ISPE_GLChapterMiltonLyophilization2010Pres

Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 1

Pharmaceutical Freeze Drying:

The Lyophilization Process


Outline

I. What is freeze drying?II. Reasons for freeze dryingIII. Steps in freeze drying

A. FreezingB. Primary DryingC. Secondary Drying

IV. Case StudiesV. Pros and Cons of Freeze Drying


I. What is Freeze Drying?

Definition of Freeze Drying

To dry (as food) in a frozen state under high vacuum esp.for preservation (Webster Dictionary)

... a means of drying, achieved by freezing the wet substanceand causing ice to sublime directly to vapor by exposingit to a low partial pressure of water vapor (Sterile PharmaceuticalManufacturing - Applications for the 1990s)


II. Reasons for Freeze Drying?

Material chemically unstable in solution Low temperature drying process Compatible with protein pharmaceuticals The amorphous form of the drug is desirable

(i.e., solubility) Low particulate contamination Compatible with aseptic/sterile processing


Pharmaceutical Freeze Drying Involves:

1. Dissolving the drug and excipients in a suitablesolvent, generally water.

2. Sterilizing the bulk solution by passing it through a bacteria-retentive filter.

3. Filling into individual sterile containers.

4. Freezing the solution by placing the opencontainers on cooled shelves in a freeze dryingchamber or pre-freezing in another chamber.

5. Applying Vacuum to the chamber and heating theshelves in order to sublime ice.


Desired Freeze Dried Characteristics

Intact cake Sufficient strength Uniform color Sufficiently dry Sufficiently porous Sterile Free of Pyrogens Free of particulate Chemically stable

III. Steps in Freeze Drying

A. Freezing Freezing of water into ice to produce a rigid frozen

solute structure Solutes concentrate between ice crystals

B. Primary Drying Removal of ice via sublimation Product temperature less than Collapse temperature

C. Secondary Drying Remove adsorbed water Achieve moisture content needed for stability



Vacuum Pump

Compressor

Heater

HeatExchanger

Shelf FluidPump

Chamber Condenser

Condensing Coils

Product Shelf

Freeze Drying Equipment


Time (Hours)0 10 20 30 40 50 60

T

e

m

p

e

r

a

t

u

r

e

(

o

C

)

-40

-20

0

20

40Shelf Temperature

Mean Product Temperature

Steps in Freeze Drying

A B C

Chamber Pressure

100

80

120

140

60

P

r

e

s

s

u

r

e

(

m

i

l

l

i

t

o

r

r

)


Freeze Drying

Solution Powder

TemperatureTime

Pressure


Cooling

Supercooling

Ice Nucleation

Crystal Growth

Concentration of SolutesIonic strengthReaction ratesPrecipitation of Buffers - pH shifts

Amorphous solute

vitrification

Metastable Amorphous Solute annealling

Crystalline / Amorphous mixture

Crystallizationof solute (eutectic)

Lyotropicliquid

crystals

A.

B. C.

D.

A. Freezing Process


Crystalline Solutes

After Freezing(Freeze Concentrate)

Some solutes crystallizewith ice during freezing

Eutectic Mixture

Crystalline solutes

The temperature where solute and ice both exist in a rigid crystallinestate is the eutectic temperature.

For example, NaCl forms a eutectic mixture containing 23.3%NaCland melts at -21.13oC.


Amorphous Solutes

After Freezing(Freeze Concentrate)

Most solutes dont crystallizeand form a random (amorphous)viscous glassy phase

Glassy Mixture

Amorphous solute

In these systems the viscosity of solute phase increases until the solute is completely immobile and behaves like a glass.

The temperature where the solute behavior changes from solutionto a rigid glass is the glass transition temperature.


Physical State of the Solute and Temperature:Significant Impact on Freeze-Drying Behavior


Types of Freeze-Drying Behavior: Crystallization of Nafcillin During Annealing


B. Primary Drying

The sublimation of ice from the frozen solution to create a dried layer of solute

Solute must form a rigid structure to support its weight after the removal of ice.

