End-to-End Approach to Surfactant Selection, Risk Mitigation, and Control Strategies for Protein-Based Therapeutics

Sreedhara, Alavattam; Buecheler, Jakob W.; Brosig, Sebastian; Chou, Danny K.; Christian, Twinkle R.; Das, Tapan K.; Jong, Isabella de; Fast, Jonas; Jagannathan, Bharat; Morales, Annette Medina; Moussa, Ehab M.; Nejadnik, M. Reza; Prajapati, Indira; Radwick, Allison; Rahman, Yusra; Singh, Shubhadra N.

doi:10.1208/s12248-022-00773-3

Cited by 2 publications

(5 citation statements)

References 115 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The range of model proteins employed increased throughout the screening process to test more accurately the best-performing surfactant candidates: P4 (mAb) was used in gate 1; P1 (partially disordered therapeutic protein), P2 (fab) and P3 (mAb) were used in gate 2; P1, P2, P3, P4, P5 (fusion protein); and P6 (mAb) were used in gate 3. Furthermore, to better replicate real-world conditions, this screening process was not only modeled after theoretical considerations but also included industry standard practices in surfactant selection …”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, to better replicate real-world conditions, this screening process was not only modeled after theoretical considerations but also included industry standard practices in surfactant selection. 34…”

Section: Identification Of Surfactant Candidates and Screening Strategymentioning

confidence: 99%

“…An agitation-induced aggregation assay was performed to mimic air−water interfacial stresses experienced by drugs during manufacturing, transportation, and administration, based on industry guidelines. 34 While multiple assays with variable parameters (i.e., primary package, shaking intensity, and time) should be performed to collect a statistically robust data set, this process would be unattainable for the number of surfactants investigated. Alternatively, we performed the same assay on three different proteins, P1, P2 and P3, in order to identify candidates retaining a stabilizing effect across multiple protein modalities.…”

Section: Screening Gate 2: Agitation-induced Aggregationmentioning

confidence: 99%

“…PS20 and PS80 possess good protein stabilization effect, − and their safety has been proven in several studies. − However, they are prone to chemical (auto-oxidation or hydrolysis) and enzymatic degradation, ,− leading to severe consequences such as loss of functions and particle formation, which may ultimately lead to product rejection or costly and lengthy root-cause investigations coupled to complicated control strategies. In addition, polysorbates are chemically heterogeneous mixtures, implying that the level of purity, process intermediates, and contaminants vary between manufactures and even lots. , While their degradation mechanisms have been extensively characterized in the last decade and their respective analytical methods have been improved and harmonized, , these procedures represent only control strategies and do not tackle the underlying issue.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, polysorbates are chemically heterogeneous mixtures, implying that the level of purity, process intermediates, and contaminants vary between manufactures and even lots. 31,32 While their degradation mechanisms have been extensively characterized in the last decade and their respective analytical methods have been improved and harmonized, 33,34 these procedures represent only control strategies and do not tackle the underlying issue.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Not the Usual Suspects: Alternative Surfactants for Biopharmaceuticals

Brosig,

Cucuzza,

Serno

et al. 2023

ACS Appl. Mater. Interfaces

Self Cite

View full text Add to dashboard Cite

Therapeutically relevant proteins naturally adsorb to interfaces, causing aggregation which in turn potentially leads to numerous adverse consequences such as loss of activity or unwanted immunogenic reactions. Surfactants are ubiquitously used in biotherapeutics drug development to oppose interfacial stress, yet, the choice of the surfactant is extremely limited: to date, only polysorbates (PS20/80) and poloxamer 188 are used in commercial products. However, both surfactant families suffer from severe degradation and impurities of the raw material, which frequently increases the risk of particle generation, chemical protein degradation, and potential adverse immune reactions. Herein, we assessed a total of 40 suitable alternative surfactant candidates and subsequently performed a selection through a three-gate screening process employing four protein modalities encompassing six different formulations. The screening is based on short-term agitation-induced aggregation studies coupled to particle analysis and surface tension characterization, followed by long-term quiescence stability studies connected to protein purity measurements and particle analysis. The study concludes by assessing the surfactant’s chemical and enzymatic degradation propensity. The candidates emerging from the screening are de novo α-tocopherol-derivatives named VEDG-2.2 and VEDS, produced ad hoc for this study. They display protein stabilization potential comparable or better than polysorbates together with an increased resistance to chemical and enzymatic degradation, thus representing valuable alternative surfactants for biotherapeutics.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Identification Of Surfactant Candidates and Screening Strategymentioning

confidence: 99%

Section: Screening Gate 2: Agitation-induced Aggregationmentioning

confidence: 99%