Evolution and Evaluation of Ultra-Low Temperature Freezers: A Comprehensive Literature Review
Abstract
1. Introduction
2. History
2.1. History of Refrigeration
2.2. History of Refrigerants
3. Refrigerants
4. Importance and Application of ULT Freezers
4.1. Importance of ULT Freezers
4.2. Applications
5. Advanced ULT Freezer Technologies
5.1. Advantages and Challenges of ULT Freezers
5.2. Overview of ULT Freezers: Technologies, Configurations, and Energy Efficiency
5.3. Industrial Examples of Advanced ULT Freezer Technologies
6. Regulatory Compliance
7. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Group | Type | Attribute | Strengths | Weaknesses | Opportunities | Threats | References |
---|---|---|---|---|---|---|---|
Hydrofluorocarbons (HFCs) | R-134a | Tetrafluoroethane | Good energy efficiency, widely available | High GWP, climate impact | Transitional use in systems already reliant on HFCs | Global HFC phase-down, regulatory pressure | [58,66,67,68,69] |
R-404A | HFC-125, HFC-143a, and HFC-134a blend | Strong low-temperature performance | Very high GWP | Use in existing industrial setups | Obsolescence due to environmental regulations | [59,64,66,70,71,72] | |
R-407C | HFC-32, HFC-125, and HFC-134a blend | Replacement for R-22, lower GWP than R-22 | Still relatively high GWP | Retrofit applications | Market shift to lower-GWP alternatives | [59,66,73,74,75] | |
R-410A | HFC-32 and HFC-125 blend | High capacity, quiet operation | High GWP, facing phase-out | Short-term high-performance use | Regulatory bans and alternatives like HFOs | [59,76,77] | |
R-507A | HFC-125 and HFC-143a mixture | Stable performance at low temperatures | High GWP | Specialized industrial systems | Environmental and legislative pressure | [62,63,65,66] | |
Hydrocarbons | R-290 | Propane | Very low GWP, high efficiency | Flammable | Domestic/commercial systems with proper safety | Safety regulations in populated areas | [67,71,78,79,80,81,82,83] |
R-600a | Isobutane | Low GWP, good performance | Flammable | Home refrigeration, small systems | Public perception, installation restrictions | [67,77,80,81,83,84,85] | |
R-170 | Ethane | Extremely low GWP, high efficiency | Flammable, limited use | Niche cryogenic applications | Narrow market scope due to safety limits | [67,79,80,81] | |
Ammonia | R-717 | Ammonia | High efficiency, low cost, No GWP | Toxicity concerns | Large-scale refrigeration, food storage | Risk of leaks, regulatory burden | [80,86] |
Carbon Dioxide | R-744 | Carbon dioxide | Low GWP, non-toxic, non-flammable | High pressure requirements | Supermarkets, heat pumps, mobile A/C | Cost of high-pressure systems | [80,87,88,89,90] |
Hydrofluoroolefins (HFOs) | R-1234yf | 2,3,3,3-Tetrafluoropropene | Ultra-low GWP | Limited infrastructure, new tech | Automotive A/C, OEM adoption | Environmental uncertainty (e.g., TFA formation) | [80,91,92,93,94,95,96,97,98,99,100] |
R-1234ze | Dia-1,3,3,3-tetrafluoropropene | Ultra-low GWP | Infrastructure not yet mature | Stationary air conditioning | Uncertain long-term performance data | [80,94,95,96,97,98,99] | |
Natural Cooling Taps | R-600 | Butane | Low GWP, effective cooling | Flammable | Household refrigerators | Safety standards and market limitations | [42,67,77,80,81,83,84,85] |
Special Cooling Taps | R-401A | HFC-125, HFC-143a, and HCFC-22 blend | R-22 replacement | High GWP, transitional | Temporary retrofit use | Not sustainable long-term | [42,101,102] |
R-421A | Azeotropic mixture to replace R-22 | Lower GWP than R-22 | Limited market availability | Retrofit for older R-22 systems | Competing low-GWP solutions becoming standard | [42,75] | |
