Targeted development of biosimilar pharmaceutical products

Targeted development of biosimilar 

pharmaceutical products 

Thomas Stangler, Hannover, Oct. 4th, 2010 

EAPB Special Interest Group Regulatory Aspects for Biopharmaceuticals

Sandoz is the world leader in developing, 

manufacturing and commercializing biosimilars 

Development expertise: 

� Pioneer - developing biosimilars since 1996 

� Four development sites, multiple clinical trials ongoing 

� 8-10 molecules in development, including mAbs 

Six decades of biotech manufacturing know-how: 

� World leader in fermentation technologies since 1946 

� Interferon alpha – first recombinant made in EU in 1980 

� Three state-of-the-art EU plants for recombinant proteins 

Commercial experience: 

� Broad global presence 

� Strong M&S capability 

� Unparalleled market experience with biosimilars 

2 | Thomas Stangler | EAPB SIG Regulatory Aspects for Biopharmaceuticals | October 4th, 2010 | Business use only

Sandoz and Novartis have cutting edge biologics 

development and manufacturing facilities 

Vacaville (California) 

Microbial production 

Holzkirchen/Oberhaching 

(Germany) 

BU management 

Clinical development 

Clinical safety 

Pharmacovigilance 

Huningue (France) 

Cell culture production 

Basel (Switzerland) 

Product development 


Menges (Slovenia) 

Tech. development 


3 | Thomas Stangler | EAPB SIG Regulatory Aspects for Biopharmaceuticals | October 4th, 2010 | Business use only 

Schaftenau (Austria) 



Kundl (Austria) 


Regulatory affairs 

Microbial production

Biologics are more complex than small molecules… 

Acetylsalicylic 

Acid 

small chemical molecule 

Molecular weight 

= 180 Daltons 

0 amino acids 

Calcitonin 

simple biologic 


= 3,455 Daltons 

~ 32 amino acids 

- w/o host cell modifications 

- produced in yeast, bacteria 


Monoclonal 

Antibody (IgG) 

complex biologic 


= 150,000 Daltons 

~ 1300 amino acids 

- w/host cell modifications 

(glycosolations, etc) 

- produced in mammalian cells

…and are produced from genetically engineered living 

organisms (not chemical synthesis) 

Modify host cells 

(e.g., bacteria, 

mammalian yeast) to 

produce recombinant 

proteins 

Grow cells 

under controlled 

conditions 

(fermentation) 

Extract, refold, 

purify – generate 

drug substance 


. 

Formulate to 

stable finished 

drug product (vial, 

syringe, cartridge)

What are Biosimilars? 

� Successor to a biological medicinal product for which patent protection 

no longer applies 

� Complex molecules manufactured by recombinant DNA technology 

(insertion of gene into the host cell to produce the protein) 

� Comparable with the reference product in terms of quality, efficacy and 

safety 

� Can be approved for the same indications for which the reference 

product is approved 

� Approved by EMA in a centralized procedure � as for innovators 

Biosimilars Biosimilars SEBs 


Source:NGx 

Generic Biological 

Biogenerics

Biosimilars development is a hybrid between 

traditional generic and originator approaches 

Development 

investment 

Time to market 

# of patients for approval 1 

Generics* Biosimilars* Originators* 

US$ 2 – 3m US$ 100 - 200m US$ 800m 

2 – 3 yrs 7 – 8 yrs 8 – 10 yrs 

20 – 50 pts ~ 500 pts 800 – 1000 pts 

1 

* Industry average 

1 Average estimates for biopharmaceutical trials, e.g., oncology 


Biosimilar competition will lead to increased 

innovation 

Competition and innovation are inextricably linked – a “virtuous circle” 

• Originators should realize fair 

profit and return on investment 

• Indefinite monopolies lead to 

stagnation 

• Biosimilars will increase 

competition and encourage “next 

wave” of biologics innovation 


Innovation 

Biosimilars 

Competition

Biosimilars: The Regulatory Landscape in EU & USA 

Legal basis 

The legal framework is provided in 

EU Directive 2001/83/EC, in Article 

10, Paragraph 4, published in EU 

Directive 2004/27/EC and 

implemented through-out the EU at 

the end of Oct 2005. 

The requirements are set forth in EU 

Directive 2003/63/EC, Annex, Part II, 

Point 4, for “Similar Biological 

Medicinal Products”. 

