Lyophilization/Freeze Drying - An Review ----[Lyophilization, Freeze drying, Freeze drying equipments, freeze drying methods ]

                          LYOPHILIZATION

     [INTERNATIONAL JOURNAL OF NOVEL TRENDS IN PHARMACEUTICAL SCIENCES]

Keywords

Lyophilization, Freeze drying,

Freeze drying equipments,

freeze drying methods

INTRODUCTION

Lyophilization or freeze drying is a process in which water is frozen, followed by its removal from the sample, initially by sublimation (primary drying) and then by desorption (secondary drying). Freeze-drying is a process of drying in which water is sublimed from the product after it is frozen . It is a drying process applicable to manufacture of certain pharmaceuticals and biologicals that are thermo labile or otherwise unstable in aqueous solutions for prolonged storage periods, but that are stable in the dry state. The term “lyophilization” describes a process to produce a product that

“loves the dry state” .

PRINCIPLE

The main principle involved in freeze drying is a phenomenon called sublimation, where water passes directly from solid state (ice) to the vapor state without passing through the liquid state.

Sublimation of water can take place at pressures and temperature below triple point i.e. 4.579 mm of Hg and 0.0099 degree Celsius . The material to be dried is first frozen and then subjected under a

high vacuum to heat (by conduction or radiation or by both) so that frozen liquid sublimes leaving only solid ,dried components of the original liquid. The concentration gradient of water vapor between the drying front and condenser is the driving force for removal of water during lyophilization .

To extract water from foods, the process of lyophilization consists of :

1. Freezing the food so that the water in the food become ice.

2. Under a vacuum, sublimating the ice directly into water vapour.

3. Drawing off the water vapour.

4. Once the ice is sublimated, the foods are freezedried and can be removed from the machine .

Abstract

On 21st century, in pharmaceutical field lyophilization has become important subject to ongoing development and its expansion. Lyophilization is common, but cost intensive. In old days process optimization was focused only on drying rather than lyophilization. But lyophilization was more (or) equally important for the process of pharmaceuticals. This review focused on the recent advances and its targets in near future. At first, the principle, steps involved, formulation aspects and importance of lyophilization was explained.

Process to produce a product that “loves dry state” Freeze drying also known as lyophilization, is widely used for pharmaceuticals to improve the stability and long term storage of labile products. Lyophilization or Freeze-drying fills an important need in pharmaceutical manufacturing technology

by allowing drying of heat-sensitive products and biologicals at low temperature under conditions that allow removal of water by sublimation, or a change of phase from solid to vapor without passing through the liquid phase . The most common application of pharmaceutical freeze drying is in the production of injectable dosage forms, the process is also used in the production of diagnostics and, occasionally, for oral solid dosage forms where a very fast dissolution rate is desired.

Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. Lyophilization is performed at temperature and pressure conditions below the triple point, to enable sublimation of ice. The entire process is performed at low temperature and pressure, hence is suited for drying of thermolabile compounds. Steps involved in lyophilization start from sample preparation followed by freezing, primary drying and secondary drying, to obtain the final dried product with desired moisture content . The concentration gradient of water vapor between the drying front and condenser is the driving force for removal of water during lyophilization. The vapor pressure of water increases with an increase in temperature during the primary drying. Therefore, primary drying temperature should be kept as high as possible, but below the critical process temperature, to avoid a loss of cake structure. This critical process temperature is the collapse temperature for amorphous substance, or eutectic melt for the crystalline substance. During freezing, ice crystals start separating out until the solution becomes maximally concentrated. On further cooling, phase separation of the solute and ice takes place. 

Fig 2. Phase diagram showing the triple point of water at 0.01°C, 0.00603 atm.

Lyophilization is carried out below the triple point to enable conversion of ice into vapor, without

entering the liquid phase (known as sublimation).Annealing is an optional step, occasionally used to

crystallize the formulation component. If the solute separates out in crystalline form, it is known as the eutectic temperature. In contrast, if an amorphous form is formed, the temperature is referred to as the glass transition temperature (Tg). Determination of this critical temperature is important for

development of an optimized lyophilization cycle. During primary drying, drying temperature should

not exceed the critical temperature, which otherwise leads to ‘meltback’ or ‘collapse’

phenomenon. In the majority of lyophilized formulations, excipients are included to improve the

functional properties and stability of the lyophilized product . The International Pharmaceutical

Excipients Council has defined excipients as“substances other than the pharmacologically active product or proproduct which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form” The fundamental process steps;

1. Freezing: The product is frozen. This provides a necessary condition for low temperature drying.

2. Vacuum: After freezing, the product is placed under vacuum. This enables the frozen solvent in

the product to vaporize without passing through the liquid phase, a process known as sublimation.