Inert Gas Refrigerant Taps | R-40 | Ethylene | Low GWP, non-toxic | Very limited applications | Experimental or niche systems | Minimal commercial demand | [103,104,105] |
Other Cooling Taps | R-12 | Dichlorodifluoromethane—has been withdrawn due to ozone depletion | Good low-temp performance | Ozone depletion, high GWP | Only in legacy systems | Banned, legally restricted | [106,107] |
R-22 | Chlorodifluoromethane—withdrawn due to HFC regulations | Good efficiency, historic widespread use | High GWP, phased out | Retrofitting with replacements | Global withdrawal under Montreal Protocol | [73,74,75] |
Category | Product Type | Storage Temperature | Examples | References |
---|---|---|---|---|
Pharmaceuticals | -Small molecular drugs | −80 °C to −20 °C | Acetaminophen, ibuprofen, aspirin | [1,32,111] |
-Organic (e.g., peptides) | −80 °C to −20 °C | Insulin, glucagon, vasopressin | [1,32,111] | |
Large Molecular/Biological | -Monoclonal antibodies | −80 °C to −20 °C | Adalimumab (Humira), trastuzumab (Herceptin) | [113,125,126] |
-Recombinant proteins | −80 °C to −20 °C | Recombinant human growth hormone (rhGH), erythropoietin | [112,113,114,125] | |
-Therapeutic proteins | −80 °C | Interferon-beta, tissue plasminogen activator (tPA) | [112,113,114,125] | |
-Enzymes | −80 °C to −20 °C | DNA polymerase, reverse transcriptase, trypsin | [12,35,41,48] | |
-Viruses | −80 °C or −196 °C | Adenovirus vectors, influenza virus stocks, lentivirus | [10,64] | |
-Antibodies against RNA lines | −80 °C to −20 °C | Anti-miRNA antibodies, anti-snoRNA antibodies | [44,122,131] | |
Biological Samples | -DNA/RNA | −196 °C to −80 °C | Genomic DNA from blood, total RNA from tissues | [144,145,146] |
-Proteins | −80 °C to −20 °C | Purified histones, protein lysates from cells | [64] | |
Vaccines | -mRNA vaccines | −80 °C to −60 °C | Pfizer-BioNTech (BNT162b2), Moderna COVID-19 vaccine | [34,119,132] |
Blood Products | -Blood | −80 °C or cooling (<4 °C) | Whole blood units, red blood cell concentrates | [2,133,134,135,136,137] |
-Platelets | 4 °C for short-term storage; −80 °C for long-term storage | Apheresis platelets, pooled platelet concentrates | [2,133,134,135,136,137] | |
Cell Culture | -Cell lines | −196 °C to −80 °C | HEK293, CHO cells, HeLa cells | [126,138,139,140] |
-Fetal/stem cells | −196 °C to −80 °C | Human embryonic stem cells, mesenchymal stem cells | [126,138,139,140] | |
Tissue Samples | -Fresh frozen samples | −196 °C to −80 °C | Frozen liver biopsy, tumor tissue slices | [142,143] |
-Paraffin (formalin) samples | −80 °C to −20 °C (for long-term storage) | FFPE tumor sections, preserved kidney samples | [142,143] | |
Genetic Material | -DNA plasmid | −80 °C | Plasmids used for gene expression, cloning vectors | [144,145,146] |
-Oligodynamic | −80 °C to −20 °C | siRNA oligos, antisense oligonucleotides | [144,145,146] | |
Research Samples | -Environment samples | −80 °C | Air particulate filters, contaminated soil extracts | [147,148,149] |
-Clinical samples | −80 °C | Nasopharyngeal swabs, serum from patients | [147,148,149] | |
-Experimental observations | −196 °C to −80 °C | Cryopreserved test specimens, bioassay controls | [147,148,149] | |
Food (Perishables) | -Frozen fruits and vegetables | −40 °C to −20 °C (for long-term storage; in ultra-low freezers) | Frozen strawberries, green beans, corn | [12,35,41,48] |
-Meat and seafood (frozen) | −30 °C to −18 °C | Frozen beef cuts, salmon fillets | [12,35,41,48] | |
-Dairy products (frozen) | −30 °C to −20 °C | Frozen cheese, ice cream, butter blocks | [12,35,41,48] | |
