Comparability to establish Biosimilarity -...

Comparability to establish Biosimilarity

CMC Strategy Forum Europe 2014, Sorrento, Italy

Jan Visser, Head Global Analytical Characterization & Bioanalytics

Sandoz Biopharmaceuticals, Hexal AG, Germany

© 2014 Sandoz. All rights reserved. All trademarks are the property of their respective owners.

2 | CMC Strategy Forum Europe 2014, Sorrento, Italy

Variability is inherent in biologics

Manufacturing changes

Manufacturing changes occur due to

process improvements, scale up, etc

Differences in attributes sometimes

significantly larger than batch-to-batch

variability

Non-identicality is a normal principle in

biologics

No batch of any biologic is “identical” to

the other batches

Variability is natural even in the human

body and usually not problematic

Batch-to-batch

C. Schneider: Biosimilarity: A better definition of terms and concepts.

25th Annual DIA EuroMeeting, 04-06/03/2013, Amsterdam

M. Schiestl et al. : Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology , 29: 310 - 312, 2011

0

10

20

30

40

50

60

02.2008 03.2009 05.2010 06.2011

Expiry date

G2F glycans

[rel. area %]

0

10

20

30

40

50

60

07.2009 08.2010 09.2011

Basic variants

[rel. area %]

Expiry date

Pre-shift

Post-shift

Pre-shift Post-shift


Characterization of commercial batches of MabThera®/Rituxan®

Significant structural change leading to a functional change and probably related

to a change in the manufacturing process

Different product qualities interchangeably on the market

No change in product label – indicating comparable safety and efficacy

extrapolated to all indications

M. Schiestl et al. : Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology , 29: 310 - 312, 2011...supplemented with new data!


C. Schneider, Ann Rheum Dis March 2013 Vol 72 No 3

Changes include e.g.

Change in the supplier of a cell

culture media

New purification methods

New manufacturing sites

Manufacturing changes are made frequently

However, the impact of manufacturing changes are well understood by

means of comparability exercises (ICHQ5E) and tightly controlled by

regulators

Changes occur at various points in

the product life cycle


Comparability exercises to assess

Manufacturing changes

ICHQ5E: Comparability of biotechnological/biological products subject to

changes in their manufacturing process

“The goal of the comparability exercise is to ensure quality, safety and efficacy of

drug product produced by a changed manufacturing process…”

“A determination of comparability can be based on a combination of analytical

testing, and, in some cases, nonclinical and clinical data.”

“The demonstration of comparability does not necessarily mean that the quality

attributes of the pre-change and post-change product are identical, but that they

are highly similar…”

The concept behind comparability generally functions with many post-

marketing manufacturing changes being approved based on analytical

testing alone

http://www.ich.org/


Revised comparability guideline as basis for

biosimilar guideline

Martina Weise, DIA Euro Meeting, March 2014


Biosimilars and comparability

EMA Guideline on Similar Biological Medicinal Products (Draft 2013) and Guideline

on similar biological medicinal products containing biotechnology-derived proteins

as active substance: quality issues (Draft 2012)

“A biosimilar demonstrates similarity to the reference medicinal product in terms of quality

characteristics, biological activity, safety and efficacy based on a comprehensive

comparability exercise.”

“A stepwise approach is normally recommended throughout the development programme,

starting with a comprehensive physicochemical and biological characterisation. The extent

and nature of the non-clinical in vivo studies and clinical studies to be performed depend on

the level of evidence obtained in the previous step(s)..”

“It is not expected that all quality attributes will be identical and minor differences may be

acceptable, if appropriately justified.”

“The scientific principles of such a biosimilar comparability exercise are based on

those applied for evaluation of the impact of changes in the manufacturing process

of a biological medicinal product (as outlined in ICH Q5E).”


Physicochemical characterization

Biological/Preclinical data

Clinical studies

Extent of comparability exercise

Release analytics

Continuum of comparability allows for appropriate control of variability in biologics

Comparable ≠ Identical

However, an originator biologic after an approved manufacturing change is

as safe and efficacious as the pre-change product!

However, an approved biosimilar is as safe and efficacious as its reference

product!


