drug product stability accelerated decision making for selecting … · 2015-10-29 · drug product...

FreeThink Technologies, Inc. 2015 freethinktech.com 1

FreeThink Technologies, Inc

Drug Product Stability—Accelerated Decision Making for

Selecting a Package

Kenneth Waterman, Ph.D.

[email protected] 2015 2

Complex Kinetics

• >50% Products show complex kinetics: cannot be fit to simple linear approach • Heterogeneous systems • Secondary degradation • Autocatalysis • Inhibitors

[email protected] 2015 3

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 7 14 21 28

%D

egr

adan

t

Time (days)

Complex Kinetics—Example Drug → primary degradant → secondary degradant

%Deg Prod

Time

30°C

60°C

70°C

Spec. Limit

1 month

Constant Time ‘k’ = Slope of line

Traditional Accelerated Stability

Copyright FreeThink Technologies, Inc. 2015 Freethinktech.com

4

-4

-3.8

-3.6

-3.4

-3.2

-3

-2.8

0.0029 0.00295 0.003 0.00305 0.0031 0.00315 0.0032 0.00325 0.0033

ln k

1/T


5

50°C

60°C

30°C?

70°C More unstable

• Appears very non-Arrhenius • Impossible to predict shelf-life

from high T results

Traditional Accelerated Stability

%Deg Prod

Time

30°C

60°C

70°C

Spec. Limit

3 days 14 days

Isoconversion

‘k’ = Slope of line

Isosconversion Accelerated Stability


6

• Isoconversion: Time to “edge of failure” • Time to specification limit (specific degradant, total

degradant, potency, color change, etc.)

-7.5

-6.5

-5.5

-4.5

-3.5

-2.5

-1.5

0.0029 0.00295 0.003 0.00305 0.0031 0.00315 0.0032 0.00325 0.0033

ln k

1/T

Using 0.5% isoconversion


7

50°C

60°C

30°C

70°C

Using 0.2% isoconversion

Accurate predictions do not depend on the kinetic form

Isosconversion Accelerated Stability

Assumption for ASAPprime models is that the shape of the curve (i.e. degradation kinetics) is similar across different stability conditions, just the timescale is different Real world example (G. Scrivens, 2015)

3.1x faster

3.1x faster

Etc.

11.7x faster


8

Isoconversion Assumption

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-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

0.00280 0.00290 0.00300 0.00310 0.00320 0.00330 0.00340

ln(k

)

1/T (K)

30C

70C

60C 50C

80C

CP-456,773/60%RH

Real time data

ASAPprime Shelf Life 1.2 yrs Experimental Shelf Life 1.2 yrs

[email protected] 2015

Accelerated Aging—Isoconversion Approach Complex Kinetics—Real Example

10

Humidity Corrected Arrhenius

Equation

ln k = ln A - Ea/(RT) + B(RH)

equilibrium relative humidity

Spec. limit/(isoconversion time)

collision frequency

activation energy

1.986 cal/deg

humidity sensitivity factor


11

B 60%RH in PVC

Blister

65%RH in PVC

Blister

0.00

low moisture sensitivity

5.0 yrs 5.0 yrs

0.04

average moisture

sensitivity

5.0 yrs 3.8 yrs

0.09

high moisture sensitivity

5.0 yrs 3.0 yrs


Impact of B Factor on Shelf-Life


Packaging

• Moisture in package equilibrates between headspace + internal components

• Ability of materials to hold moisture depends

on RH (moisture sorption isotherm) • Transfer of moisture into or out of packaging

depends on package permeability • Stability in package linked to ASAP fitting

13

Packaging for Moisture Protection

H2O H2O

H2O H2O

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Moisture Sorption Isotherm

• Weight% water as a function of equilibrium RH

• Measured using dynamic vapor sorption

(DVS) • Mixture weighted average of components • Minor temperature dependence (25-40°C)


Moisture Sorption Isotherm: Crystalline Materials

• Predominantly surface-bound water

• Described by Langmuir Equation: 𝑊𝑡%𝐻2𝑂 =𝐾𝑒𝑞(𝑅𝐻)

1+𝐾𝑒𝑞(𝑅𝐻)

