Praxair Lyophilization 01.10.10

Lyophilization (freeze-drying) isincreasingly used to gently sta-bilize pharmaceutical and bio-pharmaceutical products, and

intermediates.1–4 Its recent growth isbeing driven by the escalating globaldemand for aseptic packaging andpreservation of parenteral drugs, as wellas by the rise in the production of bio-logics, including protein-based thera-peutics and vaccines.2–4 According toindustry experts, the correspondingincrease in lyophilization capacity hasbeen fueling double-digit growth inglobal cGMP freeze-drying equipmentsales, which have reached approxi-mately $250 million per year. The globalinstalled base is estimated to be inexcess of 3,000 cGMP production units.

During lyophilization, most of thesolvent (e.g., water or alcohol) is

removed from a product after it isfrozen and placed under vacuum. Theprocess actually consists of three separate, but interdependent steps: 1)freezing, 2) primary drying (ice subli-mation), and 3) secondary drying(moisture desorption). During primarydrying, more than 90% of the solventchanges directly from solid to vaporphase through sublimation. The resid-ual solvent remains adsorbed on theproduct as moisture. Some of thisremaining solvent is desorbed duringsecondary drying to attain a moisturelevel too low to permit biologicalgrowth or chemical reactions, while stillpreserving the activity and integrity ofthe freeze-dried product.3,5

Key advantages driving the growthof lyophilization as a preferred fill-and-finish step include the enhanced

54 BioPharm International www.biopharminternational.com November 2007

Increasing LyophilizationProductivity,Flexibility,and

Reliability Using LiquidNitrogen Refrigeration

ABSTRACT Because lyophilization dries a product from the frozen state under temperaturecontrolled conditions, the refrigeration system’s process capabilities and performanceare critical to a successful commercial lyophilization operation. Part 1 of this articleoutlines recent trends in pharmaceutical manufacturing and their impact on theevolution of refrigeration technology in lyophilization. It also explains the advantagesand disadvantages of choosing a refrigeration system that uses liquid nitrogen insteadof mechanical compressors, and its affect on the overall operation. Part 2 of thisarticle, to be published in the December 2007 issue of BioPharm International, willdetail design and performance considerations for cryogenic nitrogen refrigeration in afreeze-dryer. The relative cost affect of choosing a cryogenic versus a mechanicalrefrigeration system will also be discussed as related to the lyophilization process.

Balazs Hunek, PhD, is a senior manager oftechnology, 630.320.4242,

[email protected], Alan Cheng,PhD, is a senior development associate, R&D,

and John Capettini is a manager of globalapplications market development,

all at Praxair, Inc.

Part 1Balazs Hunek, Alan Cheng, John Capettini

Vendor Notes Lyophilization

stability of freeze-dried powder, the abilityto remove solvent with minimal heatingand concentration effects, the relative easeof aseptically processing a liquid in a freeze-dryer, and rapid and easy dissolution of theproduct upon reconstitution. All theseadvantages facilitate minimizing the time tomarket of a novel therapeutic agent, estab-lishing an early marketing lead, and collect-ing increased revenues. Disadvantages ofthis method include increased handling andprocessing time, the need for a sterile dilu-ent upon reconstitution, and the cost andcomplexity of related equipment, includingits operation and maintenance.1,3,5,6

REFRIGERATION TRENDS IN FREEZE-DRYERSDuring lyophilization, the product is firstfrozen, then dried from this frozen stateunder precise temperature- and pressure-con-

trolled conditions. The refrigeration system’sprocess capabilities, flexibility, reliability,and performance are all critical to a success-ful commercial lyophilization operation.Historically, most freeze-dryers have usedmechanical refrigeration. Even thoughapproximately 80% of lyophilizer serviceproblems arise in the mechanical refrigera-tion system,7 these compressor-based unitshave accounted for 90–95% of freeze-dryerinstallations.

However, since the early 1990s, cryogeni-cally refrigerated freeze-dryers have beenclaiming an increasing market share.7–11

These reliable, flexible, and well-proven sys-tems use liquid nitrogen (LN2) or coldgaseous nitrogen (GN2) to cool the compo-nents of the freeze-dryer.

In recent years, both the efficiency andflexibility of cryogenic refrigeration systems



Key Components of a Lyophilizer

Atypical lyophilizer, or freeze-dryer, has nine main compo-nents plus auxiliary systems to carry out the lyophiliza-

tion cycle:1. A vacuum chamber contains the shelves and the

formulation to be lyophilized.2. Hollow shelves hold the formulation and control its

temperature.3. Heat transfer fluid circulates inside the hollow

shelves to precisely communicate cooling or heatingthrough the shelves to the product.

4. Product to be lyophilized is specially formulatedand typically contains the active ingredient, asolvent system, and several stabilization agents.Lyophilization of this formulation takes place inspecialized containers on the shelves. These con-tainers may be vials with stoppers, ampules,syringes, or—in the case of bulk lyophilization—pans.

