Stability Predictions by ASAP

Accurate Shelf-Life Predictions Using Accurate Shelf-Life Predictions Using ‘ASAP’ (Accelerated Stability ‘ASAP’ (Accelerated Stability

Assessment Program)Assessment Program)

Garry Scrivens, Ph.D.Garry Scrivens, Ph.D.Pfizer Global R&D, Sandwich, UKPfizer Global R&D, Sandwich, UK

[email protected]@pfizer.com

http://www.linkedin.com/pub/garry-scrivens/17/8http://www.linkedin.com/pub/garry-scrivens/17/8a0/4a1a0/4a1

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Stability Prediction by ASAPStability Prediction by ASAP

Concept Being PresentedConcept Being Presented Scientifically-driven stability tool which delivers:Scientifically-driven stability tool which delivers:

– Greater abilityGreater ability to detect anomalies/variations in to detect anomalies/variations in stability trendsstability trends

– Greater speedGreater speed than by conventional approaches than by conventional approaches– Greater confidenceGreater confidence in shelf-life projections: less in shelf-life projections: less

arbitrary than conventional expiry-settingarbitrary than conventional expiry-setting– Greater predictive powerGreater predictive power in management of risk: in management of risk:

much more stability information providedmuch more stability information provided

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BackgroundBackgroundASAP is a short duration (typically 2-3 weeks) accelerated stability protocol. The data can be used to accurately predict the stability performance of API and solid-state drug products ASAP is a short duration (typically 2-3 weeks) accelerated stability protocol. The data can be used to accurately predict the stability performance of API and solid-state drug products in any packaging.in any packaging.

ASAP has been shown to be accurate for the majority of products; we have applied ASAP to hundreds of products for over 5 yearsASAP has been shown to be accurate for the majority of products; we have applied ASAP to hundreds of products for over 5 years The effects of temperature and humidity are quantifiedThe effects of temperature and humidity are quantified The ‘isoconversion’ approach improves accuracy and avoids pitfalls associated with multiple API micro-environments in solid-state dosage formsThe ‘isoconversion’ approach improves accuracy and avoids pitfalls associated with multiple API micro-environments in solid-state dosage forms

crystal latticecrystal lattice surfacesurface amorphousamorphous solid-solutionsolid-solution

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R2 = 0.98

0

5

10

15

20

25

30

0 5 10 15 20 25 30

Experimental Shelf-Life (yrs)

AS

AP

She

lf-Li

fe (y

rs)..

ASAP: How Well Does it Work?ASAP: How Well Does it Work?

y = 1.06x

R2 = 0.984

0

1

2

3

4

5

6

0 1 2 3 4 5 6

Check predictions against real-time results

55

0

1

2

3

4

5

0 10 20 30 40 50 60 70

Days

%D

egra

dant

2 tablets

15 tablets

15 tablets +desiccant

Prediction of Prediction of Packaged ProductPackaged Product StabilityStability

open bottle

Drug Product ‘A’ in 60-cc HDPE Bottles (40C/75%RH)

Lines: stability prediction

Datapoints: Actual results

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ASAP: How Well Does it Work for ASAP: How Well Does it Work for Predicting the stability of packaged Predicting the stability of packaged

products?products?

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

0 1 2 3 4 5

Predicted

Observ

ed

T0039T

T0049T

T0069T

T0079T

The ‘observed’ values on the y-axis are the results obtained from the packaged long-term stability study; the ‘predicted’ values on the x-axis are the results predicted from the accelerated stability study. In this plot, results from:

•Four batches•3 month, 6 month and 9 month

•25ºC/60%RH, 30ºC/65%RH, 30ºC/75%RH and 40ºC/75%RH

•Foil-foil blisters and 60 cc HDPE bottles with a 1 g desiccant canister) are presented

E.g.: Product B

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Interpretation of EInterpretation of Eaa Values Values

Shelf-Life at Different Temperatures (Constant RH)Shelf-Life at Different Temperatures (Constant RH)

EEaa (KCal/mol) (KCal/mol) 2020CC 3030CC 4040CC

12 12 3 years3 years 1.5 years1.5 years 299 days299 days

24 24 3 years3 years 290 days290 days 81 days81 days

3636 3 years3 years 149 days149 days 22 days22 days

Ea = 13 Kcal/mol, degradation rate 2x between 25ºC and 35ºCEa = 25 Kcal/mol, degradation rate 4x between 25ºC and 35ºCEa = 38 Kcal/mol, degradation rate 8x between 25ºC and 35ºC

Ea = 16 Kcal/mol, degradation rate 2x between 65ºC and 75ºCEa = 32 Kcal/mol, degradation rate 4x between 65ºC and 75ºCEa = 49 Kcal/mol, degradation rate 8x between 65ºC and 75ºC

(at constant RH)

Ea Term: a measure of the temperature dependence of the degradation

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Interpretation of B ValuesInterpretation of B Values

Shelf-Life at Different %RH Values (Constant T)Shelf-Life at Different %RH Values (Constant T)

BB bottle/desiccantbottle/desiccant 75%RH75%RHopen bottleopen bottle

65%RH65%RHopen bottleopen bottle

0.090.09 3 years3 years 3 days3 days 8 days 8 days

0.040.04 3 years3 years 81 days81 days 121 days 121 days

0.000.00 3 years3 years 3 years3 years 3 years3 years

B = 0.07, degradation rate doubles for every 10% RH increaseB = 0.035, degradation rate doubles for every 20% RH increase

(at a constant temp)