0

0.05

0.1

0.15

0.2

0 20 40 60

Wt%

Wat

er

%RH

Langmuir Fitting of Sorption

Average sorption isotherm of 35 crystalline APIs


Moisture Sorption Isotherm: Amorphous Materials

• Surface-bound water at low RH • Water-water binding at higher RH: solid allows water

condensation

0

10

20

30

40

50

60

70

0 10 20 30 40 50 60 70 80

Wt%

Wat

er

%RH

MCC HEC PVP

Langmuir Region: surface-water interactions

Cooperative Adsorption Region: water-water interactions


Moisture Sorption Isotherm: Amorphous Materials

• As more waters condense, more water-water interactions possible

• Exponential increase in water as a function of RH

1

1.5

2

2.5

3

3.5

4

4.5

35 45 55 65 75

ln(W

t% W

ate

r)

%RH

MCC HEC PVP


Moisture Sorption Isotherm: Amorphous Materials • Condensation (cooperative adsorption) similar for many

excipients

• ln 𝑊𝑡%𝐻2𝑂 = ln+ 𝜷 𝑅𝐻

Excipient ß

Microcrystalline cellulose 0.018

Gelatin 0.021

Hydroxyproylcellulose 0.037

Mannitol 0.044

Hydroxyethylcellulose 0.045

Methylcellulose 0.028

Sodium starch glycolate 0.031

Lactose monohydrate 0.028

Croscarmellose sodium 0.027

Crospovidone 0.021

Povidone 0.029

Pregelatinized starch 0.016

Average 𝜷 = 0.03, same as the average ASAP B term


0

5

10

15

20

25

30

35

10 20 30 40 50 60 70 80

% W

ate

r

%RH

Moisture Sorption by Desiccant (Silica)

Capacity depends on RH


Moisture Equilibration in a Package

• Uncoated tablet: t½ 30 min (solid fraction 0.75) • Moisture barrier coated tablets: t½ 10 hr • Internal RH equilibrates fast: permeation into

package is rate-limiting step


Moisture Vapor Transmission Rate

• MVTR standard term • USP24/NF18 23°C/75%RH • ASTM 3079 37.8°C [100°F]/90%RH

• More fundamental permeability (P) • P = MVTR/ΔRH • Follows Arrhenius temperature

dependence


Pblister = Pdosage area*draw ratio

Draw ratio = surface areaformed/ surface areaunformed sheet

P proportional to V2/3

Permeability of Packaging

40%RH

10 tablets: 170 mg water

Headspace:

30-cc bottle 0.2 mg water

200-cc bottle 1.4 mg water

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Headspace

0

1

2

3

4

5

6

7

0 20 40 60

We

igh

t% W

ate

r

%RH

2:1 MCC:Lactose; 500 mg 40% RH

17 mg water/tablet

1

10

100

10 15 20 25 30 35 40

H2O

(m

g/L

)

T (ºC)

0.018 mg water/mL; 0.0072 mg water/mL @40%RH

Headspace: volume not significant! Surface area: permeability change is important


Link to Stability • Drug degradation occurs predominantly in non-

crystalline domains • Amorphous • Solid-solution • Defect

• Water sorption in these regions is exponential with RH

• Reactivity increases proportionately to amount of water: reactivity depends exponentially on RH


Packaging

• RH generally increases over time in packaging at ICH conditions

• Degradation rate increases exponentially with increased RH: ASAP predicts long-term behavior better than linear extrapolation from 1-year data

• Blisters: higher protection more expensive • Even aluminum-aluminum cold form blisters

cannot match bottles plus desiccant


Excursions • T, RH excursions can impact stability

• Change in RH inside package • T impact directly on reaction

• Can be explicitly calculated using ASAPprime®


Initial Dosage Water Content (Water Activity)

• Stability can be impacted by initial water

activity (water content) • Packaging decision can be linked to initial

water content (lower water release specifications can enable lower barrier protection)

28

•RH inside packaging depends on moisture transfer and re-equilibration inside the package

•Packaging decisions dependent on humidity can be predicted by incorporating RH vs. time into ASAP data analysis

•ASAPprime® makes these determinations easy

FreeThink Technologies, Inc. 2015 freethinktech.com

Conclusions

drug product stability accelerated decision making for selecting … · 2015-10-29 · drug product...

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