5. A condenser removes the sublimated and desorbedsolvent from the vapor phase by condensing orfreezing it to maintain adequate vacuum inside thefreeze-dryer.The condenser can be internally locatedin the chamber, or may be a separate external unitcommunicating with the chamber through an isola-tion valve. Most production freeze-dryers haveexternal condensers.The capacity of a condenser isgiven in kilograms or liters of ice that it can holdfrozen on its cooled surface.

6. The mechanical or cryogenic refrigeration system

provides refrigeration to the shelves and condenser(and sometimes the walls) of the freeze-dryer bycooling the heat transfer fluid or directly expanding arefrigerant in the space to be cooled.

7. A heater (typically electric) provides heat to the HTFto slowly sublimate the ice and desorb solvent fromthe frozen cake on the shelves.

8. The vacuum pump pulls vacuum in the chamber andcondenser.

9. Control hardware and software systems directvarious parts of the complex freeze-drying equipmentand carry out the preprogrammed lyophilizationcycle.The controller may also provide documentation,data logging, and security capabilities.

In addition, auxiliary systems provide capabilities including :• cleaning and sterilizing the lyophilizer, e.g., steam-

in-place (SIP) or clean-in-place (CIP)• stoppering vials• auto-load and unload• supplying extra or significant backup power,

cooling water, and lubrication for the mechanicalrefrigeration system (cryogenic systems do notneed these)

• supplying liquid nitrogen (LN2) to a cryogenicsystem, which includes an insulated LN2 tank andpiping to the refrigeration skid (mechanicalsystems do not need these).

All these systems must work together seamlessly to ensuredesired end-product quality.


for freeze-drying have further increased, andtheir cost of ownership has decreased.8–11

With these improvements, LN2/GN2 systemsare ready for mainstream processes. In thisarticle and the subsequent cryogeniclyophilization article, we outline key consid-erations to help users make informed deci-sions about what type of refrigeration is bestfor a particular lyophilization situation.

REFRIGERATION REQUIREMENTS IN LYOPHILIZATIONThere are two key considerations in provid-ing refrigeration to a process: 1) the refrig-eration temperature required, and 2) themaximum cooling power required. First, therefrigeration temperature required by theprocess determines the type of refrigerationsystem needed. Commercially availablerefrigeration technologies have differentfundamental thermodynamic limitations interms of operating temperature, coolingrate capability, efficiency, and coolingpower. Second, the peak and turn-downcapacities of the chosen type of system aredetermined by the refrigeration load profileover time.

Lyophilization is a unique process from arefrigeration point of view, not only forrequiring ultralow-temperature refrigeration(below –50 ºC),12 but also because the load is

extremely variable, often requiring a systemturn-down in excess of 10:1.7 Both these keyrequirements favor cryogenic refrigerationover mechanical systems.

Chamber shelves (and sometimes walls)need to be cooled down to between –40 ºCto –60 ºC. The actual target temperaturemay vary from product to product, but itmust always be set below the eutectic tem-perature of the solution to be lyophilized.The eutectic temperature is the lowest valueat which a mixture of materials will melt.Meanwhile, the lowest temperature in thecondenser typically needs to be between –60ºC and –80 ºC, and sometimes as low as–100 ºC, to make sure the solvent condensesout at a rate that will maintain an appropri-ate vacuum in the chamber. These tempera-tures depart from the comfortable realm of“industrial refrigeration,” defined as refriger-ation from –35 ºC to –50 ºC.12 Thus, therequirements of lyophilization mainly residein the “ultra low-temperature refrigeration”space, defined as –50 ºC to –100 ºC.12 Theefficiency and reliability of mechanical sys-tems deteriorates as refrigeration tempera-ture drops. Cryogenic systems, in contrast,provide practically constant cooling powerthroughout the temperature ranges of anylyophilization cycle.

Depending on the effectiveness of thecondenser, the condenser surface is kept ata temperature approximately 10–20 ºClower than the shelves, i.e., –50 to –80 ºCduring drying. It is critical to ensure thatthe temperature of the accumulating iceremains cold enough to condense out thesolvent vapors. If not, the vacuum in thechamber can be lost, leading to loss ofprocess control and possible destruction ofvaluable product. Meltdown of the cakeoccurs when the temperature of the productrises faster than the removal of the mois-ture or solvent. In addition, vacuum pumpseal fluids may become contaminated bythe solvent coming in through the con-denser. Vacuum levels are typically con-trolled by adding refrigeration to thecondenser, thus causing further condensa-tion of the solvent vapors. Some expertstherefore, view the condenser as a vacuumpump operated by refrigeration. Reliableand flexible cooling of the condenser is alsocrucial to lyophilization.


Figure 1. Typical shelf cool-down capability of large commercial freeze-dryers with >20 m2 shelf-space. Note the inferior performance ofmechanical versus cryogenic liquid nitrogen refrigeration systems in termsof cool-down rate, cooling rate sustainability, and lowest temperature.