PHS Act (CBER) 

Most biologicals approved under 

the PHS Act (e.g. EPO, interferon, 

Monoclonal antibodies). Health Care 

Reform Bill enacted in March 2010, incl. 

Biosimilars - 351(k). Details tbd 

Biosimilars 

are on a 

sound legal 

footing in 

Europe 

Biosimilar 

regulations 

being 

established 

in USA 


Further guidelines 

In Nov 2004, the EMEA/CHMP 

issued a set of guidelines for biosimilars 

which address general, 

quality -relevant and preclinical/ 

clinical requirements for specific 

products 

All general ICH, EMEA, FDA guidelines 

on the quality and safety of 

biological products apply equally 

to biopharmaceuticals and biosimilars 

FD&C Act (CDER) 

Historically some biologicals 

(e.g. somatropin, FSH, insulin) were 

approved under the FD&C Act for 

which Section 505(b)(2) applies

Biosimilar Guidelines – Overview 

Defines 

principles 

General 

guidelines 

Quality / Safety 

Efficacy 

Product class 

specific data 

requirements 

Overarching Guideline (CHMP/437/04). 

„Guideline on Similar Biological Medicinal Products.“ 

Biotechnology – derived proteins 

Quality 

Nonclinical 

Clinical 

Insulin Somatropin GCSF Epoetin IFN-a LMWH 

Nonclinical 

Clinical 

Nonclinical 

Clinical 

Nonclinical 

Clinical 

Nonclinical 

Clinical 


Nonclinical 

Clinical 

Nonclinical 

Clinical 

mAbs 

under 

discussion

Quality: A full quality dossier supplemented by 

the demonstration of comparability. 

Full CTD M3 

E.g. 3.2.S DS 

-Manufacture 

-description MP 

-control of materials 

.control of critical steps 

.process validation 

.manufacturing PD 

-Control DS 

-Reference standard 

-Container closure system 

-Stability 

Quality 

CTD M3+ 

Comparability 

vs. Reference 

-Not expected PQA are identical 

-Stepwise approach justifying 

differences in PQA 

-Differences PQA can impact 

requirements (non)clinical 

package 

-Reference product description 


• EMEA/CHMP/BWP/49348/2005 

Analytical Methods 

& Specifications 

-Use of state-of-the-art 

analytical methods 

-Physicochemical properties 

-Biological activity 

-Purity and impurities 

-Specifications defined 

and justified

Product specific (non)clinical guidance. 

Example: Somatropin 

(Non) 

Clinical 

Non-clinical studies Clinical studies 

Comparative in nature and designed to detect 

differences in pharmaco-toxicological response 

Pharmacodynamic studies 

-in vitro (receptor-binding, cell proliferation) 

-in vivo (weight gain in hypophyse sectomised rats 

Toxicological studies 

-repeat-dose study 

-local tolerance 


• EMEA/CHMP/BMWP/94528/2005 

Comparative pharmaco-kinetic and –dynamic 

-single dose cross-over study using sc admin 

-IGF-1 preferred pharmacodynamic marker 

Clinical efficacy & safety 

-children with GH deficiency target population 

-height velocity as primary end-point 

-comparative phase >= 6m, up to 12m 

-pre-treatment growth rate >= 6m, up to 18m 

-12m immunogenicity data (every 3m) 

Pharmacovigilance plan

Biosimilars are recognized around the world as 

safe and effective medicines 

EU draft 

general 

guidelines 

adopted 

Sandoz 

Somatropin 

first biosimilar 

approved and 

launched in EU 

Sandoz first 

EPO approved 

and launched in 

EU 

Filgrastim* 

approved in EU 

2004 2005 2006 2007 2008 2009 

Sandoz Somatropin 

first biosimilar – type 

medicine approved in 

Australia 

“We are confident that if a product … gets an MA 

from the Commission... the product is as safe 

and effective as any other product authorized by 

the Commission." 

- Nicolas Rossignol, former administrator of EC 

pharma division 1 

1 Source: Speech at EGA Biosimilars conference 2008, quoted in Scrip 

* First competitor product (Sandoz product approved Feb 2009) 


Japan regulatory 

guidelines 

Sandoz 

Somatropin first 

biosimilar approved 

and launched in 

Japan & Canada 

2010 

US regulatory 

pathway

Target-directed product development 

for late-phase innovative biopharmaceuticals and biosimilars 

Refinement 

of target, 

Identification 

of CQA's 

ICH Q8, Q9 and Q10 

are applicable for biosimilar 

manufacturers 

in the same way as for 

originators! 

