Imagination at work.

Fredrik Sundberg Nov. 23, 2017Wien

Global Trends and Health Authority Acceptance of SPR

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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

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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”

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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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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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400450500550600650700750800850900

Potency assay and comparability studies!Stability-indicating assays!

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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...

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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

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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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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

23

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