-80

-70

-60

-50

-40

-30

-20

-10

0

10

0 20 40 60 80 100 120 140 160

Tem

pera

ture

[ºC]

Mechanical (Liu et al.)

LN2 (Liu et al.)

LN2 (Praxair 100m 2̂)

Cool-down time [min]

Refrigeration Temperature and Cool-down Rate Operating temperatures below –50 ºC nega-tively affect the performance, efficiency, andreliability of mechanical systems. However,such operating temperatures have no impacton cryogenic systems driven by liquid nitro-gen (which has a normal boiling point of–195.8 ºC). The cooling rate and efficiencyof a mechanical compressor-based systemstarts to deteriorate below –20 ºC.7,8 Figure 1shows the typical shelf cool-down of largecommercial freeze-dryers equipped withmechanical compressors versus cryogenicheat exchangers. Cryogenic systems arecapable of providing a rapid, constant cool-down rate throughout the entire ultralowtemperature range. Mechanical refrigerationsystems, on the other hand, cannot main-tain their initial cool-down rate. This isprobably the reason why original equipmentmanufacturers (OEMs) of freeze-dryers rely-ing on mechanical compression equipmenttypically specify the cool-down rate in termsof overall time to reach a certain tempera-ture. Citing an average rate can mask a dete-riorating cooling rate over time. Onlycryogenic systems can maintain cool-downrates of 1 ºC per minute or higher over theentire temperature range of a lyophilizationcycle.

Figure 1 also shows that LN2 systems canreach –55 to –70 ºC setpoint for the heat trans-fer fluid (HTF) inlet temperature to the shelvesone to two hours faster than comparablemechanical units reaching a –50 ºC setpoint. Ifthe lyophilization cycle requires rapid cooling,this means increased productivity in terms ofcycle time reduction. The manufacturers ofsensitive products, such as vaccines, attainproduct viability benefits from rapid cooling.In addition, LN2/GN2 systems can easily go toeven lower temperatures if required. Theirlowest operating temperature is limited by thecharacteristics of the HTF, not those of therefrigeration system.

In summary, LN2 systems offer a widerprocessing window of operation leading toadded flexibility and productivity benefits.They do not suffer from the fundamentalthermodynamic limitations of mechanicalrefrigeration systems, such as deteriorationof efficiency and cool down rate, or limitson operating temperatures.

Refrigeration Load ProfileLyophilization has special demands due to theextreme variability of the refrigeration loadrequirements. There are two main cooling cir-cuits in a freeze-dryer: one for the shelves andanother for the condenser. The shelf coolingcircuit needs high-peak refrigeration power forthe relatively short time (two to three hours)required to cool down the freeze-dryer and itscontents, and to freeze the entire batch. Thispeak load on the shelf circuit is followed by arelatively longer period (one to three days)requiring significantly lower refrigerationpower for the condenser circuit, but at a lowertemperature. This load serves mainly to con-dense out the ice, which is slowly sublimatingand desorbing from the product during pri-mary and secondary drying. The correspon-ding refrigeration power required to run thecondenser circuit is typically an order of mag-nitude lower than that required by the shelvesfor initial cool down and freezing.

This type of highly variable refrigeration attemperatures between –40 ºC and –80 ºC isbest served by cryogenic refrigeration.LN2/GN2 systems are much more flexible inthis temperature range, and are capable ofefficient turn-down. Mechanical refrigerationsystems are better suited to meeting steadydemands. Compressors are ill-suited for shortduration peak loads followed by extendedoperation at low load and ultralow tempera-tures. Under such conditions, compressorsrun inefficiently, using a lot of power whileproviding minimal cooling. They aredesigned to meet the short period peak load,yet are operated under suboptimal efficiencyconditions for most of the lyophilizationcycle time. Cryogenic systems, on the otherhand, easily meet the variable refrigerationdemands of lyophilization. Unlike mechani-cal systems, cryogenic systems operate withonly small changes in thermal efficiency dur-ing the entire process cycle.

Running Hed

BioPharm International www.biopharminternational.com November 2007 59

Vendor NotesLyophilization

Highly variable refrigeration at temperatures between

–40 ºC and –80 ºC is best served by cryogenic refrigeration.


REFRIGERATION SYSTEMS USED IN FREEZE-DRYERSAll lyophilization refrigeration systems fea-ture an HTF loop, which is the passive com-ponent from a refrigeration point of view.The HTF loop includes the fluid, piping, andpumping system with controls. The main dif-ferences between refrigeration systems are in1) the active component(s) that drive the sys-tem, and 2) the necessary auxiliary systems.The active refrigeration system cools the lowtemperature HTF, which in turn refrigeratesthe shelves. Typically, a separate active circuitneeds to provide the cooling for the con-denser by direct expansion of a refrigerant,except in some advanced designs.