3. Heat: Heat is applied to frozen product to accelerate sublimation.

4. Condensation: Low temperature condenser plates remove the vaporized solvent from the vacuum

chamber by converting it back to a solid. This completes the separation process . Resulting product has a very large surface area thus promoting rapid dissolution of dried product .

APPLICATIONS

Pharmaceutical and biotechnology

Pharmaceutical companies often use freeze-drying to increase the shelf life of products, such as

vaccines and other injectables . By removing the water from the material and sealing the material in a vial, the material can be easily stored, shipped, and later reconstituted to its original form for

injection.

Food Industry

Freeze-drying is used to preserve food and make it very lightweight. The process has been popularized in the forms of freeze-dried ice cream, an example of astronaut food.

Technological Industry

In chemical synthesis, products are often freezedried to make them more stable, or easier to dissolve in water for subsequent use. In bioseparations, freeze-drying can be used also as a late-stage purification procedure, because it can effectively remove solvents. Furthermore, it is capable of concentrating substances with low molecular weights that are too small to be removed by a filtration membrane .

Other Uses

Organizations such as the Document Conservation Laboratory at the United States National Archives and Records Administration (NARA) have done studies on freeze-drying as a recovery method of water-damaged books and documents. In bacteriology freeze-drying is used to conserve special strains.

The advantages of Lyophilization include

· Chemical decomposition is minimized.

· Removal of water without excessive heating.

· Enhanced product stability in a dry state.

· Ease of processing a liquid, simplifies aseptic handling.

· More compatible with sterile operations than dry powder filling.

Disadvantages of Lyophilization include

· Increased handling and processing time.

· Volatile compounds may be removed by vacuum.

· Need for sterile diluents upon reconstitution.

TRADITIONAL LYOPHILIZATION TECHNOLOGY

Traditional lyophilization is a complex process that requires a careful balancing of product, equipment, and processing techniques. For nearly 30 years, lyophilization has been used to stabilize

many types of chemical components. In their liquid form, many such biochemicals and chemical reagents are unstable, biologically and chemically active, temperature sensitive, and chemically reactive with one another. Because of these characteristics, the chemicals may have a very short shelf life, may need to be refrigerated, or may degrade unless stabilized. When performed properly, the process of lyophilization solves these problems by putting reagents into a state of suspended activity . Lyophilization gives unstable chemical solutions a long shelf life when they are stored at room temperature. The process gives product excellent solubility characteristics, allowing for rapid reconstitution. Heat- and moisture-sensitive compounds retain their viability.

Most proteins do not denature during the process, and bacterial growth and enzyme action, which normally occur in aqueous preparations, can be eliminated. Thus, lyophilization ensures maximum

retention of biological and chemical purity .

PROCESSING

There are four stages in the complete drying process: pretreatment, freezing, primary drying, and secondary drying.

Freeze-drying process

Freeze drying is mainly used to remove the water from sensitive products, mostly of biological origin, without damaging them, so they can be preserved easily, in a permanently storable state and be reconstituted simply by adding water . Examples of freeze dried products are: antibiotics, bacteria,

sera, vaccines, diagnostic medications, proteincontaining and biotechnological products, cells and tissues, and chemicals. The product to be dried is frozen under atmospheric pressure. Then, in an initial drying phase referred to as primary drying, the water (in form of ice) is removed by sublimation; in the second phase, called secondary drying, it is removed by desorption. Freeze drying is carried out under vacuum .

Pretreatment

Pretreatment includes any method of treating the product prior to freezing. This may include concentrating the product, formulation revision (i.e., addition of components to increase stability and/or improve processing), decreasing a high vapor pressure solvent or increasing the surface area. In many instances the decision to pretreat a product is based on theoretical knowledge of freeze-drying and its requirements, or is demanded by cycle time or product quality considerations . Methods of pretreatment include: Freeze concentration, Solution phase concentration, Formulation to Preserve Product Appearance, Formulation to Stabilize Reactive Products, Formulation to Increase the Surface Area, and Decreasing High Vapor

Pressure Solvents.