Maintaining product below the collapse temperature is critical to produce acceptable material

Consequences of improper temperature control Collapse product Shrunken freeze dried plug Melt-back


Product Collapse - during freeze drying product temperatureexceeds the collapse temperature and the material collapse as ice is sublimed.

SoluteIce

Fill volume

After ice sublimed a dried residue of solute is produced.


Types of Freeze-Drying Behavior: Collapse


Example Of Collapse Annealed vs. Unannealed Sucrose/Glycine

Formulations


Significance of Temperature

Collapse temperatures are formulation dependent

During Freeze Drying Primary drying (I.e., ice sublimation), Glass transition temperature, Tg

TTg

"Rigid" Solid Semi-solid "Fluid" Liquid

Increasing molecular mobility & "reactivity"


How is Product Temperature Controlled during Primary Drying?

Product temperature is controlled indirectly:a. Chamber pressure

- Heat Transfer- Mass Transfer (Product Resistance)

b. Shelf temperature- Heat Transfer

TFreeze Dryer Shelf

Condensingcoils


Properly dried material produces a well formed cake with no apparent shrinkage.

Product temperature is critical during primary drying

Important Points about Primary Drying

Changes in product temperature during drying may influenceappearance of final product

Damage which occurs during primary drying can not be repaired.


m

Freeze drying is a process where heat and mass transfer are coupled!

Tb

TiPo

Pc

Rp

Kv

Shelf Temp - Ts

Ice

Q


Influence of Vapor Flow Resistance on Product Temperature

m

Rp

Ice

Dried Layer

Ice

Vacuum Interface

Water vapor must have enough energy to pass through the dried layer and to the condenser

As resistance increases more energy (heat) is needed for water vapor to escape

Product temperature increases with increasing resistance

Heat Heat

Mass

Water vapor

Nitrogen

Ice/ProduceInterface


Why Does Product Collapse => Product Resistance

SolutionFrozen

ProductHeated

IceSublimes

(Heat Removed)

ProductResistanceIncreases

VaporPressureIncreases

TemperatureIncreases

IsT > Tc

?

Yes

Collapse

NoDry?

Yes

Dry Cake

No


Heat and Mass Transfer Equations Describing Freeze Drying

( ) ( )m

A P PR R

A P P

R

p o c

p s

p o c

p

=

+ =

Eq. 1

wherePc = chamber pressure/

(above dried solute)Rp = product resistanceRs =stopper resistancem = rate of sublimationPo = vapor pressure of ice

.

Relationship between chamber pressure and vapor pressureof ice (I.e., ice temperature)

mQ A K T T T

s

v v S I

s

= =

( )

Eq. 2

Relationship between shelf temperature and ice temperature

Av = surface of vialKv = vial heat transfer coefficientTs = shelf temperatureHs = enthalpy of sublimationT = temperature difference

across ice slabTI = temperature at the ice

interface


TPI o

= 6144 9624 01849

27315.ln .

.

The relationship between the vapor pressure of ice and ice temperature is

Eq. 3

Combining Eq. 1, 2, and 3 yields Eq. 4

( )( )

RP P

K T TP

psAA o c

v so

p

v

=

6144 96

24 0184927315.

ln ..

Eq. 4

Eq. 4 describes the relationship between product resistance, vapor pressure of ice (product temperature), the shelf temperature, and chamber pressure).


Product Resistance (torr cm2 hr gm-1)0 2 4 6 8 10 12 14 16 18

V

a

p

o

r

P

r

e

s

s

u

r

e

o

f

I

c

e

(

t

o

r

r

1

0

-

3

)

200

400

600

800

1000

AB

C

Regression analysis of vapor pressure of ice and product resistance datacollected at a shelf temperature of 20C and 100 millitorr (A), shelf temperature 0C and 100 millitorr (B), and shelf temperature of -20C and chamber pressure 80 millitorr with Eq. 4 assuming a 2 degree temperature gradient across the ice slab.