Low Temperature HTFThe thermophysical properties of the HTF cir-culating in the freeze-dryer have a significantimpact on the unit’s performance. Many of

these properties are highly temperature-dependent. For example, the viscosity of theHTF can significantly increase as the tempera-ture declines and approaches first the HTFpour point and then the freezing point.Although high pump-around rates ensure lowtemperature differences between the shelfinlet and outlet temperatures of the HTF, theymay also lead to significant frictional parasiticheat generation. Hence, care must be taken inchoosing the proper HTF. Table 1 summarizeskey properties of some popular HTFs.

Mechanical Refrigeration SystemsIn mechanical systems, compressors driven bysignificant electric power provide the activecooling. In general, ultralow-temperaturemechanical systems that match the refrigera-tion demand at the necessary operating tem-peratures are increasingly complex and lessflexible. They involve multistage or multire-frigerant cascade compression systems.12 Thecomplex refrigeration package includes com-pressors, heat exchangers, expansion devices,evaporators, and extensive controls. Necessaryauxiliary systems include a cooling waterloop, oil lubrication system, and an extrapower infrastructure (including an extra sup-ply and backup system) to support the signifi-cant power draw of the compressors. Therotating compression equipment involvedcan be screw or reciprocating types, with atrend towards costlier screw compressors


Table 1. Overview of the properties of some low-temperature heat transfer fluids (HTFs)12,13

Heat transfer fluid

Density[kg/m3] @

–80 ºC Viscosity at –80 ºC

[mPa(s)] Flash point [ºC]Reported freezing

point [ºC]Boiling point

[ºC]

Temperature at which kinematic

viscosity >10 cSt [ºC]

d-Limonene 43 –96 176 –80

Dynalene HF 870 60 >60 <–112 186

Dynalene MV >920 10 53 –118 176–179

Ethanol 810 6.3 @ –50 ºC 12 –117 78 –60

Novec HFE 7000 1700 Not flammable –122 34 <–110

Novec HFE 7100 1720 Not flammable –135 61 <–95

Hydroflouroether Not flammable –130 60 –30

Methanol 867 6.1 12 –98 65 –90

Polydimethylsiloxane 965 @ 25 ºC >110 –50 <200

Syltherm XLT 968 33.7 42 –111

The thermophysical properties of the

heat transfer fluid circulating in the

freeze-dryer have a significant impact

on the unit’s performance.

The above data are derived from manufacturers’ websites, MSDS publications, and public sources.

because of their better reliabil-ity.7,10,12 The cooling duty is pro-vided by appropriately chosenrefrigerants, such as R-23, R-404a,R-507, and R-508b (an azeotropicmixture of R-23 and R-116).12 Therefrigerants are first vapor com-pressed, condensed, adiabaticallyexpanded, and evaporated 1) in aheat exchanger to cool the HTF,and 2) directly in the condenser tofreeze out the solvent ice. Theserefrigerants are typically single ormultiple component mixtures ofhydrofluorocarbons (HFCs), whichare often toxic or flammable.

Cryogenic Refrigeration SystemsCryogenic cooling systems recoverthe stored cold from liquid nitrogenin specially engineered cryogenicheat exchangers. The necessary aux-iliary systems include a liquid nitro-gen storage tank, a set of cryogenicvalves, and piping from the tank tothe refrigeration skid. All of thesecomponents are highly insulated tominimize cryogen losses, e.g., byvacuum jacketing or superinsula-tion. The cryogenic LN2/GN2 coolsthe HTF in an initial cooling circuit.Typically, a second LN2/GN2 cool-ing circuit cools the condenser bydirect expansion in the coils orplates. A more advanced cryogenicrefrigeration system is noq availablethat uses a single nonfreezing cryo-genic heat exchanger to simultane-ously cool both the shelves and thecondenser at different temperatureset-points using two HTF loops.

SUMMARYAs demand for parenteral and bio-logically-derived productsexpands, companies are increas-ingly using lyophilization to pro-tect and stabilize their sensitivepharmaceutical and biologic prod-ucts. Freeze-dryer performance iskey to achieving the requiredactivity, stability, quality, andshelf-life for the finished products.As products are becoming more

complex, cryogenic nitrogenrefrigeration is gaining favor overmechanical refrigeration becauseof its inherent reliability andresponsiveness to meet stringentand flexible cooling profiles whileachieving ultra-low shelf and con-denser temperatures. This will befurther discussed in Part 2 of thisarticle, to be published in theDecember 2007 issue. u

REFERENCES1. Rey L. Introduction: the saga of

freeze-drying. Pharma Techn2004;Mar 5.

2. Thomas P. The needle gets anothershot. 2006. Available fromwww.pharmamanufacturing.com/articles/2006/093.html.

3. Przic DS, Ruzic DS, Nenad NL,Petrovic SD. Lyophilization—theprocess and industrial use. ChemInd 2004;58(12):552.

4. Shanley A. PAT advances freeze dryercontrol. Available from:www.pharmamanufacturing.com/articles/2004/107.html.

5. US Food and Drug Administration.Guide to inspections of lyophilizationof parenterals. Available from:www.fda.gov/ora/inspect_ref/igs/lyophi.html.