Traditionally, lyophilization cycle design has been divided into three parts :

1. Freezing, in which the liquid sample is cooled until pure crystalline ice forms from part of the liquid and the remainder of the sample is freeze-concentrated into a glassy state where the viscosity is too high to allow further crystallization.

2. Primary drying, wherein the ice formed during the freezing is removed by sublimation under vacuum at low temperatures, leaving a highly porous structure in the remaining amorphous solute that is typically 30% water. This step is carried out at pressures of 10-4 to 10-5 atmospheres, and a product temperature of –45 to –20°C; Sublimation during primary drying is the result of coupled heat- and mass-transfer processes.

3. Secondary drying, wherein most of the remaining water is desorbed from the glass as the temperature of the sample is gradually increased while maintaining low pressures. Ideally, the final product is a dry, easily reconstituted cake with a high surface area (ca. 10 m2/g) .

LYOPHILIZATION EQUIPMENT

There are essentially three categories of freeze-dryers: the manifold freeze-dryer, the rotary freeze-dryer and the tray style freeze-dryer. Two components are common to all types of freezedryers: a vacuum pump to reduce the ambient gas pressure in a vessel containing the substance to be dried and a condenser to remove the moisture by condensation on a surface cooled to −40 to −80°C (−40 to −112°F). The manifold, rotary and tray type freeze-dryers differ in the method by which the dried substance is interfaced with a condenser. In manifold freeze-dryers a short usually circular tube is used to connect multiple containers with the dried product to a condenser . The rotary and tray freeze-dryers have a single large reservoir for the dried substance. Rotary freeze-dryers are usually used for drying pellets, cubes and other pourable substances. The rotary dryers have a cylindrical reservoir that is rotated during drying to achieve a more uniform drying throughout the substance . Tray style freeze-dryers usually have rectangular reservoir with shelves on which products, such as pharmaceutical solutions and tissue extracts, can be placed in trays, vials and other containers. Manifold freeze-dryers are usually used in a laboratory setting when drying liquid substances in small containers and when the product will be used in a short period of time . A manifold dryer will dry the product to less than 5% moisture content. Without heat, only primary drying (removal of the unbound water) can be achieved. A heater must be added for secondary drying, which will remove the bound water and will produce lower moisture content. Tray style freezedryers are typically larger than the manifold dryers and are more sophisticated. Tray style freeze-dryers are used to dry a variety of materials. A tray freezedryer is used to produce the driest product for long-term storage. A tray freezedryer allows the product to be frozen in place and performs both primary (unbound water removal) and secondary (bound water removal) freeze-drying, thus producing the driest possible end-product. Tray freeze-dryers can dry products in bulk or in vials or other containers . When drying in vials, the freeze-dryer is supplied with a stoppering mechanism that allows a stopper to be pressed into place, sealing the vial before it is exposed to the atmosphere. This is used for long-term storage, such as vaccines. Improved freeze drying techniques are being developed to extend the range of products that can be freeze dried, to improve the quality of the product, and to produce the product faster with less labor. A lyophilizer consists of a vacuum chamber that contains product shelves capable of cooling and heating containers and their contents. A vacuum pump, a refrigeration unit, and associated controls are connected to the vacuum chamber . Chemicals are generally placed in containers such as glass vials that are placed on the shelves within the vacuum chamber. Cooling elements within the shelves freeze the product. Once the product is frozen, the vacuum pump evacuates the chamber and the product is heated. Heat is transferred by thermal conduction from the shelf, through the vial, and ultimately into the product .

Lyophilization Container Requirements

The container in which a substance is lyophilized must permit thermal conductivity, be capable of

being tightly sealed at the end of the lyophilization cycle, and minimize the amount of moisture to

permeate its walls and seal . The enclosed reagents can only remain properly lyophilized if the container in which they are processed meets these requirements.

Lyophilization Heat Transfer

Successful lyophilization is heavily dependent on good thermal conductivity. For this, containers used in the lyophilization process must be capable of meeting a number of heat-transfer requirements. Such containers should be made of a material that offers good thermal conductivity; should provide

good thermal contact with the lyophilizer shelf, which is the source of heat during processing; and should have a minimum of insulation separating the source of heat from the product requiring heating. Poor thermal conductivity often results from the use of containers made of materials with low coefficients of heat transfer. It can also be caused by the shape, size, or quality of the container . It may come from thermal barriers, such as excessive amounts of material, which can act as insulation, preventing energy from being transferred to the point at which the frozen ice and dried product interface .

