture media
Batch 1
Batch 3
Batch 2
Batch n
Downstream
Predictable, repeatable and economic process required
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How to establish comparability? Extended analytical characterization
Developing the Nation's Biosimilars Program, Steven Kozlowski, M.D., Janet
Woodcock, M.D., Karen Midthun, M.D., and Rachel Behrman Sherman, M.D.,
M.P.H. N Engl J Med 2011; 365:385-388 August 4, 2011
Small & Easy!
Huge & Complex!
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• Safety• Efficacy• Manufacturability
Analytical control strategies Bridging the gap from R&D to QC
6
Data courtesy of MSDGE © 2017 – All Rights Reserved
Analytical characterization employs multiple orthogonal techniques
• ”Tool-box” approach
• Physicochemical and biological characterization
• Assays used are product/process dependent and should be QC-friendly
PubMed search of SPR biosensor literature Increasing use and number of publications
Search phrase: Surface plasmon• Continued intense research on SPR sensors
• Rapid growth in biologics development
• Biosimilars and novel drugs (ADCs, Bi-specifics, etc.)
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GE © 2017 – All Rights Reserved
Yes/no binding?
Specificity of binding?
How strong?
Affinity
How fast?
Kinetics
How much?
Concentration
How similar?
Sensorgram Comparison
Biacore™ T200
Increasing use of SPR for complex biologics...Bi-specifics, ADCs and Sensorgram Comparison
FDA
ADC
Application of kinetic analysis Straightforward “fingerprint” of interaction
• Active proteinka = [M-1 s-1]kd = [s-1]
• In comparison with denaturated protein
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Potency assay and comparability studies!Stability-indicating assays!
GE © 2017 – All Rights Reserved
SPR biosensor use in Biosimilar development Analytical platform approach with multiple applications
Target binding (1st MoA)
Fc-receptor binding (2nd MoA, PK, etc.)
Immunogenicity (screening & characterization)
Product and process support E
D
A
B
C Binding specificity & potential off-target effects SPR assay formats
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Biacore SPR receptor binding studies for approved Biosimilars!
Approved drugs: • ZARXIO® (Filgrastim, G-CSF)
• Binocrit® (EPO) • RemsimaTM/InflectraTM (Infliximab) • CyltezoTM (Adalimumab-adbm)
Filgrastim…highly similar to reference medicineSPR data critical for decision-making
Data courtesy of SandozGE © 2017 – All Rights Reserved
FDA view on SPR...
GE © 2017 – All Rights Reserved
Global trends SPR • Increasing use of kinetics in drug
submissions globally• Increasing use of for comparability,
stability and potency
Antigen
Stability
HCP
Complement
FcγR
C1qSPR assay formats
Immunogenicity testing – hot topic! • Regulatory and technical concern
Data courtesy of USFDA
Japan Health Authorities view on SPR...
NEWS - SPR listed in Japanese Pharmacopeia and recommended analytics!
Example: Chapter 4, describes various SPR drug-testing methods
• Identification testing
• Binding affinity testing
• Relative potency assay
Note: Draft valid on Mar. 2016, 17th revision JP. Additionally, SPR and kinetics information are described in Antibody Therapeutics Guidance (chapter 3.3.3.1. binding attributes) issued in 2012.
GE © 2017 – All Rights Reserved Data courtesy of Japan Health Authorities
FDA-approved SPR potency assays Rapid methods with superior precision (CV <5%)
GE © 2017 – All Rights Reserved Data courtesy of GSK
Approved
in EU, US and Japan
Indication: Diabetes
Contains: GLP-1 & HSA
Indication: Asthma
Contains: hu-MAB
FDA-approved SPR release assays
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In-process control and release testing…
• Improving productivity in downstream processing
Process step Mouse-IgG ELISA Biacore
Harvest pool 7h 2h
30 KD Diafiltration 7h 2h
IEX Chromatography 7h 2h
Total time 21h 6h
Courtesy of Boehringer-Ingelheim
Sterile Filtration
Virus Clearance
Cell Harvesting
Polishing
Intermediate
Ultrafiltration
Cell Culture
Capture
QA/QC
• FDA-approved release testing
Courtesy of Biogen
Reynhardt et al., 2001,
Int J of Biochromatography,
v6, 255-267
Amevive®
Alefacept/CD2 interaction
Sterile Filtration
Virus Clearance
Cell Harvesting
Polishing
Intermediate
Ultrafiltration
Cell Culture
Capture
QA/QC
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How much of the “iceberg” can we see? Challenges measuring binding
Characterization
? “Process is the product … ”
Release tests
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• Similar affinity - different kinetics…• Kinetic data provides more info, but…• Binding mechanism can be complex…
1) Receptor is heterogeneous with respect to glycosylation…
2) Antibody is heterogeneous with respect to glycosylation…
3) Conformational changes cannot be excluded either…
4) Other issues?
Novel methodology for comparability Quantitating binding similarities (ref. Biacore™ T200 3.0 Software)
Compare entire curves
✓ Batch-to-batch comparison or potency✓ Study effect of:
o Cell culture conditions o Purification o Formulation o Forced degradationo Change of key reagents in assay
✓ Understand effects of structural changes✓ Identify binders with a certain curve shape✓ Selection of candidates or reagents
Other applications???
…not constants or report points
Sensorgram Comparison
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Rituximab Infliximab Omalizumab Trastuzumab
Sim
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co
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GE © 2017 – All Rights Reserved Courtesy of GE & NIBRT
IgG FcR analysis
The Similarity Score describes in a single number, how close a sample sensorgramis to established upper and lower limit sensorgrams.
Key steps for SPR instrument and assay validation All activities should be documented and traceable
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?
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Analyst GLP/GMP and system training
NEWS:
SPR Validation
Guidelines
2017
Re-validation?
Change control?
Data management?
Technology transfer?
Biacore qualification process overview
Keep system in a validated state!
Qualification Maintenance & Re-qualification
IQ
OQ
PMGxP
PMGxP
PMGxP
PMGxP
Qualification
Approval
PQ
IPQIPQ IPQ IPQ IPQ
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Method Development
SPR assay validation guidelines…
Specificity
Linearity
Accuracy
Precision
Range
Quantitation Limit
Detection Limit
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Summary and conclusions
• SPR analytics is used by top-10 pharma companies and fully accepted by health authorities in regulated applications
• Biacore is a platform technology for Biosimilars and increasingly used in manufacturing QC
• Growing interest for novel SPR assay formats and standardization of validation strategies
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• Safety• Efficacy• Manufacturability
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