6. Trappler EH. Assure batch uniformityfor freeze-dried products. Availablefrom:www.pharmamanufacturing.com/articles/2005/191.html.

7. Stewart P. Liquid nitrogen: why isprogress slow? economic andenvironmental factors. Pharma TechnEurope 1997;3:44.

8. Liu J, Rouse D. Using liquid nitrogento maximize lyophilizationmanufacturing capacity. BioProcessInt. 2005 Feb.

9. Praxair, Inc. Praxair announcesagreement with Hull Company tojointly market freeze dryer systemswith cryogenic refrigeration. NewsRelease 2001;Mar 20.

10. Usifroid. Liquid nitrogen applied tofreeze drying: performance, reliability,flexibility. 2006. Available from:www.usifroid.com/lks/fichiers/1/tele/1115/LN2%204%20pages%20Anglais.pdf.

11. Telstar. GN2-Tech. Productbrief;2005.

12. ASHRAE Refrigeration Handbook.Ultralow-temperature refrigeration.2002;Chapter 39.

13. Lines J. How low can you go? ChemProcess 2003 Jan;35.

Running HedVendor NotesLyophilization

1/3 pageVertical

Ad

F lexible, precise, and reliable cool-ing of the shelves and condenserin a lyophilizer is critical to effec-tively freeze-dry and protect a

broad range of sensitive, high valuepharmaceutical products. Conventionalcooling methods, as introduced in part 1of this article, include using eithermechanical or cryogenic nitrogen-basedrefrigeration. Part 2 begins with anoverview of the fundamental thermody-namic characteristics of cryogenic nitro-gen and the factors influencing themaximum amount of refrigeration avail-able from cryogenic systems. An optimalrefrigeration design provides flexible,robust cooling at reduced cost of owner-ship versus mechanical alternatives.

We will now review the fundamentalthermodynamic characteristics of cryo-genic nitrogen, and the factors influenc-ing the maximum amount of refrigerationavailable from the cryogenic fluid.

FUNDAMENTALS OF CRYOGENIC REFRIGERATION Liquid and Gaseous Nitrogen Pressure and temperature are two keyintensive thermodynamic variables thatdetermine the state of any saturatedfluid and thus the refrigeration avail-able from it. The saturation pressure ofliquid nitrogen as a function of temper-ature is shown in Figure 1.

Maximum Refrigeration from Liquid Nitrogen

Saturated liquid nitrogen stores refrigera-tion in the form of its latent heat ofvaporization, i.e., the energy associatedwith the liquid changing state to gaswithout a temperature change. Boilingthe liquid nitrogen (LN2) to gaseousnitrogen (GN2) provides the refrigerationin a cryogenic heat exchanger. Figure 2illustrates the available latent heat as afunction of operating pressure and tem-

48 BioPharm International www.biopharminternational.com December 2007

Increasing LyophilizationProductivity,Flexibility,and

Reliability Using LiquidNitrogen Refrigeration

ABSTRACT In part 1 of this article, published in the November 2007 issue of BioPharmInternational, the lyophilization process, related equipment, and refrigerationrequirements were discussed. This part 2 introduces key design considerations relatedto cryogenic refrigeration systems and provides guidance on relative cost factors forusing cryogenic versus mechanical refrigeration in lyophilization operations. The articlealso discusses reliability and maintenance requirements; flexibility in terms ofoperating temperature range, cooling rate capability, and precision of temperaturecontrol; cost of ownership; footprint; and environmental impact.

Balazs Hunek, PhD, is a senior manager oftechnology, 630.320.4242,

[email protected], Alan Cheng,PhD, is a senior development associate, R&D,

and John Capettini is a manager of globalapplications market development,

all at Praxair, Inc.

Part 2Balazs Hunek, Alan Cheng, John Capettini




perature. The lower the pressure and tempera-ture, the more refrigeration is available forrecovery.

Maximum Refrigeration from Gaseous Nitrogen

Sensible heat is the energy associated with achange in the temperature of a substance.Depending on the cryogenic system design,the sensible heat from warming the gas mayalso be recovered in the same or another heatexchanger. The two key factors that determinethe maximum amount of refrigeration recov-erable per unit mass of cryogen are the heatcapacity and the temperature rise of the fluid.

Maximum Refrigeration Recoverable from Liquid and Gaseous Nitrogen

We can calculate the total recoverablerefrigeration from cryogenic nitrogen byadding the two key components, i.e., thelatent and sensible heat. Figure 3 shows anexample of total available refrigeration as afunction of gas exhaust temperature fornear-atmospheric-pressure operation. Thelatent heat from vaporizing the liquid andthe sensible heat from warming the gaseach account for approximately 50% of theavailable refrigeration capacity under typi-cal operating conditions. At higher pres-sures, the latent heat of vaporizationdecreases, as shown in Figure 2, thus reduc-ing the total available refrigeration.

