General consideration for Process design of lyophilized product
By.Rajeev Sharma
Lyophilization is commonly used in the pharmaceutical and biotech industries to improve stability and shelf life of parenteral dosage forms.
The scope of molecules that are typically lyophilized include proteins, peptides, liposomes etc. .
Lyophilization
Solution Lyophilized Cake
Lyophilization Lyophilization
•Definition- A dehydration process typically used to preserve a perishable material or make the material more convenient for transport.
A process where water is removed from a product after it is frozen and placed under vacuum Ice “sublimates” from solid to vapor without forming a liquid“Three” steps
Freezing (Ramping Time , Annealing or Not, Freezing Temp)
Primary drying (Collapse T, Eutectic T, Glass Transition T,
Pressure Rise , Dew Point & Vacuum Degree )
Secondary drying (Temp. of Drug degradation , Pressure rise )
Lyophilization
Lyophilization
Form Of Water
Desired Freeze Dried Characteristics Sterile & Free from Pyrogen Uniform appearanceIntact cake (Remains intact after shipping/handling)Low moisture contentMinimal particulatesReasonable reconstitution timeChemically Stable
RobustReproducibleScale of manufacture, clinical? commercial?QbDAnalytical testingSpecification settingStability studies
Desired Process design for Lyophilization
Challenges to the pharmaceutical scientist in developing a lyophilized dosage form include:
Excipient selection
Container/closure system
Biocompatibility
Pre formulation and formulation development studies
Reconstitution must result in a biocompatible solution suitable for IV infusion, IM injection or SC injection
Critical Points for Consideration
Critical Points For Consideration
Critical Points for Consideration
Excipients
Bulking Agent- Build structure upon sublimationSucroseMannitolMaltoseDextrose Lactose
ExcipientsStabilizers
• Cryoprotectants (during freezing) they dissolve in water and lower the melting point of water / A cryoprotectant is a substance used to protect biological tissue from freezing damage (i.e. that due to ice formation)
Eg. - PEG, ethylene glycol, propylene glycol, and dimethylsulfoxide (DMSO)
• Lyoprotectants (during drying) Lyoprotection was defined as the stabilization and prevention of the degradation of a macromolecule both during freeze-drying and afterwards, during storage.)
Eg. – Disaccharides (Sucrose, Maltose , Lactose)
Excipients
Buffers• Citrate• Histidine
Avoid salts that undergo pH change during freezing such as
• Phosphates
Excipients
Tonicity Adjusters•NaCl•Mannitol•Sucrose(caution using in some patient populations)•Glycine•Glycerol
Container Closure Selection
Vial size•2 mL, 5 mL, 10 mL, 20 mL, >20 mL
Vial type•Glass•Other
Stopper•Material•Coating•Size - 13 mm, 20 mm
•Crimp seal•Color•Type
Vials, Rubber stopper & Seals Vials , Rubber stopper & Seals
Glass Transition Tg and Collapse Tc Temperatures
In the great majority of cases the solutes do not crystallize at the solubility limit, ice continues to form as the temperature is decreased and the solution continues to concentrate until it is so viscous it turns to glass.
This it does at a characteristic and reproducible temperature, the glass transition temperature Tg'. The “prime” mark is used to denote this is the glass formed by freeze concentration, a glass which may still contain 20-50% by weight of unfrozen water.
Glass Transition Tg and Collapse Tc Temperatures
This water is not bound in any way but diffusion is limited by the extremely high viscosity of the glass. For products that behave like this, Tg' is the temperature at which the ice starts to melt back and the product starts to collapse. (i.e. Tc=Tg′).
The glass transition and the eutectic melt have quite different profiles in a DSC scan, the glass transition is a step like transition whereas a eutectic melt appears as a peak, or trough depending upon the set up of the DSC.
Collapse Temperature
Crystalline state-If decreasing the temp crystal appears (liquid to solid) is known as eutectic temp. and latent heat was released in this process.Glassy state- if decreasing the temp. where liquid changes in glass (not solid) that temp is know as glass transition temp.
Collapse Temperature
In Drying process ice sublimates through the pores as shown in picture (left side) but if we increase the temp continuously brown layer of drug change (shown at right side) the pores start blocking up above the layer of ice , where water does not removed at the point, this temp is known as collapse temp.The value of collapse temp. depends on the drugs properties, formulation , cooling methods and so on.
Collapse temp. can be determined by Freeze drying microscope (FDM). Light black is frozen layer , black portion is drying layer and border line between both is sublimation front.If we increases temperature continuously the drying layer starts increasing and sublimation front starts increasing from left to right. at the particular temperature The water blockage starts which is shown in right pic (white border) which is collapse region. We can not make the product collapse. The collapse temperature is the safest temp of primary drying.
Components Tg Tc
Protein
Glycosidase -29 -15Ovalvumin -11 -10
ruhMAB HER - -20
Sugar
Sucrose -32 -31Trehslose -29 -28.5Lactose -28 -30.5Maltose -30 -
PolyolsGlycerol -65 -Sorbitol -46 -Mannitol -35 -1.4
Polymers
Dextran (70K) -10 -10Polyvinylpyrrolidone
(PVP) (40 KD) -21 -24Ficoll -19 -20
Gelatin -9 -8
Hydroxyethyl Starch -12 >-5
Amino AcidGlycine -62 -3.5Alarrine -65 -Histidine -33 -
Salts
Sodium acetate -64 -Sodium citrate -41 -
KH2PO4 55 -K2HPO4 65 -
NaCl -60 -CaCl2 -95 -ZnCl2 -88 -
Preformulation Studies
SolubilitypH stabilityStability under different temp. DSC thermo gramsGlass transition temperatureCounterionBuffer saltPolymorphism
Formulation Process Studies
Aseptic process designSterile filter selection
•Compatibility•Formulation•Microbial retention•Filter validation
Compatibility with compounding vessels, tubing, etc.Bulk solution stabilityBioburdenFill volume
Process Design Studies
Pre-freeze•Shelf temp
Freeze•Pore structure determined by freezing rate•Desired crystalline structure•Maintain well below Tg
AnnealPrimary Drying
•Sublimation under vacuum•Avoid melt back while achieving reasonable cycle time
Secondary Drying•Isothermal desorption of bound water
Post Cycle•Stopering
Process Flow
Process Flow
Stability Testing
AppearanceReconstitution timePotencyPurityWater contentpHSterilityEndotoxin
Setting of Specification
In-process•Potency•pH•Osmolality•Density•Bioburden•Appearance
Fill weight
Setting of Specification
Finished product•Potency•Purity•Reconstitution time•Appearance•Sterility•Endotoxin
Thanks
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