Cold Atmospheric Plasma in Pharmaceutical Sterilization and Formulation Engineering: Mechanistic Foundations and Translational Barriers

Background

Sterilization and surface modification are critical operations in pharmaceutical manufacturing, particularly for heat-sensitive formulations, biodegradable polymers, and advanced drug delivery systems. Conventional sterilization approaches such as moist heat, irradiation, and chemical sterilant, although effective, may induce thermal degradation, polymer instability, or toxic residue concerns. Cold atmospheric plasma (CAP), a non-thermal ionized gas technology, has emerged as a promising alternative capable of delivering controlled antimicrobial activity and surface functionalization under mild conditions.

Objective

This review critically examines the mechanistic basis, formulation engineering applications, and translational challenges of cold atmospheric plasma in pharmaceutical sterilization and surface modification. The aim is to evaluate CAP not only as an antimicrobial tool but as a scalable and regulatory-compatible pharmaceutical processing technology.

Methods

A comprehensive analytical synthesis of recent literature was conducted, focusing on mechanistic pathways of microbial inactivation, plasma–material interactions, polymer compatibility, sterility assurance considerations, and regulatory integration barriers. Emphasis was placed on studies relevant to pharmaceutical dosage forms, packaging systems, and biodegradable delivery platforms.

Results

Cold atmospheric plasma achieves microbial inactivation primarily through reactive oxygen and nitrogen species-mediated oxidative damage, affecting membranes, proteins, and nucleic acids without substantial thermal stress. In formulation engineering, CAP enables targeted surface functionalization, enhancing wettability, adhesion, and drug–carrier interactions while preserving bulk material properties. Despite these advantages, challenges remain in process reproducibility, parameter standardization, long-term stability assessment, and validation of sterility assurance levels under Good Manufacturing Practice frameworks.

Conclusion

Cold atmospheric plasma represents a multifunctional technology with significant potential in pharmaceutical sterilization and surface engineering. However, its industrial adoption requires rigorous mechanistic standardization, comprehensive toxicological evaluation, and regulatory harmonization. With continued technological refinement and validation, CAP may evolve into a sustainable and scalable component of next-generation pharmaceutical manufacturing.

Graphical Abstract