FREEZE DRYER DESIGN

Fig. 5: Freeze Dryer

Essential Components

Chamber

This is the vacuum tight box, sometimes called the

lyophilization chamber or cabinet. The chamber

contains shelf or shelves for processing product.

The chamber can also fit with a stoppering system.

It is typically made of stainless steel and usually

highly polished on the inside and insulated and clad

on the outside . The door locking arrangement

by a hydraulic or electric motor.

Shelves

A small research freeze dryer may have only one

shelf but all others will have several. The shelf

design is made more complicated because of the

several functions it has to perform. The shelf act as

a heat exchanger, removing energy from the

product during freezing, and supplying energy to

the product during the primary and secondary

drying segments of the freeze drying cycle. The

shelves will be connected to the silicone oil system

through either fixed or flexible hoses. Shelves can

be manufactured in sizes up to 4 m2 in area .

Process Condenser

The process condenser is sometimes referred as just

the condenser or the cold trap. It is designed to

trap the solvent, which is usually water, during the

drying process. The process condenser will consist

of coils or sometimes plates which are refrigerated

to allow temperature. These refrigerated coils or

plates may be in a vessel separate to the chamber,

or they could be located within the same chamber

as the shelves. Hence there is designation “external

condenser” and “internal condenser”. Physically, the

external condenser is traditionally placed behind

the chamber, but it may be at the side, below or

above . The position of the condenser does not

affect trapping performance. For an internal

condenser the refrigerated coils or plates are placed

beneath the shelves on smaller machines, and

behind the shelves on larger machines, but again

there is no performance constraint, only the

geometry of the chamber.

Shelf fluid system

The freeze-drying process requires that the product

is first frozen and then energy in the form of heat is

applied throughout the drying phases of the cycle.

This energy exchange is traditionally done by

circulating a fluid through the shelves at a desired

temperature . The temperature is set in an

external heat exchange system consisting of cooling

heat exchangers and an electrical heater. The fluid

circulated is normally silicone oil. This will be

pumped around the circuit at a low pressure in a

sealed circuit by means of a pump.

Refrigeration system

The product to be freeze dried is either frozen

before into the dryer or frozen whilst on the

shelves. A considerable amount of energy is needed

to this duty. Compressors or sometimes-liquid

nitrogen supplies the cooling energy. Most often

multiply compressors are needed and the

compressor may perform two duties, one to cool

the shelves and the second to cool the process

condenser.

Vacuum system

To remove solvent in a reasonable time, vacuum

must be applied during the drying process. The

vacuum level required will be typically in the range

of 50 to 100μ bar. To achieve such a low vacuum, a

two stage rotary vacuum pump is used. For large

chambers, multiple pumps may be used.

Control system

Control may be entirely or usually fully automatic

for production machines. The control elements

required are as mentioned above, shelf

temperature, pressure and time. A control program

will set up these values as required by the product

or the process. The time may vary from a few hours

to several days. Other data such as a product

temperatures and process condenser temperatures

can also be recorded and logged .

THE FREEZE-DRYING CYCLE:

Lyophilization is the most common method for

manufacturing solid pharmaceutical products and is

central to the preservation of materials which must

be dried thoroughly in order to ensure stability. To

meet this requirement, a solution’s lyophilization

occurs in three steps: (1) freezing to convert most of

the water into ice, (2)primary drying to sublime the

ice, and (3) secondary drying to remove unfrozen

water by desorption . To technically realize this

manufacturing process, a freeze dryer is commonly

constructed with two main parts: a “drying”

chamber holding temperature controlled shelves is

connected by a valve to a “condenser” chamber,

which contains coils capable to achieve very low

temperatures between -50°C and -80°C. The freezedrying

process consists of three stages.

1) Freezing

2) Primary drying

3) Secondary drying

Freezing

Freezing is a critical step, since the microstructure

established by the freezing process usually

represents the microstructure of the dried product.

