la saga de la liofilizacion

7/27/2019 La Saga de La Liofilizacion

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Pharmaceutical Technology LYOPHILIZATION 2004 5

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rying from the frozen state is

not uncommon in nature. Inthe winter, snow vanishesalong the roads in dry cold air with-out melting. In Central Siberia, sci-entists have found the large bodiesof mammoths that have been pro-gressively freeze-dried during thepast 15,000 years. In the Peruvianhigh plateau, the Incas reportedly

stored, in their tambos, meat thathad been dried in the sun at the re-duced pressure of the Andes. Andfreeze-drying is in no way restrictedto water systems. Dry ice, for exam-ple, can sublimate at 78.8 C.

Scientific interest in freeze-dryingbegan at the turn of the twentieth

century with a publication by Bor-das and d'Arsonval at the FrenchAcademy of Sciences. Followingthat publication, Altman and laterGersh used this technique to pre-pare undistorted dry samples formicroscopy. Indeed, freezing anddrying from the frozen state wasparticularly appropriate for the

preparation and preservation ofsensitive materials, especially bio-logicals.

Ronald Greaves, in Cambridge,UK, began his work along thoselines in the 1930s by preparing dry

The Saga of

Freeze-DryingLouis Rey

D

Louis Rey, PhD, is a

biologist, scientific and

industrial adviser, and

lyophilization pioneer based

in Switzerland, Chemin deVerdonnet, 2, CH-1010

Lausanne, Switzerland,

tel. +41 21 652 09 66,

fax +41 21 652 09 67,

[email protected].

Though recognized by

the public since freeze-

dried coffee hit the

market 30 years ago,

lyophilization remains

far from mature and

deserves more research.


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suspensions of living bacteria. How-ever, this technique still was only fa-miliar to a handful of scientists inisolated laboratories.

Then came World War II. Withtens of thousands of casualties onthe battlefields, human plasma wasin great need, and freeze-dryingagain entered the limelight. Thanksto Greaves in England, FranoisHenaff in France, and Earl Flosdorfin the United States, thousands of

liters of blood were processed to iso-late plasma, which was then pre-served by freezing and drying.

As the use of lyophilization ex-panded, the process began to be in-dustrialized. Loire, Stokes, Edwards,and others designed and built thefirst equipment for the purpose.Called lyophilization by Flosdorf,

the process faced its first major chal-lenge under Sir Ernst Boris Chain,who used the technique to preserveantibiotics. Given Chains results, itis no wonder that Charles Mrieuxturned to lyophilization to preparevaccines and, later on, to refineblood fractions.

By the mid-1950s, many indus-tries were already using freeze-drying to preserve pharmaceuticaland biological products, as were thephysicians and surgeons who devel-oped tissue-banking for plastic andreconstructive surgery. Drs. Hyatt,Bassett, and Meryman of the UnitedStates Navy were among the early

pioneers in the field. At the time,the process was quite simple, andthe equipment was robust and un-sophisticated. Because freeze-dryingwas still considered an expensiveoperation, however, its extension to

the food industry, though poten-tially feasible, remained almostnonexistent.

Today, lyophilization is thriving

and is even recognized as an every-day technology thanks to the intro-duction of freeze-dried coffee 30years ago.

In the pharmaceutical industry,freeze-dried drugs are well-recognized products. At the sametime, in some specialized laborato-

ries, scientists are developing more-sophisticated processes that combinefreeze-drying technology with elec-tron microscopy, biochemistry, andrefined surgery.

In parallel, equipment manufac-turers continually search for more-reliable automated systems capableof handling many different prod-

ucts in large batches under fullysterile conditions. They compete toimprove efficiency and safety andreduce costs.

At the same time, the cosmeticsindustry is increasing its use oflyophilization to help preparebeauty masks, hair dyes, and sophis-

ticated supports for face creams.Chemical industries also are begin-ning to use freeze-drying to preparerefined chemicals, catalysts, and se-lective filters.

At first sight, the health profile oflyophilization looks good, becauseit appears to be a ubiquitous tech-nology strictly controlled both by

manufacturers and operators. Thisview is short-sighted, however, be-cause freeze-drying is facing diffi-cult challenges as the sensitivity,complexity, and price of treatedproducts steadily rise. New antibi-


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otics and drugs, immunologicalproducts, substances derived fromgenetic engineering, high molecularweight proteins, and sophisticated

peptides are very fragile, difficult tofreeze, and all highly sensitive toresidual moisture content. As a re-sult, each product deserves a dedi-cated process and sometimes dedi-cated equipment as well (as in thecase of oncolytic drugs).

In-depth knowledge of eachproducts thermodynamic proper-ties at low temperature is compul-sory, which means that variousproduct-specific questions must beanswered. For example, how does itfreeze? Does it form metastableglassy structures, which often needto be annealed? How far can itswater content be reduced without

disrupting its steric configuration?What type of bulking agent is re-quired to form a stable plug whenthe active substance is present onlyat the milligram level? Will it dis-play product elegance?What arethe potential surface actions of thecontainerclosure system? Do the

glass walls of the vial release unde-sirable ions or adsorb, irreversiblyor not, very dilute active substances?Do the stoppers remain neutral andhermetic to gas and water vapor?

All of these factors must be givenappropriate weight in the context ofthe overall technical and financialbudget. This is especially true when

it is understood that the whole op-eration must be sterile, sometimeswith the use of isolators that requireremote handling and automation.As an alternative, a manufacturermay want to consider whether it

would be more advisable to use ahygenic process and then sterilizethe finished product by irradiation.

Other key questions also must be

answered. For example, can themanufacturer guarantee that all vialsin a batch of 50,000 or 150,000 havethe same end-moisture content,whatever their respective position inthe drying cabinet? Can the manu-facturer present to regulatory au-thorities and compliance officersprocess and data sheets that areprecise and stable enough to obtainvalidation?

Today, considering all these is-sues, we can say that lyophilization is an increasingly essential tool for

the pharmaceutical industry although a highly sophisticated

technology, still is far from mature

and deserves substantial funda-mental and applied research

presents constant challenges forequipment manufacturers thatmust provide instruments thatcan process, in a reproducible andreliable way, large batches of hightherapeutic and material value.

(One batch of a peptide or an on-colytic drug often is worth morethan the freeze-dryer itself!)For all of these reasons, it is an

appropriate time to devote this spe-cial issue to lyophilization. Lyo-philization is a demanding andchallenging technology that de-serves an educated and multidisci-

plinary approach.PT

la saga de la liofilizacion

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