The evaluation of biosimilarity is based on comparability gained at all levels

A comprehensive analytical comparability exercise forms the foundation for

establishing biosimilarity as very sensitive to differences

Once a proposed biosimilar is shown to be ‘highly similar’ at the analytical level,

this demonstration should allow for tailored pre-clinical and clinical studies

Physicochemical and biological

characterization

Sen

sitiv

ity to

dete

ct d

iffere

nces

Higher

Lower A

naly

tic

al

co

mp

ara

bilit

y

PK/PD

Preclinical

Biological

characterization

Physicochemical

characterization

Clinical


Sensitivity of analytics has greatly improved during the last decades

Year Detection limit of peptide (pmol)

1990 100

1993 10

1997 1

2000 0.1

2003 0.01

2005 0.001

2008 0.0001

2011 0.00001

Adapted from: Mire-Sluis, T.: The Regulatory Implications of the ever increasing power of Mass Spectrometry and its role in the Analysis of

Biotechnology Products – Where do we draw the line? CASSS MassSpec 2012.

Sensitivity increase in mass spectrometry


Attributes e.g.:

Primary structure

Mass

Disulfide bridging

Free cysteines

Higher order

structure

N- and C-terminal

heterogeneity

Glycosylation

Glycation

Fragmentation

Oxidation

Deamidation

Aggregation

Particles

Target-binding

Fc effector

functions

Methods e.g.:

MS

Peptide mapping

Ellman‘s

CGE

SDS-PAGE

CD, FT-IR

H-D exchange

NMR, X-ray

HPLC

HPAEC

IEF

2AB NP-HPLC

SE-HPLC

FFF

AUC

DLS

MALLS

Bioassays

SPR

State-of-the-art analytics allow for the thorough characterization of biosimilars and its reference

Combination of attributes • MVDA, mathematical algorithms

Primary

Structure Higher

Order

Structure

Charge

Variants

Biological

functions

Glycosylation

Size

variants


Purification process

development

Bioprocess development

Recombinant cell line development

Drug product

development

Reference

product variability

Process

development

Analytics

3. Confirmation

of biosimilarity Biological variability

2. Target directed

development

Target range

1. Target definition

Biosimilars must be systematically engineered to

match the reference product (QbD)


QbD elements directing biosimilar development - Quality Target Product Profile

QTPP contains the elements/considerations as described in ICH Q8 (R2)

Intended use in clinical setting, route of administration, dosage form, delivery systems;

Dosage strength(s)

Container closure system

Drug product quality criteria (e.g., sterility, purity, stability and drug release)

For biosimilar based on reference product characteristics

Additionally specific for biosimilars

Ranges of quality attributes of marketed reference product

Quality attribute ranges are based on analytical data of many individual reference product batches of different shelf life age


Quality attribute ranges - Target definition

At project start:

Several originator batches are being purchased from main

geographic regions

Basic analytical methods are being developed

The amino acid sequence of the originator is being determined

Preliminary originator ranges (target specifications or goal posts) are set

During the project:

Continue to purchase originator batches and analyze upon purchase and

end-of-shelf life

Update target specifications & QTPP


Target definition: global biosimilar development

Showing that reference products (RP) from main geographic areas are analytically

indistinguishable aids global biosimilar development

US and EU reference product indistinguishable for all quality attributes with the

“apparent” exception of N-terminal variants

N-terminal variants were found to significantly change during shelf life

To have good guidance during early development purchase „old“ and “new“ RP

batches and perform a dev. stability study with RP

For regulatory filing analyze RP batches upon purchase and at end of shelf life

50

55

60

65

70

75

80

85

90

95

100

0 200 400 600 800 1000

% N

-term

ina

l V

ari

an

t

Days of Remaining Shelf-Life (when analyzed)

EU intact molecule US intact molecule

0.0

5.0

10.0

15.0

20.0

25.0

0 200 400 600 800 1000

% N

-term

inal

Vari

an

t

Days of Remaining Shelf-Life (when analyzed)

US Leu clipped EU Leu clipped

EU Leu+Pro clipped US Leu+Pro clipped

N-terminal variant 1 N-terminal variant 1

N-terminal variant 2 N-terminal variant 2


QbD elements directing biosimilar development - Criticality assessment of Quality Attributes

Efficacy / Potency

PK/PD

Immunogenicity

Safety

Imp

act

Un

cert

ain

ty

Criticality

High = 20 High = 7

Low = 2 Low = 1

API-related quality

attributes e.g. deamidation, oxidation,

afucoslylation,...

CQA by definition e.g. strength, composition,

appearance, potency,...

Process- and

excipient-

related quality

attributes e.g. HCP,

antifoam,

endotoxins,...