Define Quality Target 

Process Development 

Building Quality into Product 

Quality Risk Management 

Thorough process understanding 

Confirmation: 

Characterization & 

Comparability 


Physicochemical 

and biological 

characterization

Target-directed product development 

for Innovative Biopharmaceuticals and Biosimilars 

Define target 

Process 

development 

Characterization 

& Comparability 

New biopharmaceutical Biosimilar 

Quality: safety, efficacy 

Performance: low COGS, robustness, facility-fit 

Comparability: to previous clinical DS Comparability: to originator 

Start from platform process, rational DoE 

Extensive product quality analytics 

2-step development 

1-step development 

(early phase, late-phase) → more time to 

gain experience with cell line/ product 

→ most efficient capacity use 


increased challenge: rarely platform process 

useable, tight quality targets to combine with high 

yield 

Extensive set of state-of-the-art analytical methods: phys.-chem., biol. 

Need to know structure-function relations 

better than originator 

Pre-clinics – PhI – PhII – PhIII Pre-clinics – PhI – PhIII → No PhII, but 

comparative PhI/III studies

Targeted Development: timing of the 3 steps 

(target, development, characterisation) 

Year 1 

Biosimilar: 

Originator characterisation 

Cell line 

dev. 

2 

Full process 

dev. 

3 

PhI manufacture 

4 

Process 

Charact. 

New Biopharmaceutical (timelines exemplary): 

Cell line + 

Platform 

Process 

PhI manufacture 

Tox. 

PoC study 

PhII manufacture 

5 

PhIII man. 

+ Process 

Validation 

Tox. PhI study Phase III study 


Tox. 

POC read out 

Full process 

dev. 

PhIII manufacture 

Phase II study 

6 

Process 

Charact. 

7 

Process 

Validation 

Launch 

Manuf. 

Phase III study 

8 

Launch 

Manuf.

Starting a biosimilar development project 

� Target Product Profile 

� Indications 

� Dosage strength & form 

� Target country & reference product 

�� Initial target specification 

� Project start: 

� Technical & Clinical Development Plan 

� Start with QbD Development 


COM 

IP 

RA 

PM 

CD 

TD 

QA

Defining the target! 

� Initial target definition (before project start): 

� Characterize originator-batches with extensive 

set of state-of-the-art methods 

� Develop bioassays reflecting MoA 

� First risk-assessment to evaluate CQAs 

� Refined target (during project): 

� Characterize additional originator batches 

� Broad quality ranges obtained during cell line / 

process dev. allow establishment of 

correlations phys.-chem. ↔ bioactivity 

� Refine definition of CQAs 


ICH Q8, Q9 and Q10 


� High level guidance (not 

prescriptive) 

� Science and risk-based 

� Encourages systematic 

approaches 

� Applicable over the entire 

product lifecycle 

� Intended to work together 

to enhance 

pharmaceutical product 

quality

ICH Q8 concepts for targeted process 

development: QTPP & CQAs 

Quality Target 

Product Profile 

(ICH Q8R2) 

Critical Quality 

Attributes 

(ICH Q8R2) 

� A prospective summary of the quality characteristics of a drug 

product that ideally will be achieved to ensure the desired 

quality, taking into account safety and efficacy of the drug 

product. 

� Basis of design for development of the product. Considerations 

include: 

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

systems; 

� Dosage strength(s); 

� Container closure system; 

� Therapeutic moiety release or delivery and attributes affecting 

pharmacokinetic characteristics; 

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

� Physical, chemical, biological or microbiological property or 

characteristic that should be within an appropriate limit, range 

or distribution to ensure the desired product quality 


Elements of QbD Pharmaceutical Development 

QTPP 

CQAs 

Risk Assessment 

� Establish Quality Target Product Profile – “the QTPP forms the 

basis of design for development of the product“ 

� Determine Critical Quality Attributes – linking quality attributes to 

clinical safety and efficacy (risk-based) 