-Ready-to-eat frozen meals | −30 °C to −18 °C | Frozen lasagna, chicken stir-fry packs | [12,35,41,48] |
Category | Type | Specifications | References |
---|---|---|---|
1. Based on Cooling Technology | Cascade Refrigeration System (Traditional) | Most common ULT freezer technology. Uses two hermetically sealed compressors and refrigerants in a cascade cycle. Can reach temperatures of –80 °C to –86 °C. Pros: Proven, reliable. Cons: Higher energy use, more moving parts. Energy Consumption: 16–25 kWh/day. Examples: Thermo Fisher TSX, PHCbi MDF series, Haier DW-86 series. | [11,17,18,79] |
Stirling Engine (Free-Piston) | Uses a free-piston Stirling engine with no oil or traditional compressor. Environmentally friendly (helium gas as the working fluid). Ideal for energy efficiency and low maintenance. Energy Consumption: 6–9 kWh/day. Examples: Stirling Ultracold SU780XLE. | [164] | |
2. Based on Compressor Configuration | Single Compressor | Not typical for –86 °C but used in –40 °C to –60 °C units. Simpler and cheaper design, often used for transport or backup. Energy Consumption: 5–10 kWh/day. | [83,98] |
Dual Compressor (Cascade) | Two-stage cascade system, standard for most –80 °C to –86 °C ULT freezers. Reliable performance with moderate energy consumption. Energy Consumption: 16–25 kWh/day. | [83,98,132] | |
Multi-Stage or Multi-Compressor | More than two compressors, often used for large-capacity units or those requiring redundancy. Provides increased cooling power and failsafe operation. Energy Consumption: 20–30+ kWh/day. | [165] | |
3. Based on Form Factor | Upright ULT Freezers | Most common in labs. Easy access with adjustable shelves or racks. Capacity typically ranges from 300–800+ liters. Energy Consumption: 16–25 kWh/day. Examples: Thermo TSX Series, PHCbi MDF-DU702VH. | [4,8,83,98] |
Chest ULT Freezers | Top-opening design offers better insulation and temperature stability. Generally more energy-efficient than upright models. Capacity: 300–900 L. Energy Consumption: 12–18 kWh/day. Examples: So-Low U85-25, Stirling SU105UE. | [164] | |
Under-Counter ULT Freezers | Compact and space-saving, often used in clinical or point-of-care labs. Capacity: 100–200 L. Energy Consumption: 6–10 kWh/day. Examples: PHCbi MDF-U33, Thermo Fisher TSX Series Compact. | [8] | |
Portable/Mobile ULT Freezers | Designed for safe transport of biological samples at ultra-low temperatures. May be battery-powered, compressor-driven, or use dry ice. Energy Consumption: 2–6 kWh/day. Examples: Stirling Ultracold ULT25NEU. | [164] | |
4. Based on Application or Special Features | Energy-Efficient or Green ULT Freezers | Use hydrocarbon refrigerants (e.g., R-170, R-290) with low global warming potential (GWP). ENERGY STAR® certified, optimized for low power consumption. Energy Consumption: 6–14 kWh/day. Examples: PHCbi VIP ECO Series, Thermo TSX Series. | [51,56,98] |
ULT Freezers with Redundant Compressor Systems | High-reliability systems featuring backup compressors or modular components for critical storage applications such as biobanking or clinical trials. Energy Consumption: 20–30+ kWh/day. Examples: Custom or pharma-grade configurations. | [165] |
Features | Hermetic Compressor | Free-Piston Engine | Multi-Compressors |
---|---|---|---|
References | [156,164,165,166] | [156,164,165,166] | [156,164,165,166] |
Capacity | 706 L | 780 L | 59,720 L |
Temperature Range | −85 °C to −40 °C | −86 °C to −20 °C | −60 °C to 0 °C |
Construction Material | AISI 304 stainless steel | Blank insulation panels | Special design with two systems |
Cooling Technology | Hermetic compressors | Free-piston Stirling | Dual cooling system |
