Development of a multidose formulation for a humanized monoclonal antibody using experimental design techniques

Gupta, Supriya; Kaisheva, Elizabet

doi:10.1208/ps050208

Cited by 59 publications

(79 citation statements)

References 6 publications

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“…In previous studies, APs have been shown to induce protein aggregation over a period of days or months (Maa and Hsu 1996, Katakam and Banga 1997, Remmele Jr. et al 1998, Gupta and Kaisheva 2003, Tobler et al 2004, Roy et al 2006, Thirumangalathu et al 2006). In order to test the effects of different APs on protein aggregation on a convenient laboratory timescale, we accelerated aggregation kinetics by conducting isothermal incubation studies at an elevated temperature.…”

Section: Resultsmentioning

confidence: 98%

“…One of the earliest reports demonstrated that the addition of various aromatic compounds induced the aggregation of recombinant human growth hormone (Maa and Hsu 1996). Numerous studies have shown the ability of APs to cause destabilization and aggregation of many proteins (Gupta and Kaisheva 2003, Tobler et al 2004, Zhang et al 2004, Roy et al 2005). Aggregates in these formulations cause a decrease in the effective concentration of the delivered drug as well as result in immunogenic and toxic responses in patients (Ratner et al 1990, Bucciantini et al 2002, Hermeling et al 2006, Rosenberg 2006, Fradkin et al 2009, Sauerborn et al 2010, Vazquez-Rey and Lang 2011).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antimicrobial preservatives induce aggregation of interferon alpha-2a: The order in which preservatives induce protein aggregation is independent of the protein

Bis

Mallela

2014

International Journal of Pharmaceutics

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Antimicrobial preservatives (APs) are included in liquid multi-dose protein formulations to combat the growth of microbes and bacteria. These compounds have been shown to cause protein aggregation, which leads to serious immunogenic and toxic side-effects in patients. Our earlier work on a model protein cytochrome c (Cyt c) demonstrated that APs cause protein aggregation in a specific manner. The aim of this study is to validate the conclusions obtained from our model protein studies on a pharmaceutical protein. Interferon α-2a (IFNA2) is available as a therapeutic treatment for numerous immune-compromised disorders including leukemia and hepatitis c, and APs have been used in its multi-dose formulation. Similar to Cyt c, APs induced IFNA2 aggregation, demonstrated by the loss of soluble monomer and increase in solution turbidity. The extent of IFNA2 aggregation increased with the increase in AP concentration. IFNA2 aggregation also depended on the nature of AP, and followed the order m-cresol > phenol > benzyl alcohol > phenoxyethanol. This specific order exactly matched with that observed for the model protein Cyt c. These and previously published results on antibodies and other recombinant proteins suggest that the general mechanism by which APs induce protein aggregation may be independent of the protein.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Antimicrobial preservatives induce aggregation of interferon alpha-2a: The order in which preservatives induce protein aggregation is independent of the protein

Bis

Mallela

2014

International Journal of Pharmaceutics

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“…Compatibility depends both on the antibody and the preservative. In the evaluation of the effect of several preservatives, including benzyl alcohol, chlorobutanol, methylparaben, propylparaben, phenol, and m-cresol, on the stability of a humanized monoclonal antibody, Gupta and Kaisheva 94 found that the antibody was most stable in the presence of methylparaben and propylparaben, compatible with benzyl alcohol and chlorobutanol at low concentrations, and not compatible with phenol and m-cresol, as measured by a variety of assays, including SEC-HPLC, DSC, light scattering, UV, and potency assay.…”

Section: Effect Of Preservativesmentioning

confidence: 99%

Antibody Structure, Instability, and Formulation

Wang

Singh

Zeng

et al. 2007

Journal of Pharmaceutical Sciences

817

667

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“…Otherwise, it can be difficult to achieve desired preservative efficacy while maintaining protein stability. In some cases, preservatives have been successfully screened using a design of experiments approach [106]. Preservatives should only be considered if there is a need for a multiple-use vialed formulation, and other marketing options are not feasible.…”

Section: Preservativesmentioning

confidence: 99%

Development of Stable Lyophilized Protein Drug Products

Remmele¹,

Krishnan²,

Callahan³

2012

CPB

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Freeze drying, or lyophilization is widely used for biopharmaceuticals to improve the long term storage stability of labile molecules. This review examines general theory and practice of rational lyophilization of biopharmaceuticals. Formulation development involving the selection of appropriate excipients, their associated physical properties, and mechanism of action in achieving a stable drug product are primary considerations for a successful lyophilization program. There are several parameters considered critical on the basis of their relationship to lyophilization cycle development and protein product stability. This along with the importance of analytical methods to provide insight toward understanding properties of drug product stability and cake structure are discussed. Also, aspects of instability found in lyophilized biopharmaceutical products, their degradation pathways and control are elucidated. Finally, container-closure requirements and drug product handling are described in context of the caveats to avoid compromising drug product quality.

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Development of a multidose formulation for a humanized monoclonal antibody using experimental design techniques

Cited by 59 publications

References 6 publications

Antimicrobial preservatives induce aggregation of interferon alpha-2a: The order in which preservatives induce protein aggregation is independent of the protein

Antimicrobial preservatives induce aggregation of interferon alpha-2a: The order in which preservatives induce protein aggregation is independent of the protein

Antibody Structure, Instability, and Formulation

Development of Stable Lyophilized Protein Drug Products

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