Criticality Score (2-140)

Quantitative measure for an attribute‘s impact on

safety and efficacy. Using best possible surrogates

for clinical safety and efficacy

Impact (2-20)

Known or potential consequences on safety and

efficacy, considering, biological activity, PK/PD,

immunogenicity, safety

Uncertainty (1-7)

Relevance of information e.g. literature, prior

knowledge, in vitro, preclinical clinical or

combination of information

Criticality Calculation

Criticality Criticality Score

Very High 121 – 140

High 86 – 120

Moderate 56 – 85

Low 31 – 55

Very Low 2 – 30


How comparable do biosimilars need to be?

Biosimilar needs to be as safe and efficacious as the reference product

The more critical a quality attribute is, the more comparable it should be –

knowing your protein is essential!

The more comparable a biosimilar is to the reference analytically, the smaller

the residual uncertainty, the more tailored the non-clinical and clinical program

Criticality Criticality Score

Very High 121 – 140

High 86 – 120

Moderate 56 – 85

Low 31 – 55

Very Low 2 – 30

Lower

Higher

Strin

gen

cy

co

mp

ara

bility

ran

ge

QA

critic

ality


How comparable do biosimilar mAbs need to be?

M. Shapiro, ACR annual conference 2012

Know your protein and

analyse it using state-of-

the-art analytical methods!


Year 1 2 3 4 5 6 7 8

Cell line

dev. Process

Opt.

Clin.

man

Comm

man

Clin.

man

Full process

dev.

Val

Process

Charact.

TPoS Confirm

comparability

Formulation

Dev.

GLP

PC PK/PD study Conf. clin. study

Exploratory PC

studies

Target specification: Originator characterization

Analytical tool box

Val

Confirm

comparability

Final

comparability

Analytical comparability exercises during biosimilar development

Develop highly similar product Confirm biosimilarity


Final comparability exercise

Use of a wide range of sensitive and orthogonal analytical methods

Head-to-Head (H2H) analysis with selected originator batches

Comparison of physicochemical and biological characterization results with

H2H originator batches and “historical” target specification

Identification of variants in both biosimilar and originator

Justification of differences in QAs

Comparison of stability data:

intended conditions (=> stability profile)

accelerated, stress conditions (=> forced degradation profile)


Quality Attribute

Criticality

Process Control

Testing Strategy

Capability of the process to control the quality attribute

Testing for the quality attribute

Quality Attribute Criticality considering impact on safety and

efficacy

Design Control Elements Process Control Elements Process Parameter Controls

Process Qualification

Input Material

Control Elements Raw material testing

Testing Control Elements

Stability testing

Characterization

In-process testing

Release testing

CQA Control

Strategy

CQA control strategy for biosimilars


Setting specifications for biosimilars

ICH Q6B Specifications: Test Procedures and Acceptance Criteria

for Biotechnological/Biological Products

“Specifications are critical quality standards that are proposed and justified by

the manufacturer and approved by regulatory authorities as conditions of

approval.”

“Specifications are chosen to confirm the quality of the drug substance and drug

product...and should focus on those molecular and biological characteristics

found to be useful in ensuring the safety and efficacy of the product.”

Specification acceptance criteria (LL & UL) for biosimilars are initially defined by

a combination of the originator range and process capability and later by

process capability alone!


Divergence a risk for biosimilars?

After approval in EU a biosimilar is managed as an independent product

Divergence = Different patterns of product drift and evolution (=shift) contributing,

over time, to clinically meaningful differences Ramanan & Grampp BioDrugs Feb 2014

Does divergence between a biosimilar and its reference product pose a bigger risk

than divergence between pre- and post-shift reference product or between

interchangeably used originator products?

Divergence between post- and pre-change product shown in PRCA Eprex case

resulting in increased regulatory scrutiny regarding primary packaging and leachates

However, to date not aware of data showing that divergence is an issue for

biosimilars or interchangeably used originator products

Quality systems of biologics manufacturers should ensure the detection and

management of drift (unintended changes) via their control strategy, while evolution

(intended changes) is well managed according to ICHQ5E guidance


Conclusions

The scientific principles behind the comparability exercise supporting manufacturing

changes and assessment of biosimilarity are the same!

The analytical comparability between the proposed biosimilar and reference product

forms the foundation for establishing biosimilarity as very sensitive to differences!

The QTPP, which includes ranges of QA’s of the reference product, and the QA

criticality assessment are key elements in directing biosimilar development!

The closer the proposed biosimilar and its reference product are analytically, the less

residual uncertainty and the more tailored the (non)clinical program should be!

A good quality system should prevent divergence between pre- and post-change

biologics, biosimilars and reference products, and interchangeably used biologics

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