The product must be frozen to a low enough

temperature to be completely solidify. Since freeze

drying is a change in state from the solid phase to

the gaseous phase, material to be freeze-dried must

first be adequately pre-frozen. The method of

prefreezing and the final temperature of the frozen

product can affect the ability to successfully freeze

dry the material39. Rapid cooling results in small ice

crystals, useful in preserving structures to be

examined microscopically, but resulting in a

product that is, more difficult to freeze dry.Slower

cooling results in large ice crystals and less

restrictive channel in the matrix during the drying

process. Products freeze in two ways, the majority

of products that are subjected to freeze-drying

consists primarily of water, the solvent and

materials dissolved or suspended in the water, the

solute. Most samples that are to be freeze dried are

eutectics, which are mixtures of substances that

freeze at lower temperature than the surrounding

water. This is called the eutectic temperature.

Eutectic point is the point where all the three

phases’ i.e. solid, liquid and gaseous phases coexist.

It is very important in freeze-drying to pre

freeze the product to below the eutectic

temperature before beginning the freeze-drying

process.

The second type of frozen product is a suspension

that undergoes glass formation during the freezing

process. Instead of forming eutectics, the entire

suspension becomes increasingly viscous as the

temperature is lowered. Finally the products freeze

at the glass transition point forming a vitreous solid.

This type of product is extremely difficult to freeze

dry .

Primary drying

After prefreezing the product, conditions must be

established in which ice can be removed from the

frozen product via sublimation, resulting in a dry,

structurally intact product.

This requires very carefully control of the two

parameters.

1) Temperature and 2) Pressure involved in

freeze-drying system.

The rate of sublimation of ice from a frozen product

depends upon the difference in vapor pressure of

the product compared to the vapor pressure of the

ice collector. Molecules migrate from the highpressure

sample to a lower pressure area. Since

vapor pressure is related to temperature, it is

necessary that the product temperature is warmer

than the cold trap (ice collector) temperature. It is

extremely important that the temperature at which

a product is freeze dried is balanced between the

temperature that maintains the frozen integrity of

the product and the temperature that maximizes

the vapor pressure of the product. This is the

balance is key to optimum drying.

Most products are frozen well below their eutectic

or glass transition point (point A), and the

temperature is raised to just below this critical

temperature (Point B) and they are subjected to

reduced pressure. At this point the freeze-drying

process is started. Vacuum pump is an essential of a

freeze drying system, and is used to lower the

pressure of the environment around the product

(point C). The other essential is a collecting system,

which is a cold trap used to collect the moisture

that leaves the frozen product.

The collector condenses out all condensable gases,

i.e. the water molecules and the vacuum pump

removes all non-condensable gases. The molecules

have a natural affinity to move toward the collector

because its vapor pressure is lower than that of the

product. Therefore the collector temperature, (Point

D) must be significantly lower than the product

temperature.

A third component essential in freeze-drying

system is energy. Energy is essential in the form of

heat. Almost ten times, much energy is required to

sublime a gram of water from the frozen to the

gaseous state as is required to freeze a gram of

water, (2700 joules per gram of ice).

Heat must be applied to the product to encourage

the removal of water in the form of vapor from the

frozen product. The heat must be very carefully

controlled, as applying more heat than the

evaporative cooling in the system can warm the

product above its eutectic or collapse temperature.

Heat can be applied by several means one method

is to apply heat directly through a thermal

conductor shelf such as is used in tray drying.

Another method is to use ambient heat as in

manifold drying .

Heat enters the products by one of several

mechanisms: -

1) By direct contact between the container base and

the shelf, so here the shape of the container is

important.

2) By conduction across the container base and

then through the frozen mass to the drying front

(also called the sublimation interface)

3) By gaseous convection between the product and

residual gas molecules in the chamber.

4) By radiation, this is low due to low temperature

encountered in freeze-drying. Convection is

certainly the most important of these mechanisms.

Secondary drying

After primary freeze-drying is complete, and all ice

has sublimed, bound moisture is still present in the

product. The product appears dry, but the residual

moisture content may be as high as 7-8% continued

drying is necessary at warmer temperature to

reduce the residual moisture content to optimum

values. This process is called ‘Isothermal Desorption’

as the bound water is desorbed from the product

.

Secondary drying is normally continued at a

product temperature higher than ambient but

compatible with the sensitivity of the product. In

contrast to processing conditions for primary drying

which use low shelf temperature and a moderate

vacuum, desorption drying is facilitated by raising

shelf temperature and reducing chamber pressure

to a minimum. Care should be exercised in raising

shelf temperature too highly; since, protein

polymerization or biodegradation may result from

using high processing temperature during

secondary drying. Secondary drying is usually

carried out for approximately 1/3 or 1/2 the time

required for primary drying.