� Linking process parameters to critical quality attributes 

Quality – Process �� Based on prior knowledge & process development experience 

Design Space 

Process Knowledge 

Control Strategy 

Continual 

Improvement 

� Develop a design space 

� Process characterization 

� Design and implement control strategy – e.g. by linking CQAs to 

process capability and detectability 

� Manage product life cycle, including continual improvement 


Quality Attribute Criticality Assessment 

A-Mab case study risk assessment tool #1: 

Risk ranking & filtering 

Criticality = Impact (2-20) × Uncertainty (1-7) 

Risk that an attribute 

impacts safety and 

efficacy (risk score) 

Known or potential 

consequences on safety 

and efficacy, considering: 

• Biological activity 

• PK/PD 

• Immunogenicity 

• Safety 

Risk scores range between 2 and 140 (criticality continuum) 


Relevance of information 

e.g. literature, prior knowledge, 

in vitro, preclinical, clinical

Typical product quality attributes 

Primary & higher order structure 

Glycoforms 

Charge Variants 

Aggregation / Degradation 

Process-rel. impurities 

Biological characteristics Physicochemical characteristics 

Fab 

V H 

Antigen binding 

V L 

C L 

C H 1 

- S - S - 

- S - S - 

SS SS 

-S-S- 

SS SS 

Heavy chain 


Fc 

Effector functions 

- Complement interaction 

- Fc Receptor interaction 

C H 2 C H 3 

Heavy chain 

-COO - 

S S 

S S 

-NH 3 + 

Light chain 

SS SS 

SS SS 

Pyroglutamate formation 

Other modifications 

-NH 3 + N-terminal heterogeneity 

Amino acid modifications 

Deamidation, Oxidation, Glycation, 

Isomerization 

Fragmentation 

Cleavage in hinge region, Asp-Pro 

Oligosaccharides 

Fucosylation, Sialylation, Galactosylation,... 

Disulfide Bonds 

Free thiols, disulfide shuffling, thioether 

C-terminal heterogeneity 

Lysine processing, Proline amidation

Bioassays addressing multiple MoAs 

CDC 

complement 

dependent 

cytotoxicity 

C1 

Membrane 

attack 

complex 

Target cell 

FcγRIIIa 

Blocking/ Inhibiting RB 

Dimerization / Shedding / Internalization 

PCD 

Effector cell 

(NK cells) 

ADCC 


Antibody dependent 

cellular cytotoxicity 

Programmed cell death (apoptosis )

Factors Impacting Quality: Curse or Opportunity? 

� Host cell line & clone 

� Growth medium composition 

� Culture conditions (pH, T, aeration...) 

� USP type and regime (fed batch, perfusion...) 

�� Culture history (genetic stability, process stability...) 

� Individual DSP steps 

� Hold times & storage (formulation, container, conditions...) 

Cell line & process knowledge allows to 

• use diversity and variability to our advantage 

• design the desired quality into the product 

• “to ensure the desired quality, taking into account safety and efficacy” 


QbD Biosimilar Dev.: Managing Variability 

Glycoforms 

Charge Variants 

Biological activity 

Process rel. impurities 

Aggregates / Degradation 

Primary and higher order structure 

Target range 

Variability at project start 

Cell Line Development 

Bioprocess Development 

DSP Development 

DS/DP formulation 

Target range 

Target range 


Titer 

DSP Yield 

Scalability 

Consistency 

Raw Materials 

Growth Characteristics

Targeted cell line development: Drilling down! 

Cell lines 

Pools Pools Clones Clones Clones Selected 

Clone 

Hundreds Thousands Hundreds Tens One 

96/24/6 well plates Shake flask Lab-scale bioreactor 

Primary & higher order structure Glycoforms Charge Variants Aggregation / Degradation Process-rel. impurities Biological activity Titer 


Process Dev .