COMPARISON OF VARIOUS CRYOGENIC REFRIGERATION SYSTEMSThis section describes cryogenic heatexchange technologies in terms of freezingcharacteristics, efficiency of refrigeration uti-lization, and operating parameters as relatedto system design. Additional critical designconsiderations are also outlined.

Refrigeration Utilization Efficiency of Cryogenic Systems

At a given operating temperature and pressure,the fundamental thermophysical properties ofcryogenic nitrogen (discussed earlier) make acertain amount of refrigeration available fromthe fluid. If a 100% efficient cryogenic refriger-ation system existed, thermodynamics wouldstill limit the amount of refrigeration avail-able. The design and implementation of thecryogenic cooling system determines whatpercentage of the available refrigeration isactually recovered by first vaporizing the LN2,and subsequently warming the GN2. Themajority of current designs recover most of thelatent heat of vaporization. However, designsvary in their capability of recovering the sensi-ble heat by warming the gas. The closer theapproach temperature of the gas exhaust is tothe heat transfer fluid (HTF) outlet tempera-ture, the higher the efficiency of the cryogenicheat exchanger. We have demonstrated adesign that recovers 95–98% of the availablerefrigeration in a single cryogenic heatexchanger. These efficiencies have beenachieved in commercial systems with refrigera-tion capacities up to 150 kW and operatingtemperatures as low as –80 ºC.

Freezing Characteristics

When cryogens are used to cool anything,freezing the entire heat exchange system is aserious concern. LN2 boils at –195.8 ºC atatmospheric pressure. As discussed earlier,almost all HTFs used in lyophilization freeze atwell above this temperature. Freezing of theHTF has limited the widespread application ofcryogenic heat exchangers. Some cryogenicheat exchanger designs freeze after only a fewhours of operation.2 For longer cooling cycles,several such units are needed to enable paralleldefrosting of the frozen heat exchangers andto compensate for refrigeration capacity lossesdue to the insulating properties of ice.

Recent years have seen the development of

Figure 1. Saturation pressure and temperature of liquid nitrogen up tothe critical point (marked in red), above which a distinct liquid phasecannot exist1

Saturated liquid nitrogen

Satu

ratio

npr

essu

re[b

ar]

Saturation temperature [ºC]

40

35

30

25

20

15

10

5

0-210 -190 -170 -150


nonfreezing cryogenic heat exchanger designsthat eliminate the need to switch betweenfrozen and defrosted units. Such nonfreezingdesigns enable cooling over the long cyclesused by lyophilization. They include both asingle heat-exchanger design3 and multi-heat-exchanger systems, which use high-pressurefluid ejectors4 or plate-and-frame designs.5

These designs avoid any heat transfer surfaceswhere HTF is on one side and boiling LN2 onthe other by first boiling the LN2 against GN2,and then using only the GN2 to cool the HTF.Consequently, the HTF exchanges heat withonly nitrogen gas, thus avoiding the extremelylow temperatures of LN2. The nonfreezing sin-gle heat exchanger incorporates this capability

into one special heat exchanger unit using aproprietary design.3 Nonfreezing multi heat-exchanger systems need multiple heatexchangers, and in some cases an ejector, toaccomplish the same result.4,5

Impact of Operating Pressure on Cooling Capacity and LN2 Use Efficiency

The absolute amount of refrigeration recov-ered from the LN2 will also depend on theoperating pressure of the cryogenic system.As Figure 1 shows, increased pressure leadsto warmer operation. This is a strategy oftenused to delay or avoid freezing the HTF inthe cryogenic heat exchanger.2,4,5 The maindownside to this approach becomes obviousin examining Figure 2. While the warmertemperature may alleviate freezing prob-lems, the available latent heat of vaporiza-tion drops significantly with increasingpressure and temperature. An example ofsuch a system is the LN2/GN2 recirculationsystem with high-pressure fluid ejector tech-nology as shown in Figure 4. The proposed11-bar LN2 may boil almost 30 ºC warmerthan at atmospheric pressure, however, italso has over 40 kJ/kg less heat of vaporiza-tion to give off. That is approximately 20%of all the available refrigeration from thephase change. Praxair has developed a sys-tem that operates with as little as 3 bar LN2pressure. Operating at a lower pressure helpsthe system recover more refrigeration,which is available for cooling, reducing theamount of LN2 consumed in the process.

Impact of HTF Velocity

Many conventional cryogenic heat exchangersrequire a high HTF velocity to delay freezeup.2 A highly viscous fluid like an HTF at lowtemperature flowing at high velocity will gen-erate significant frictional heat, i.e., parasiticheat, which will add to the refrigerationdemand of the system. Therefore, choosing arefrigeration system with the lowest minimumHTF fluid velocity requirement is important.