Energy Consumption | Energy saving strategies | ~6.67 kWh/d, up to 40% less energy | Requires maintenance for stable operation |
Connectivity | USB, SIM, Wi-Fi, Ethernet | Remote monitoring | Limited options |
Temperature Stability | Superior thermal performance | ±1 °C | Constant temperature control |
Operating Safety | Safety thermostats | Lock and PIN for access | Diagnostics and warnings |
Maintenance Procedures | Regular programs necessary | Maintenance with GUI and automated monitoring | Regular maintenance and checks with automated diagnostics |
Useful Life | 10–12 years | 12 years | 10–12 years |
Refrigerant Safety | HCFC or CFC-free R-170 and R-1270 | Uses R-170 (Ethane), eco-friendly | Uses HFCs, requires caution due to flammability |
Operating Noise | Noise during operation | <48 dB(A) | Noise during operation |
Environmental Policy | Eco-friendly refrigerants | Uses natural refrigerants | Low ozone depletion potential |
Resistance to Temperature Fluctuations | High | High | High via dual compressors |
Reliability Price | High reliability | Variable operation with minimal maintenance | Excellent due to redundancy |
Measurement | 1990 × 1060 × 1000 mm | 1994 × 870 × 915 mm | 10,945 × 2154 × 2896 mm |
Source | Title of the Regulation | Article | References |
---|---|---|---|
EU | Eudralex; Volume 4 GMP Guidelines | Volume 4 | [170] |
Good Distribution Practice of Active Substances for Medicinal Products for Human Use (2015/C 95/01) | 2015/C 95/01 | [171] | |
Directive 2000/54/EC Protection of Workers from Risks Related to Exposure to Biologic Agents at Work | 2000/54/EC Annex V and VI | [172] | |
Directive 2009/41/EC on the Contained Use of Genetically modified Micro-organisms | 2009/41/EC | [173] | |
European Medicines Agency Scientific Guidance Documents on Biological Drug Substances | N/A | [174] | |
US FDA | Title 21 Code of Federal Regulations, Electronic Records, and Electronic Signatures | Part 11 | [175] |
Title 21 Current Good Manufacturing Practice In Manufacturing, Processing, Packing, Or Holding Of Drugs; General | Part 210 | [176] | |
Title 21 Code of Federal Regulations, Current Good Manufacturing Practice for Finished Pharmaceuticals | Part 211 | [176] | |
ASME | Bioprocessing Equipment | ASME BPE-2014 | [159] |
PIC/S | Guide to Good Manufacturing Practice for Medicinal Products, Part I | PE-009-9 | [159] |
Guide to Good Manufacturing Practice for Medicinal Products, Part II | PE-009-11 | [159] | |
ISPE | Baseline Guide: Biopharmaceuticals | Volume 6, 2nd | [21,22] |
Baseline Guide: Commissioning and Qualification | Volume 5, 2nd | [21,22] | |
Good Practice Guide—Cold Chain Management | 2011 | [21,22] | |
Good Practice Guide—Controlled Temperature Chamber Mapping and Monitoring | 2016 | [21,22] |
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Kypraiou, C.; Varzakas, T. Evolution and Evaluation of Ultra-Low Temperature Freezers: A Comprehensive Literature Review. Foods 2025, 14, 2298. https://doi.org/10.3390/foods14132298
Kypraiou C, Varzakas T. Evolution and Evaluation of Ultra-Low Temperature Freezers: A Comprehensive Literature Review. Foods. 2025; 14(13):2298. https://doi.org/10.3390/foods14132298
Chicago/Turabian StyleKypraiou, Christos, and Theodoros Varzakas. 2025. "Evolution and Evaluation of Ultra-Low Temperature Freezers: A Comprehensive Literature Review" Foods 14, no. 13: 2298. https://doi.org/10.3390/foods14132298
APA StyleKypraiou, C., & Varzakas, T. (2025). Evolution and Evaluation of Ultra-Low Temperature Freezers: A Comprehensive Literature Review. Foods, 14(13), 2298. https://doi.org/10.3390/foods14132298