Strategy for Design Space/stability Considerations

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Strategy for Design Space/stability Considerations Generate process materials Chemical Evaluations Physical Evaluations Develop correlation Correlate to shelflife Build Design Space

description

Strategy for Design Space/stability Considerations. Generate process materials. Build Design Space. Physical Evaluations. Chemical Evaluations. Develop correlation. Correlate to shelflife. Incorporating Stability in Design Space. Manuf. Design Space Model. End of Expiry. - PowerPoint PPT Presentation

Transcript of Strategy for Design Space/stability Considerations

Page 1: Strategy for Design Space/stability Considerations

Strategy for Design Space/stability Considerations

Generate process materials

ChemicalEvaluations

PhysicalEvaluations

Develop correlation

Correlate to shelflife

Build Design Space

Page 2: Strategy for Design Space/stability Considerations

Incorporating Stability in Design SpaceManuf.Design SpaceModel

Endof

Expiry

• Key Research Objectives• What Design Space Outputs Link to Shelf-life• How can the Design Space/Stability Model be

used to strengthen or simplify manufacturing design

Page 3: Strategy for Design Space/stability Considerations

Key LinkageManuf.Design SpaceModel

Post-Manuf.

StabilityModel

Endof

Expiry

• Post-manufacturing stability model that accounts for storage effects in a predictive way

Page 4: Strategy for Design Space/stability Considerations

Incorporating Stability in Design SpaceManuf.Design SpaceModel

L0F0

Post-Manuf.

Degradation

Model

LtEndof

Expiry

• Key Research Objectives• Characterize process altered API• Identify methods to measure L0 and F0

• Develop predictive degradation model• Define effect of processing variation on

predictive model• Validate predictive model with long term studies

Page 5: Strategy for Design Space/stability Considerations

Underlying premise

Physical Forms

Chemically-active API Degraded API

FormulationManufacturing Attributes

Tendency to

transform

Page 6: Strategy for Design Space/stability Considerations

STEPWISE 1

Manuf.Design SpaceModel

Man

ufac

turin

g

Varia

bles

Stab

ility

-rele

vant

Outp

uts

1. What are “Stability-relevant” outputs?

2. Data base to develop design space models

Page 7: Strategy for Design Space/stability Considerations

STEPWISE 2

Post-Manuf.

StabilityModel

Time to

Expiry(Shelf-

life)

Stor

age

Varia

bles

Desig

n sp

ace

Outp

uts

3. Form of post-manufacturing stability model to account for storage variables (RH, temperature, excipients)

4. Parameterization of model: short-term deg studies

5. Demonstrate of model predictability: long-term deg. studies

Page 8: Strategy for Design Space/stability Considerations

Effects of manufacturing stress

API

MANUFACTURINGSTRESS CONDITIONS

IntactAPI

DegradedAPI

AlteredAPI

formulation

• SSNMR• Initial rate• in-process lactam

Page 9: Strategy for Design Space/stability Considerations

Development of degradation model

Post-Manuf.

StabilityModel

Time to

Expiry(Shelf-

life)

Stor

age

Varia

bles

Desig

n sp

ace

Outp

uts

3. Form of post-manufacturing stability model to account for storage variables (RH, temperature, excipients)

4. Parameterization of model: short-term deg studies

5. Demonstrate of model predictability: long-term deg. studies

Page 10: Strategy for Design Space/stability Considerations

Preliminary Post-Manufacturing Degradation Model

GABA (G): crystalline (Form II) gabapentinDisorderd-GABA (D): gabapentin with some loss of critical crystallinityLactam (L): Chemically –altered and non-crystalline

GABA

DisorderedGABA

LACTAM

Page 11: Strategy for Design Space/stability Considerations

Linking Stability in Design SpaceManuf.Design SpaceModel

L0D0

Post-Manuf.

