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Lyophilization of Small-Molecule Injectables: an Industry Perspective on Formulation Development, Process Optimization, Scale-Up Challenges, and Drug Product Quality Attributes

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Abstract

Lyophilization is a pivotal manufacturing process to obtain a stable drug product that is unstable as a ready-to-use formulation. Some formulations may require the addition of drug-specific excipients such as stabilizers, buffers, and bulking agents to support the cake appearance and ensure long-term stability of the drug product. Optimization of the lyophilization process parameters at each stage including freezing and primary and secondary drying is important because these parameters can have a direct impact on the process efficiency (shortened cycle time) and product performance (cake appearance and homogeneous moisture content). Several parameters of the formulation, including properties of the active pharmaceutical ingredient, excipients, solvent system, and container closure, determine the success of lyophilization. Development, scale-up, and transfer of the lyophilization cycle are challenging; hence, a comprehensive understanding of the critical parameters related to the formulation, lyophilization process, and lyophilizer design allows designing a quality drug product. One approach for a successful transfer of the lyophilization cycle between the laboratory and commercial-scale lyophilizer is using vial heat transfer coefficient and ice slab test to establish a maximum sublimation rate. This review provides a general overview of the lyophilization process and discusses several key considerations and product development aspects of formulation, process optimization, container closure system, scale-up principles, and drug product quality attributes from the industrial viewpoint.

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Abbreviations

API:

active pharmaceutical ingredient

atm:

atmospheric pressure

TBA:

tertiary butyl alcohol

USP:

United States Pharmacopeia

Tg:

glass transition temperature

Tc:

collapse temperature

Teu:

eutectic temperature

CT:

critical temperature

FDM:

freeze-dry microscopy

mDSC:

modulated differential scanning calorimetry

mTorr:

millitorr

ST:

shelf temperature

CP:

chamber pressure

PRT:

pressure rise test

CCS:

container closure systems

EU:

European

WFI:

water for injection

ICH:

International Conference on Harmonization

EDTA:

ethylene diaminetetraacetic acid

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Acknowledgments

Arun Butreddy would like to thank Susmitha Kasina (Research Scientist, Pharmascience Inc., Montreal, Quebec, Canada) for her helpful comments and suggestions on this manuscript.

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Authors and Affiliations

  1. Formulation R&D, Biological E. Limited, IKP Knowledge Park, Shameerpet, Hyderabad, Telangana State, 500078, India

    Arun Butreddy & Rajendra Prasad Gaddam

  2. Nanotechnology and Novel Drug Delivery Laboratory, Department of Pharmaceutics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana State, 506009, India

    Narendar Dudhipala & Karthik Yadav Janga

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  1. Arun Butreddy
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  2. Narendar Dudhipala
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Conceptualization, Arun Butreddy; writing—original draft preparation, Arun Butreddy; writing—review and editing, Narendar Dudhipala and Karthik Yadav Janga; writing—review, editing, and supervision, Rajendra Prasad Gaddam.

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Correspondence to Rajendra Prasad Gaddam.

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Butreddy, A., Dudhipala, N., Janga, K.Y. et al. Lyophilization of Small-Molecule Injectables: an Industry Perspective on Formulation Development, Process Optimization, Scale-Up Challenges, and Drug Product Quality Attributes. AAPS PharmSciTech 21, 252 (2020). https://doi.org/10.1208/s12249-020-01787-w

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