Lyophilization Basics

LYOPHILIZATION BASICS What is lyophilization ? ❚Lyophilization is defined as a process of making a product lyophilic i.e. water loving. ❚Material that has been lyophilized has been described as bone dry. ❚Freeze drying or lyophilization is a process of drying in which water is sublimated from the product after it is frozen.

FREEZE DRYING PROCESS Evolution of freeze drying. Important terms ❚Phase : a phase is defined as a any homogenous and physical part of system which is bounded by surface and is mechanicallly seperated from the other parts of the system. ❚Triple point : it is a point were 3 phases namely liquid,solid and vapour coexist at particular temperature and pressure. ❚Eutetic point : the components are completely missible with one another in the liquid state.they do not from any compound and on solidification they give rise merely to an intimate eutetic mixture and the temperature this process occur known as eutetic point. ❚Eutetic temperature : temperature at which all the areas of concentrated solutes are frozen. ❚Latent heat : heat is gained by a substance or system without accompaining rise in temperature during a change of a stage.

Important terms

❚Latent heat of fusion : it is the amount of heat necessary to convert a unit mass of substance form solid state to liquid state at temperature .the pressure being to allow the coexistence of the two phases. ❚Latent of sublimation : it is the amount of heat necessary a unit mass of substance from solid state to gaseous state at same temperature . The pressure being to allow the coexistence of the two phases.

Why lyophilization ?

❚Ease of processing a liquid ,hence easy aseptic handling. ❚Increase stability of a dry powder. ❚Rapid and easy dissolution of dry powder. ❚Enhanced product stability in a dry state.

Disadvantages of lyophilization

❚Increased handling and processing time. ❚Need for sterile diluent upon reconstitution. ❚Cost and complexity of equipment.

Structure of freeze dryer Drying chamber ❚The drying chamber of freeze dryer consist of a vaccum tight unit containing loading door and one or more inspection window. Each chamber contains a set of shelves that has hydrolic stoppering mechanism and gas bleed system. Heat is applied directly through electrical resistance coills or by circulating hotwater, silicon or glycol. Condenser ❚The condenser in the freeze dryer is a vacuum tight unit seperated from chamber by a vacuum valve. They contained a set of cooling plates refrigerated by refrigeration system. Condenser is supplied with hot water defrosting system. It was a cold trap used to collect the moisture. Vacuum pump ❚Each freeze dryer was equiped with a two stage rotary gas ballast vacuum pump.vacuum pump was an essential component of the freeze dryer and is required for evacuated envouriment around the product. Vacuum pump kept the chamber and condensor sufficiently free from the residual gases,

water vapour stream to be able to flow from the drying material. Refrigeration system ❚The freeze dryer is provided with twin independent direct expansion,single or multi-component refrigeration plant. The commonly used refrigerant is Freon R- 502 gas. Control facilities ❚The freeze dryer is instrumented to control and operate the various plant components like shelf staking mechanism,hydraulic stoppering device & chamber condensor valve. ❚Instrumentation is also available to measure and record the various process variables like chamber pressure,shelf temperature, product temperature and condenser temperature.

Typical lyophilization process Operation of freezedryer Operation of freezedryer ❚Secondary drying stage involves the removal of adsorbed water from the frozen product . This is the water which did not as a ice during freezing and so did not sublime. To accomplish the removal of this water the product temperature is usually raised and the chamber pressure reduced further. The product is usually processed until there is less than 1% moisture left in the dried product.

Factors affecting process rate.

❚1) Depth of product in container : the greater the depth of the product in the container the longer will be the drying process. ❚2) vapour pressure differential: the actual driving force for the process is the vapour pressure

differential between the vapour at the surface where drying of the product is occuring and that at the surface of the ice on the condenser.

Factors affecting process rate.

❚3) amount of solid in the product, their particle size & their thermal conductance : the amount of solids in the product ,their thermal conductance will affect the rate of drying. The more solid present,the more impedment will be provided to the escape of the water vapour. ❚The smaller the ice crystal size ,faster the drying rate.

Factors affecting process rate.

❚The poor the thermal conducting properties of the solids in the product , the slower will be the rate of heat transfer through the frozen material to the drying boundary.

Factors affecting formulation

❚The active constituent of many pharmaceutical products is present in such a small quantity that if freeze dryed alone its prescence will be hard to detect visually. Therefore excipents often are added to increase the amount of solids. ❚The solids contents of original products must be between approx 5 to 25%. Therefore mannitol or gelatin are used as bulking agents.

Lyophilization cycles- facts

❚Eutectic determination is very essential for optimizing the drying cycle. ❚For a cycle it is necessary to go atleast 10°c below eutectic point. Any further reduction in the

temperature will ultimately increase the cycle time.Also this reduces the drying cycle time by 50%. ❚By proper freezing the ultimate cycle time can be reduced. ❚Optimizing of the drying cycle is done on lab scale.

Lyophilization cycles- facts

❚In drying the condenser temperature must be atleast 15°c below the drying temperature. ❚During cycle breakage of vials at final stoppering stage is seen which is upto 0.25%.this can be reduced using siliconized rubber stoppers. ❚Cake drying if observed is a result of fast drying.

Lyophilization cycles- facts ❚Greater product thickness in vials will cause more time to freeze dry the product. ❚Thumb rule for fill volume versus vial capacity is 2ml for 10ml. But you can go max. upto 50%. But not more than 50%. ❚The lyophilizer is sterilized after each product change.

Lyophilization cycles- facts

❚For SIP cycle, it is not necessary to defrost the condenser chamber. And similarly for CIP cycle. ❚Lyophilizers can be run on less load also, it is not required to take dummy loads. ❚Cracks in cake come due to thermal changes ,slow middle steps of drying can remove this.

lyophilizer Validation of lyophilizer

❚Validation of filling and stoppering process using media fill.

❚Validation of filling volume into containers. ❚Validation of sterilization of lyophilizer. ❚Validation of handling of partially stoppered vials. ❚Validation of lyophilization cycle using media fill. ❚Validation of the lyophilization cycle based upon eutectic point of the product.

Validation of lyophilizers ❚Product validation in lyophilizer costs 150% of the total cost of lyophilizer. ❚It is not necessary to use thermocouples in production runs. ❚Direct correlation between the thermocouples and the shelf temperature should be established and then remove the thermocouples.

Validation of lyophilizers

❚Any minor change in the formula demands complete validation of the cycle and stability study of the product. ❚Probe placement in the vials should always be in the center very close to bottom. ❚It is always recommended to use thermocouples than R.T.D’s.(PT100).

Validation of lyophilizers ❚Power failures in validation studies should be included and then stability study should be carried out. ❚For cycle development always use the product probes. ❚Hydraulic system validation include checking of stoppered vials manually.

Finished product testing of lyophilized products. ❚Dose uniformity - content uniformity and weight variation. ❚Sterility testing ❚Stability testing - done since some amount of moisture is still present in the product.

Finished product inspection

❚Melt back - generally the lyophilized drug is in form of cake but the cake may collapse due to change from solid to liquid state because of incomplete sublimation. ❚Poor solubility - this may decrease the potency of the drug.