COOLING THE CONDENSERThe condenser is typically cooled by directexpansion of a refrigerant into the coils orplates (DX condenser). In the case of amechanical refrigeration system, the refriger-ant is usually a hydrofluorocarbon typechemical or a mixture of chemicals.


Figure 2. Latent heat of vaporization of liquid nitrogen as a function ofsaturation pressure and temperature1

Liquid nitrogen

Saturation pressure [bar]

Heat

ofva

poriz

atio

n[k

J/kg

]

250

200

150

100

50

00 10 20 30 40

250

200

150

100

50

0

Liquid nitrogen

Saturation temperature [ºC]

Heat

ofva

poriz

atio

n[k

J/kg

]

-210 -190 -170 -150

Cryogenic systems oftenuse direct expansion ofLN2 and/or GN2 to coolthe condenser surfaces. Asimplified process-flow dia-gram is shown in Figure 5.In all these cases, the liq-uid refrigerant vaporizes inthe DX condenser, forminga two-phase flow. The sig-nificant heat transfer coef-ficient difference betweenthe liquid and gas phaserefrigerant causes unevencooling rates at differentpoints in the condenser.The result is uneven iceformation and nonuni-form use of the condensersurface.

To avoid two-phase flowand the related nonuni-form performance of the condenser, a so-called fluid condenser option is also available.In this case, one or more dedicated compres-sors or cryogenic heat exchangers may cool aseparate HTF loop, which in turn cools thefluid condenser. The downside of a fluid con-denser is the potential for frictional heat gen-eration. If a cryogenic heat exchanger isapplied, a low HTF velocity helps minimizethe parasitic heat generation. The efficiencybenefits gained from more uniform use of thecondenser surface often outweigh the minorincrease in frictional heat generation. A sim-plified process flow diagram of the refrigera-tion system for a freeze-drying applicationdeveloped by Praxair is shown in Figure 6. Inplace of separate dedicated refrigeration sys-tems for the shelves and condenser, we rec-ommend a unique configuration with a singlenonfreezing cryogenic heat exchanger. Thisheat exchanger cools two HTF loops with dif-fering temperature setpoints and refrigerationdemands. The warmer HTF loop cools theshelves, the colder one the condenser. Majoradvantages of the single-heat-exchanger con-figuration include significantly reduced capi-tal cost for the refrigeration system and lowerLN2 consumption compared to cryogenicrefrigeration systems that use both a heatexchange system and a LN2 DX condenser tomeet the cooling requirements of thelyophilization process.

COST OF OWNERSHIP ANALYSIS FOR LIQUID NITROGEN AND MECHANICALREFRIGERATION IN FREEZE-DRYINGTable 1 illustrates the key components of thecost of ownership of the refrigeration part of afreeze-dryer. Both the capital items and oper-ating costs were considered. Overall, if oneconsiders the cost of auxiliary systems andmaintenance for mechanical refrigeration,LN2 units are less expensive. After many yearsof operation of commercial mechanical units,the same conclusion was drawn by Liu.6

The amount of nitrogen required forrefrigeration will depend largely on the ther-mal efficiency of the cryogenic heatexchange system. High efficiency, nonfreez-ing systems that operate at low pressure use15–30% less nitrogen than high-pressurenonfreezing systems and systems that do notuse a nonfreezing design. LN2 costs canaccount for as much as 50% of the overallcosts to operate a cryogenic freeze-dryingsystem. Therefore, LN2 refrigeration effi-ciency should be considered while selectingthe cryogenic refrigeration system.

OTHER KEY CONSIDERATIONSReliabilityThe inherent reliability of cryogenic refrigera-tion systems is important to manufacturers ofhigh-value and sensitive products, such as

Running Hed

BioPharm International www.biopharminternational.com December 2007 53

Vendor NotesLyophilization

Figure 3. Total available refrigeration from liquid and gas nitrogen atatmospheric pressure as a function of the exhaust temperature of the gas.

LN2 latent heat + GN2 sensible heat

LN2 latent heat

Nitrogen exhaust temperature [ºC]

600

500

400

300

200

100

0-200 -150 -100 -50 0 50

[kJ/

kg]

protein therapeutics and vaccines.Lyophilization production managers oftenworry about the breakdown of the mechanicalcompressors on their freeze-dryers, whichwould lead to the loss of entire batches. Acryogenic refrigeration skid contains no mov-ing parts unlike compressor-based mechanicalrefrigeration skids. Properly used and main-tained, LN2/GN2-based refrigeration systemscan run for decades with minimal mainte-nance requirements and a low chance of fail-ure. The resulting savings in maintenance andrepair of both parts and labor can amount tohundreds of thousands of dollars over the life

of a commercial freeze-dryer. In addition, thevalue of the significantreduction in the risk ofmechanical failure andsubsequent loss of a batchdue to catastrophic com-pressor or power failurecan often be measured inexcess of a million dol-lars, depending on theproduct.