The general practice in freeze-drying is to increase

the shelf temperature during secondary drying and

to decrease chamber pressure to the lowest

attainable level. The practice is based on the ice is

no longer present and there is no concern about

“melt track” the product can withstand higher heat

input . Also, the water remaining during

secondary drying is more strongly bound, thus

requiring more energy for its removal. Decreasing

the chamber pressure to the maximum attainable

vacuum has traditionally been thought to favor

desorption of water.

EXCIPIENTS IN LYOPHILIZED FORMULATION

The design of aq lyophilized formulation is

dependent on the requirements of the active

pharmaceutical ingredient (API) and intended route

of administration. A formulation may consist of one

or more excipients that perform one or more

functions. Excipients may be characterized as

buffers and pH adjusters, bulking agents, stabilizers,

and tonicity modifiers.

Buffers

Buffers are required in pharmaceutical formulations

to stabilize pH. In the development of lyophilized

formulations, the choice of buffer can be critical.

Phosphate buffers, especially sodium phosphate,

undergo drastic pH changes during freezing. A

good approach is to use low concentrations of a

buffer that undergoes minimal pH change during

freezing such as citrate and histidine buffers.

Bulking agents

The purpose of the bulking agent is to provide bulk

to the formulation. This is important in cases in

which very low concentrations of the active

ingredient are used. Crystalline bulking agents

produce an elegant cake structure with good

mechanical properties. However, these materials

oftren are ineffective in stabilizing products such as

emulsions, proteins and liposomes but may be

suitable for small chemical products and some

peptides. If a crystalline phase is suitable,mannitol

can be used. Sucrose or one of the other

disaccharides can be used in a protein or liposome

product.

Stabilizers

In addition to being bulking agents, disaccharides

form an amorphous sugar glass and have proven to

be most effective in stabilizing products such as

liposomes and proteins during lyophilization.

Sucrose and trehalose are inert and have been used

in stabilizing liposome, protein, and virus

formulations. Glucose, lactose, and maltose are

reducing sugars and can be reduce proteins by

means of the mallard reaction.

Tonicity adusters

In several cases, an isotonic formulation might be

required. The need for such a formulation may be

dictated by either the stability requirements of the

bulk solution or those for the route of

administration. Excipients such as mannitol, sucrose,

glycine, glycerol, and sodium chloride are good

tonicity adjusters. Glycine can lower the glass

transition temperature if it is maintained in the

amorphous phase. Tonicity modifiers also can be

included diluent rather than the formulation.

FREEZE DRYING METHODS

Three methods of freeze drying are commonly used

Manifold method

In the manifold method, flasks ampoules or vials are

individually attached to the ports of a drying

chamber. The product either frozen in a freezer, by

direct submersion in a low temperature bath, or by

shell freezing, depending on the nature of the

product and the volume to be freeze dried.The

prefrozen product is quickly attached to the drying

chamber or manifold to prevent warming. The

vacuum must be created in the product container

quickly, and the operator relies on evaporative

cooling to maintain the low temperature of the

product. This procedure can only be used for

relatively small volumes and product with high

eutectic and collapse temperatures.

Manifold drying has several advantages over batch

tray drying. Since the vessels are attached to the

manifold individually, each vial or flask has a direct 

path to the collector. This removes some of the

competition for molecular space created in a batch

system, and is most ideally realized in a cylindrical

drying chamber where the distance from the

collector to each product vessel is the same. Heat

input can be affected by simply exposing the

vessels to ambient temperature or via a circulating

bath. For some products, where precise

temperature control is required, manifold drying

may not be suitable .

Batch method

In a batch drying, large numbers of similar sized

vessels containing like product are placed together

in a tray dryer. The product is usually prefrozen on

the shelf of the tray dryer. Precise control of the

product temperature and the amount of heat

applied to the product during drying can be

maintained. Generally all vials in the batch are

treated during drying process, although some

variation in the system can occur. Slight difference

in heat input from the shelf can be expressed in

different areas.Vials located in the front portion of

the shelf may radiantly through the clear door.

These slight variations can result in small difference

in residual moisture.

