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Comparative Study
. 2019 Aug;36(8):2106-2121.
doi: 10.1007/s12325-019-00988-5. Epub 2019 May 28.

Development of a Lyophilized Formulation of Pegaspargase and Comparability Versus Liquid Pegaspargase

Alexander M Faschinger  1 , Nicole Sessler  2
Affiliations
Comparative Study

Development of a Lyophilized Formulation of Pegaspargase and Comparability Versus Liquid Pegaspargase

Alexander M Faschinger et al. Adv Ther. 2019 Aug.

Abstract

Introduction: Pegaspargase, a pegylated asparaginase, is a core component in the treatment of acute lymphoblastic leukemia. Pegaspargase in liquid form has a limited shelf life of 8 months due to depegylation, leading to changes in purity and potency over time. Lyophilization is an approach that can improve the stability of biological drug conjugates.

Methods: Here we describe the development of a lyophilized formulation of pegaspargase and present results of a series of tests demonstrating that the lyophilized form has comparable physicochemical properties to the liquid form.

Results: Stability tests of critical quality attributes, including purity, potency, aggregates and total free polyethylene glycol, demonstrate that lyophilized pegaspargase remains stable for at least 3 years, with optimum stability achieved with storage under refrigerated conditions (2-8 °C).

Conclusions: Lyophilization improved the stability of pegaspargase without altering other physicochemical properties, permitting a prolonged shelf life of at least 2 years when stored at 2-8 °C. This may enable greater storage flexibility and allow for better management of pegaspargase.

Funding: Study Sponsor: Baxalta (now part of Takeda). Publication Sponsor: Servier Affaires Médicales.

Keywords: Cancer chemotherapy; Enzymes; Formulation; Lyophilization; Pediatric; Pegylation; Stability; Stabilization.

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Conflict of interest statement

Alexander Faschinger was an employee of Shire (now part of Takeda) at the time of the reported analyses and is currently an employee of Servier; Nicole Sessler is an employee of Baxalta Innovations Gmbh (now part of Takeda).

Figures

Fig. 1
Fig. 1
Development process for liquid and lyophilized pegaspargase. Black boxes represent core process steps; grey boxes show intermediate steps and tests; blue boxes highlight different pegaspargase concentrations in drug substance for liquid and lyophilized pegaspargase. a Free PEG, 10K PEG, NHS. b Dibasic and monobasic sodium phosphate and sodium chloride at half the concentrations of PBS used for production of bulk drug substance/liquid pegaspargase. NHS N-hydroxysuccinimide, PBS phosphate buffered saline, SS–PEG monomethoxypolyethylene glycol succinimidyl succinate
Fig. 2
Fig. 2
Heat stress profiles for liquid (Lot A) and lyophilized (Lot 1) pegaspargase: purity (a), potency (b), aggregates (c) and total free PEG (d) of/in liquid and lyophilized pegaspargase stored at 40 °C for 6 months. a Determined by GF-HPLC. b Determined by RP-HPLC. Results from a representative lot of liquid and lyophilized pegaspargase are presented. Each lot was tested once at each time point. Liquid and lyophilized lots were tested using validated methods. GF-HPLC gel filtration high-performance liquid chromatography, LSL lower specification limit, PEG polyethylene glycol, RP-HPLC reversed-phase high-performance liquid chromatography, USL upper specification limit
Fig. 3
Fig. 3
Stability of lyophilized pegaspargase stored at 5 °C and 25 °C (60% RH) over 45 months: trend analyses for purity (a), potency (b), aggregates (c) and residual water (d) substance for lyophilized pegaspargase. Lots stored in an inverted orientation. Results from a representative lot of liquid and lyophilized pegaspargase are presented. Each lot was tested once at each time point. Liquid and lyophilized lots were tested using validated methods. Acceptance criteria for purity (% active components) are lower at end of shelf life than on release; acceptance criteria for other quality attributes (aggregates, potency, residual water) are the same at release and end of shelf life. RH relative humidity
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References

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