Flexibility

Calculating the exactcycle specifications for

product cool-down rate, freezing, and temper-ature profiles to be delivered by the refrigera-tion and heating system depend heavily onthe particular characteristics of the product.These profiles may differ radically dependingon the product formulation. The more flexiblethe design of the refrigeration system, themore versatile the unit will be. Additionalflexibility and control will better position theowner for processing new formulations withnew requirements. Cryogenic refrigerationusing LN2/GN2 enables manufacturers tooperate across a broad range of processingparameters, both at cool-down and at con-stant cooling to temperatures lower than –80ºC. Using a cryogenic system, the lowest tem-perature on the shelves is limited by thethermo-physical properties of the HTF, not therefrigerant. Direct expansion of cryogens inthe condenser or a nonfreezing cryogenic heatexchanger with a high performance HTF canprovide temperatures below –100 ºC in thecondenser.

Footprint

A cryogenic refrigeration system requiresfewer and less complex components.Typically, a cryogenic refrigeration skid onlyrequires approximately one-half to one-thirdthe space of a comparable mechanical com-pressor-based skid.

Environmental Impact

Nitrogen is an inert molecule that is nontoxicand nonflammable, with no ozone-depletingor global warming potential. It comes from,and returns to the atmosphere after giving offits refrigeration. Most HFC-based refrigerants

Figure 4. LN2/GN2 recirculation heat exchange system using high-pressure ejector technology4

Recirculation HX

Ejector

Absorb heatfrom HTF orcondenser

LN2 inlet11 bar~30% mass flow

N2 gas exhaust7 bar~30% mass flow

Table 1. Comparison of estimated cost of ownership formechanical versus cryogenic refrigeration of a typicalcommercial freeze-dryer operating in North America.7

Relative capitalexpense

Mechanicalcompressors

>95% efficiencycryogenic heatexchanger

Refrigeration skid Comparable Comparable

Cooling water systems Moderate None

Upgrade power Low None

Liquid nitrogen vacuumjacketed piping

None Low

UPS battery Low Low

Operating cost factors Mechanical Cryogenic

Cooling water/treatment Low None

Power Moderate Low

Liquid nitrogen Not applicable Moderate

M&R parts Moderate Low

M&R labor High Low

LyophilizationVendor Notes


are either toxic, flammable, or both. LN2/GN2refrigeration of the lyophilization operationreduces space requirements and noise, and isenvironmentally friendly.

CONCLUSIONThe growth of LN2/GN2 freeze drying is par-ticularly driven by the need for 1) increased

reliability for high-valueproducts, 2) enhancedflexibility, 3) increasingnumber of formulationscontaining biologics and4) dosages with high-filldepth and high volume.The users of lyophilizationtechnology and relatedequipment are just start-ing to realize many of itsbenefits. Many decisionmakers, still unaware ofthe benefits associatedwith LN2/GN2 systems,are also surprised at thelower cost of ownership ofa well-designed LN2/GN2system offering high LN2efficiency at a low capitalexpenditure. These fea-tures are also worth con-sidering for manufacturersaiming to increase the effi-ciency, operating flexibil-ity, and profitability oflyophilization systemswhile controlling costs. u

REFERENCES1. Perry RH, Green DW. Perry’schemical engineers’ handbook7th ed. McGraw-Hill;1997.2. Lines J. How low can you go?Chem Process 2003 Jan;35. 3. Cheng ATY, Devack DL.(Praxair) Nonfreezing heatexchanger. US Patent5,937,656. 1999;Aug 17.4. Stewart P. Liquid nitrogen:why is progress slow?economic and environmentalfactors. Pharm Technol Europe1997;3:44.5. Telstar. GN2-Tech. Productbrief;2005.6. Liu J, Rouse D. Using liquidnitrogen to maximizelyophilization manufacturingcapacity. BioProcess Int. 2005Feb. 7. Based on Praxair analysis

of actual customer experience. 8. Usifroid. Liquid nitrogen applied to freeze drying:

performance, reliability, flexibility. 2006. Availablefrom: http://www.usifroid.com/lks/fichiers/1/tele/11-2-15/LN2%204%20pages%20Anglais.pdf.

Circulation pump

Silicone oilexpansion tank

GN2to vent

GN2to vent

Electricalheater

Coil

Condenser

Shelves

Heat exchanger

LN2 tank

LN2 supply line

LYO chamber

LN2supplytank

HTF for condenser

Heat transferfluid loops

Cryogenicheat

exchanger

To vacuumpump

GN2 (ventor use)

Heater

Pump

Freeze drying chamber

Figure 5. Liquid nitrogen (LN2) freeze-dryer unit with heat transfer fluid heat exchanger and directexpansion of liquid nitrogen in condenser8

Figure 6. Simplified process flow diagram of a liquid nitrogen freeze-dryer using a fluidcondenser and a single cryogenic heat exchanger to cool both the shelves and the condenserheat transfer fluid circuits.

LyophilizationVendor Notes


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