181115 poster pegs18 advanced formulation allianz v3 wtl · molecule design host cell selection...
TRANSCRIPT
Moleculedesign
Host cellselection
Upstreamprocess
Downstreamprocess
Formulation Fill &Finish
Storage
§ Sequence
§ Hydrophobicity
§ Proteases
§ Oxidative stress
§ Media
components
§ Posttranslational
modifications
§ Stirring
§ Temperature
§ Trace metals
§ pH
§ Air/liquid interface
§ Osmolality
§ Pressure
§ Shear forces
§ Mixing
§ pH
§ Air/liquid interface
§ Light
§ Shear forces
§ Excipients
§ Oxidation
§ Light
§ Agitation
§ Shear forces
§ Excipients
§ Oxidation
§ Freeze-thaw
§ Light
§ Temperature
§ Freeze-thaw
§ Shear forces
Advanced Formulations of Biopharmaceuticals
INTRODUCTION: In the past, the role of customized and tailored formulations during the development of biopharmaceuticals has been largely underestimated.
An advanced formulation strategy can significantly protect and stabilize the molecular integrity of the biomolecule and thus strongly improve the product quality,
leading to significant benefits for patients, physicians and pharma alike. The rapidly growing and increasingly competitive biopharmaceutical market requires on the
one hand individual solutions, particularly for higher product stability and a prolonged shelf life. On the other hand, there is a continuous pressure to reduce
development timelines and thus the time to clinic, which favors intelligent platform approaches. Since changes in the formulation after phase II clinical trial may
require additional clinical and toxicological studies, an early integration of all drug product-generating steps is aimed to avoid additional costs and a delayed market
entry. Here we show how a commercially attractive, individualized formulation based on the amino acid-driven Stabilizing and Protecting Solutions (SPS®) technology
platform can be generated without extending the timelines to the first clinical trials by using a highly integrated development process.
Missed opportunities in formulation development
Cosentyx® (secukinumab) Taltz® (ixekizumab) Siliq® (brodalumab)Novartis (1
st to market) Eli Lilly (2nd to market) Valeant (3
rd to market)
Shelf life, storage and handling
18 months shelf life,
refrigerated at 2–8 °C
24 months shelf life,
refrigerated at 2–8 °C;
In EU Taltz® may be stored
unrefrigerated for up to
5 days at ≤ 30 °C
24 months shelf life, refrigerated at
2–8 °C;
In US Siliq® may be stored
unrefrigerated for up to
14 days at room temperature ≤ 25 °C
§ Short development processes
§ Meeting specific needs, e.g.
§ Storage at elevated temperature
§ High concentration
§ Liquid formulation
§ Shortened re-suspension of lyoproducts
§ Reduction of viscosity and better stability
§ Providing freedom to operate
§ Extra patent protection
Formulation stability impacts costs in many ways
SPS®-based stabilization leads to less aggregates
The SPS® Formulation Technology Platform
SPS® improves high concentrated antibody formulations
The SPS® Formulation Rational Design Approach
CONCLUSION: The higher product quality achieved by the SPS® technology built in gene-to-vial
processes and manufacturing supports the customer to accomplish a significant
competitiveness in the market without compromising the development timelines.
FROM GENE-TO-VIAL PROCESSING
Jadranka Koehn2; Jens Altrichter1; Birgit Schwab2; Konstantin Petropoulos1; Sabine Hauck1
1LEUKOCARE AG, Am Klopferspitz 19, 82512 Martinsried, Germany, [email protected] Biopharma SE, Erwin-Rentschler-Str. 21, 88471 Laupheim, Germany, [email protected]
§ Excipients listed in pharmacopoeias (USP, EP, JP)
§ Many excipients also listed as inactive ingredient by FDA
§ Excipients easily sourceable
§ Formulations easily adaptable to specific target molecules and needs
§ Used for dry and liquid formulations
0
5
10
15
20
1 2
dyna
mic
visc
osity
[mPa
* s]
original formulation SPS®
Dynamic Viscosity of Trastuzumab (200 mg/mL) in Liquid Formulation
-40 %
1.89
0.230,0
0,5
1,0
1,5
2,0
aggr
egat
es [%
]
Aggregate Formation of Trastuzumab (200 mg/mL) in Liquid Formulation after 21 days at 30 °C
original formulation SPS®
§ SPS® database
§ Excipient library
§ Design matrix approach
SPS® IN GENE-TO-VIAL PROCESSING
Example: Advanced formulations for mAbs in psoriasis
Potential of advanced formulations
Method 1 Method 2
Excipient 2
Excip
ien
t 1
Excip
ien
t 3
Excipient 2
Excip
ien
t 1
Excip
ien
t 3
Method 3 Method 4
LC 1
804
Setup Acc. Aging Stability study
Tox
MCBClone stabilityCell line development
Analytical Development
MSR-FDDSP Development CR
Tox
MCBClone stabilityCell line developmentMSR CRUSP Confirmation
Analytical DevelopmentDSP Development CR
COMPARABLE TIMELINESTime to Tox based on USP platform without formulation development
Time to Tox based on USP platform with development of market-readyformulation
Formulation Development (FD) Tasks
General Development Task
MSR CRUSP Confirmation
(may be needed)
2018 Informa Survey: Project failure or delay because of formulation
challenges
Base: All respondents (n=105).
NO40%
YES60%
Have you ever experienced a project failure or a significant delay, because of formulation challenges?
38%52%
10%
Less than 12 months More than 12 months No delay, butproject/product
candidate completelystopped due to
formulation challengesBase: Respondents who experienced a project failure or delay (n=63).
How long was the project delayed because of the formulation challenges?
• Formulation issues led to project failure and significant delays for about 60% of responding companies
• Of those, a delay of more than 12 months was reported by 52%, 10% experienced complete failure
MCB, master cell bank preparation and release
MSR, material supply run; CR, consolidation run;
Tox, material supply for toxicology studies