Increase Rp related to increase Po (i.e., Temperature)


Removal of adsorbed water from the dried solute (no ice present)

5% water 0.1% water

Controls moisture level in product to maintain proper chemical and physical stability.

Reversible process (can de-humidify and humidify product to change moisture content)

C. Secondary Drying


DegradationConcentration effects during freezing

ReconstitutionDisperse material in freeze dried cake

CollapseGlycine and mannitol bulking agents raise Tc

Damage during freezing and dryingCryoprotectants and lyoprotectants

Stabilizers (amorphous)Sugars (sucrose, lactose), glycine

Adherence to glassSurfactants, silicone

Critical Points for Consideration


Critical Points for Consideration Physical state in frozen solution

Excipient and active pharmaceutical ingredient Physical state in freeze dried powder

Impact on physical and chemical stability Influence of processing conditions

Changes in thermal history can changed the physical state of material(s) and effect process compatibility and chemical stability

Understanding facilitates formulation development, process design and control

Case Study


Nafcillin SodiumN. Milton and S. L. Nail. The physical state of nafcillin sodium in frozen aqueous solutions and freeze-dried powders.Pharmaceutical Development and Tech, 1 (3), 269-277, 1996.

Buffers and pH control


Isothermal Crystallization

Photomicrographs of 25% nafcillin sodium frozen solution using crossed polars and first order red compensator: A) frozen solutionat -10C, B) frozen solution at -4C, C) frozen solution after 5 minutes at -4C, and D) frozen solution after 15 minutes at -4C.


Solid state decomposition at 50C of nafcillin sodium unannealed(open symbols) and annealed (closed symbols) stored at 11%

(squares) and 23% (triangles) relative humidity.Unannealed less stable than Annealed


Case Study - Buffer Selection

Preliminary data suggested the optimal solution pH between 4 - 5

Formulations prepared with acetate, citrate and tartrate buffers

All buffers were prepare in equal molar concentrations and adjusted with NaOH

Acetate buffer least stable (Why?)


pH 4.0

02468

10121416182022

0 1 2 3 4 5Time, (Weeks)

%

T

R

S

Acetic acidCitric acidTartaric acid

pH 4.5

02468

10121416182022

0 1 2 3 4 5Time, (Weeks)

%

T

R

S

Acetic acidCitric acidTartaric acid

Effect of various Buffers on Stability (100 mM)

Review of Data pH of reconstituted acetate buffer formulation

increased 1.58 - 1.78 pH units Acetic acid component of buffer system Acetic acid is volatile and evaporates Loss of acetic acid leads to increase in

formulation pH and poor stability Avoid use of volatile buffer species or other

materials (I.e., ammonium salts)


Conclusions


Advantages of Freeze Drying

Disadvantages of Freeze Drying

1. Low particulate contamination2. Solid more stable than solution3. Low temperature process => less in-process degradation4. Compatible with aseptic processing5. Can be easily reconstituted

1. Cost => capital expenditures, process long and expensive2. Difficult to produce crystalline material


Freeze drying provides a method of drying temperature labilematerials.

The freeze drying process is divided into 3 steps:- Freezing- Primary Drying- Secondary Drying

Freeze drying is often the last choice in methods for dryingmaterials, because the cost and time required.

Changing the freezing, primary drying, or secondary dryingconditions can influence the physical and chemical stability of the final product

Conclusions

Pharmaceutical Freeze Drying:Outline I. What is Freeze Drying?II. Reasons for Freeze Drying?Slide Number 5Slide Number 6Slide Number 7III. Steps in Freeze DryingSlide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Influence of Vapor Flow Resistance on Product TemperatureSlide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Case StudySlide Number 34Slide Number 35Slide Number 36Slide Number 37Slide Number 38ConclusionsSlide Number 40

Documents

ISPE_GLChapterMiltonLyophilization2010Pres