Quality Attribute [%] 

10 

Using diversity for targeted cell line development 

� Screening cell lines, pools and 

clones to meet quality target 

8 

6 

4 

2 

0 

Parental 

Cell Line 

Pools 

Screening of USP conditions 

Clones 

Cell Line X 

Pool A 

Clones 

Cell Line X 

Pool A 

Clones 

Cell Line X 

Pool B 

Final Clone 

Cell Line X 

Pool B 

Target 

≤ 2 % 

� Target defined as comparability 

range 

� Generate and use diversity 


� Choose the right stage to target a 

quality attribute: 

– Cell line 

– USP 

– DSP 

– Drug Product 

� Cell line, process and product 

understanding is key

Charge variant (%) 

80 

60 

40 

20 

0 

Targeting Quality Attributes by Upstream Process 

Development 

� Defined quality targets as guidance for process development 

� Charge-variants can be adjusted via USP 

– process parameters, e.g. pH 

– media components 

� Glycosylation can be adjusted via USP 

– media components 

Targeting a 

charge variant 

via pH in 

bioreactor 

Target 

Range 

Charge Variant (%) 

14 

12 

10 

8 

6 

4 

2 

0 

Targeting a charge 

variant via media 

components in bioreactor 

Target 

Range 

0,0 

0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 

7.2 7.0 6.8 

Media Component A 

Media Components 


Media Component B 

Targeting galactosylation 

via media components in 

bioreactor 

2,0 

1,5 

1,0 

0,5 

32,6 

43,8 

55,0 

66,2 

77,4 

Galactosylation

Fab 

Fc 

Using variability to identify CQAs 

Establishing structure- function relationships 

Afucosylated glycans as CQA 

Glycosylation impacts 

Effector functions 

- Complement interaction 

- Fc Receptor interaction 

- S - S - 

- S - S - 

� Minor glycan structure with high impact on in vitro potency 1 

� Established quantitative relationship between afucosylation 

and ADCC potency 

� Highly predictive model as ADCC = f(ManX,G0) 

1 Shields et al.(2002), Shinkawa et al. (2003), Kanda et al.(2007) 

HILIC glycan analysis 


C H2 C H3 

Heavy chain 

S S 

S S 

G0 

G0F 

Man5 

21 23 25 27 29 [min] 

ADCC potency actual vs predicted 

ADCC Actual [%] 

500 

450 

400 

350 

300 

250 

200 

150 

100 

ADCC = f(ManX,G0) 

RSq=0,99 RMSE=11,298 

(filled circles only) 

50 

50 100 150 200 250 300 350 400 450 500 

ADCC Predicted [%] P

QbD for Biosimilars and novel Biopharmaceuticals 

QTPP 

CQAs 

Risk Assessment 

CQA – CPP 

Design Space 

Process Knowledge 

Control Strategy 

Continual 

Improvement 

� QTPP is a key concept for targeted and prioritized development 

of biopharmaceutical, e.g. biosimilars 

� QTPP and CQAs are applicable to both biosimilars and novel 

biopharmaceutical 

� Quality targets for biosimilars can take advantage of originator 

quality ranges 

� No difference in the application of ICH Q8 QbD to biosimilars 

and novel biopharmaceuticals 

� Same standards and requirements for 

� Process development 

� Quality risk management 

� Design space 

� Control strategy 

� Product life cycle management and continual improvement 


Sandoz designs processes from the start to 

specifically ensure quality and consistency 

Proving biosimilarity with comparability 

to reference product at all stages 

Clinical 

Trials 

PK/PD 

Preclinical 

Biological 

characterization 



Process 


Analytics 


� Appropriate clinical trials to 

show safety / efficacy 

� Design manufacturing 

processes to ensure 

comparability 

� Science-based process 

development to deliver 

target quality 

� Characterization to prove that 

product is safe and efficacious

Final remarks! 

� Biosimilars are reality and will continue to gain ground in the future! 

– Today: dev. & manufacturing of Somatropin, EPO & G-CSF 

– The next steps: more complex proteins 

� Product quality of biopharmaceuticals can be targeted to biosimilarity 

through QbD cell line and process development. Managing DS 

variability is essential! 

� Quality: Biopharmaceuticals to be registered via the biosimilar pathway 

are developed and manufactured according to the same quality 

standards as originator products 

� Safety & Efficacy: guaranteed by comparability to the reference product 

by characterization of physico-chemical properties, biological activity, 

and pre-clinical & clinical studies 


Design Design Design specification 

specification 

specification 

Validation Validation Validation 

Clinical 

Trials 

PK/PD 

Preclinical 

Biological 




Process 


Analytics

Thanks for listening! 

Thanks for contributing! 

Mengeš, Schaftenau & Kundl, Oberhaching & Holzkirchen

Targeted development of biosimilar pharmaceutical products

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