Batch drying allows closure of all vials in a lot at the

same time, under the same atmospheric condition.

The vials can be stoppered in a vacuum, or after

backfiling with inert gas . Stoppering of all vials

at the same time ensures a uniform environment in

each vial and uniform product stability during

storage. Batch drying is used to prepare large

numbers of ampoules or vials of one product and is

commonly used in the pharmaceutical industry.

Bulk method

Bulk drying is generally carried out in a tray dryer

like batch drying. However, the product is poured

into a bulk pan and dried as a single unit.

Although the product is spread through out the

entire surface area of the shelf and may be the

same thickness as product in vials, the lack of empty

spaces within the product mass changes the rate of

heat input .The heat input is limited primarily to that

provided by contact with the shelf.

Technology transfer

In pharmaceutical industry “technology transfer”

refers to the processes that are needed for

successful progress product discovery to product

development to full scale commercialization .

Technology transfer can be divided in to 2 types

Tech transfer

In tech transfer, the product is developed in labscale,

subjected to scale-up, exhibit batch to full

scale commercialization.

Site transfer

In site transfer the products from the outside

customer are subjected to lab-scale feasibility trials

and then to commercial scale depending on

customer need. The importance of technology

transfer,

· To gather necessary information to transfer

technology from R&D to actual

· Manufacturing by sorting out various

information obtained during R&D.

· To elucidate necessary information to

transfer technology of existing products

between various manufacturing places.

V.Lavakumar et al., Lyophilization/Freeze Drying - An Review

VOLUME 3 | NUMBER 4 | OCT | 2013 |96

In most cases, technology transfer occurs in several

stages. Small scale laboratory development from

100 ml to 500 ml can be scaled up to 5-10 liters and

then 20-100 liters on an Exhibit batch scale.

Production scale can typically range from 200 liters

to 1000liters.For a successful scale-up of freeze

drying process, it is important to develop a

systematic strategy to correlate the cycle

parameters obtained from small-scale operation to

final results obtained from full-scale production

operations under various operational conditions,

such as shelf temperature, chamber pressure, type

of vial, and solution depth. The product from

manufacturing had lower moisture from the pilot

plant batches despite the similarity of the

Lyophilization cycles applied at the two facilities.

The product temperature during the two steps of

secondary drying in pilot plant unit is lower than

the attained in a manufacturing lyophilizer. The

differences is attributed to different heat transfer

characteristics of the lyophilizer, with the

manufacturing lyophilizer having a‘more efficient’

heat transfer coefficient than the pilot plant unit at

secondary drying conditions. Freeze drying cycle

transfer must be based on equivalent drying rates

and extent of drying at the different scales,

especially product final moisture content is critical.

Appropriate scale-up of a freeze drying process in a

cost effective and efficient manner involves smart

use of experimental tools to monitor the drying

process of product. It is hypothysed that cycles

developed and/or used in the laboratory drier will

correlate to cycles used in the production dryer .

Predicting production freeze dry cycle parameters

from laboratory experiments has obvious

advantage.

CONCLUSION

Lyophilization (freeze-drying) is often used to

prepare dry pharmaceutical formulations to achieve

commercially viable shelf lives. The process

comprises three steps: freezing, primary drying, and

secondary drying. As water freezes in the first step,

the dissolved components in the formulation

remain in the residual liquid, a phase termed the

freeze concentrate. At the point of maximal ice

formation, the freeze concentrate solidifies between

the ice crystals that make up the lattice. Under

appropriate lyophilization conditions, the ice is

removed by sublimation during primary drying,

leaving the remaining freeze-concentrate in the

same physical and chemical structure as when the

ice was present. Residual water in the freeze

concentrate is removed in the secondary drying

step. About 50% of the currently

biopharmaceuticals are lyophilized, representing

the most common formulation strategy. In the

freeze dried solid state, chemical or physical

degradation reactions are inhibited or sufficiently

decelerated, resulting in an improved long term

stability. Besides the advantage of better stability,

lyophilized formulations also provide easy handling

during shipping and storage. The awareness of the

complexity of the freezing process and its

consequences on product quality and process

performance is essential for successful lyophilization. The knowledge of how to control, or atleast manipulate, the freezing step will help to develop more efficient lyophilization cycles and biopharmaceutical products with an improved stability.

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REGARDS

Dr. ALI  MANSOOR MALIK

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