B Term: a measure of the moisture dependence of the degradation

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Example B-Values in Drug ProductsExample B-Values in Drug Products

0

1

2

3

0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.1

B-Value

Nu

mb

er i

n R

ang

e

Oxidation

Cyclization

Hydrolysis

1010

Typical ETypical Eaa and B values and B values(n=60 ASAP Studies)(n=60 ASAP Studies)

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

0 10 20 30 40 50

Ea / Kcal/mol

B

29.8

0.043

(temperature-dependence)

(moi

stur

e-de

pend

ence

)

1111

The formulation that performs best under traditional The formulation that performs best under traditional accelerated conditions may not perform the best under accelerated conditions may not perform the best under

long-term stability conditions:long-term stability conditions:

Ln k

(1/T)25ºC30ºC40ºC50ºC60ºC

ICH

Formulation A

Formulation B

The ASAP approach can detect when this is the

case

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The main degradation product in traditional The main degradation product in traditional accelerated studies is not necessarily the shelf accelerated studies is not necessarily the shelf

life limiting one in real-time:life limiting one in real-time:

Ln k

(1/T)25ºC30ºC40ºC50ºC60ºC

ICH

Deg Prod A

Deg Prod B

The ASAP approach can detect when this is the

case

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Other Applications of ASAP:Other Applications of ASAP:a) In-Use Stability and b) Excursionsa) In-Use Stability and b) Excursions

ASAP data could underwrite in-use stabilities with no additional workASAP data could underwrite in-use stabilities with no additional work Temperature / humidity excursions: better quantification of risk:Temperature / humidity excursions: better quantification of risk:

– Excursions are becoming increasingly common due to increased pharma Excursions are becoming increasingly common due to increased pharma industry activity in India and Chinaindustry activity in India and China

– T and %RH data from environmental loggers can be translated directly into T and %RH data from environmental loggers can be translated directly into [%Deg] using Ln A, B and E[%Deg] using Ln A, B and Eaa parameters parameters

– Also, scientific approach involves determination of the ‘Mean Kinetic Also, scientific approach involves determination of the ‘Mean Kinetic Temperature’ (MKT) over the duration of the excursionTemperature’ (MKT) over the duration of the excursion

MKT = (EMKT = (Eaa/R) / ln { [e/R) / ln { [e-E-Eaa/RT/RT11 + e + e-E-Eaa/RT/RT22 + …. + e + …. + e-E-Eaa/RT/RTnn] / n }] / n }

(as defined by USP)(as defined by USP)

– Calculation of MKT requires knowledge of ECalculation of MKT requires knowledge of Eaa, and is assumed to be , and is assumed to be

~20KCal/mol for all products~20KCal/mol for all products

– ASAP provides actual EASAP provides actual Eaa

– ASAP can be used to calculate the amount of additional chemical degradation ASAP can be used to calculate the amount of additional chemical degradation that results from the excursionthat results from the excursion

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Other Applications of ASAP:Other Applications of ASAP:Humidity ExcursionsHumidity Excursions

Analogously, ASAP allows the calculation of a ‘Mean Kinetic Humidity’ (MKH) Analogously, ASAP allows the calculation of a ‘Mean Kinetic Humidity’ (MKH) which could also prove useful in quantifying risk from humidity excursionswhich could also prove useful in quantifying risk from humidity excursions– Humidity excursions are common and regulators have expressed a Humidity excursions are common and regulators have expressed a

desire for a scientific approaches for assessing impact, and in particular desire for a scientific approaches for assessing impact, and in particular were receptive to the concept of ‘MKH’.were receptive to the concept of ‘MKH’.

MKH = ln { [eMKH = ln { [eB(RH)B(RH)11 + e + eB(RH)B(RH)22 + …. + e + …. + eB(RH)B(RH)nn] / n } / B] / n } / B

– Calculation of MKH requires knowledge of B (therefore can only be Calculation of MKH requires knowledge of B (therefore can only be

calculated through ASAP studies)calculated through ASAP studies)

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ConclusionConclusionWe have successfully applied ASAP in the following areas:We have successfully applied ASAP in the following areas:

Shelf-life assignment for clinical supply productsShelf-life assignment for clinical supply products During DevelopmentDuring Development

– Use ASAP to predict stability for changes in:Use ASAP to predict stability for changes in: Formulations/processesFormulations/processes Synthetic routesSynthetic routes PackagingPackaging Climatic Zone changes (e.g. Zone 3 and 4)Climatic Zone changes (e.g. Zone 3 and 4)

Packaging SelectionPackaging Selection At RegistrationAt Registration

– Use ASAP as supportive data or as an alternative to traditional stability to Use ASAP as supportive data or as an alternative to traditional stability to minimize stability commitmentsminimize stability commitments

– Use diagnostic tools to demonstrate applicability of the ASAP model applied Use diagnostic tools to demonstrate applicability of the ASAP model applied for each drug productfor each drug product

QBD for Stability:QBD for Stability:– ASAP is in-line with the QBD principle of understanding and modelling the ASAP is in-line with the QBD principle of understanding and modelling the

effects of parameters that may affect stability performance (e.g. temperature effects of parameters that may affect stability performance (e.g. temperature and humidity). ASAP can also be used as a tool for rapidly quantifying the and humidity). ASAP can also be used as a tool for rapidly quantifying the stability effects of changes to the product or processstability effects of changes to the product or process

Post-ApprovalPost-Approval– Use ASAP to justify changes that will not affect stabilityUse ASAP to justify changes that will not affect stability– Replace annual commitment with ASAP commitmentReplace annual commitment with ASAP commitment