Degradation

Model

LtEndof

Expiry

• Key Research Findings• Methods characterize process altered API: MSM• Solid state degradation model form accounts for

temperature, humidity, excipients• Preliminary correlation between MSM and shelf-

life• SSNMR methods to verify manufacturing effects

Page 12: Strategy for Design Space/stability Considerations

The Pharmaceutical Stability Predicament

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PerformanceDrug release kinetics

PotencySafetyUtility

Acceptability

Manufacturing stress

Storage stress

Shipping stress

Product use stress

Prob

abili

ty o

f fai

lure

(mul

timod

al

Accumulative stress and time

gradual

catastrophic

stable

critical failure

Page 13: Strategy for Design Space/stability Considerations

Current and Future Paradigm• Deterministic

– stable or not• Measurability-based

– “significant change” based on detection

• Impact arbitrary– historical rather than

situational-based• Prediction based on

post-assembly stress– storage environment and time

• Stochastic– based on probability

• Performance-based– “significant change” based

on performance• Therapeutic impact

– evaluation of the effects dose regimen, patient population, in vivo performance on stability limits

• Prediction includes design, assembly and post-assembly stress

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Page 14: Strategy for Design Space/stability Considerations

Research Opportunities

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Current state

Future state

Fundamental physical and biophysical studies of exemplary drug instability processes in complex systems

Tools to assemble scientifically-rational stability design space models

Methodologies for incorporatingdesign space models into stability

prediction models

Design of models to link design space-stability to clinical performance in relevant patient populations

based on intended therapeutic use regimens

Page 15: Strategy for Design Space/stability Considerations

Overarching objective: integrating stability in QbD

2. Design Space Model

L0&F0

3.Post-Manufacturing Degradation Model

Lt

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1.Physical and Chemical Markers

4. Therapeutic Utility/Safety Model

Page 16: Strategy for Design Space/stability Considerations

NIPTE Project Team for Gabapentin Case Study

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Research• H. Arastapour , ChE, IIT

Fluidization & multiphase systems• R.Bogner, PhSci, UCONN

Drug release, solid dosage forms• A.Cuitino, ME, Rutgers

Material mechanics, Multiscale modeling

• J. Drennen, PhSci, DuquesnePAT and Risk Management

• S. Hoag, PhSci, Umarylandcompression modeling

• M. Khan, PhSci, FDAPharmaceutical Technology

• L. Kirsch, PhSci, IowaDrug stability & quality

• J. Litster, ChE & IPPH, PurdueGranulation & Powder Technology

• E. Munson, PhSci, KansasCharacterization of solid pharmaceuticals

• F. Muzzio, ChE, RutgersPowder mixing & flow behavior

• G.Reklaitis, ChE, PurdueProcess systems engineering

• R. Suryanarayanan, PhSci, UMinnMaterial science of pharmaceuticals

NIPTE Administration• P. Basu, Exec Director, NIPTE

QbD & Pharmaceutical economics• V. Gurvich, Assoc Director, NIPTE

Medicinal chemistry & organic technology

Page 17: Strategy for Design Space/stability Considerations

Essential research questions for addressing instability mechanisms

• What are the relevant structural probes for identifying and quantifying reactive forms?

• What is the relationship between physical and chemical transitions?

• Are there underlying rules that can be used to predict instability based on inherent chemical and physical properties of drug substances and excipients in complex milieu (e.g. solid state formulations) or for complex drugs (e.g. biopolymers)?

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Page 18: Strategy for Design Space/stability Considerations

2. Integrating stability probes into design space models: Traditional approach using response surface (e.g. milling)

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Batch size2 4 6 8 10

Mill

ing

Spee

d

4

5

6

7

8

5 10 15 20 25 30

Batch Size

2 4 6 8 10M

illin

g Sp

eed

4

5

6

7

8

0.6 0.8 1.0 1.2 1.4 1.6 1.8

Predicted Degradation (% mole)

Surface Area Stability

220

2111211222110, PPPPPPStabilitySA

Page 19: Strategy for Design Space/stability Considerations

Design Space: acceptable surface area and stability

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Batch Size2 4 6 8 10

Mill

ing

spee

d

4

5

6

7

8

Page 20: Strategy for Design Space/stability Considerations

Essential research questions for advancing design space

• What are sophisticated modeling approaches that move away from the flashlight in the cave syndrome?– Methods that incorporate prior knowledge (e.g. Bayesian

approaches)– Methods that make realistic parameter distribution

estimations– Modeling methods that incorporate our understanding of

unit operations physics and material properties• Dr. Drennen’s review of recent approaches

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Page 21: Strategy for Design Space/stability Considerations

3. Linking shelf-life and manufacturing models

STORAGESTRESS CONDITIONS

IntactAPI

DegradedAPI

AlteredAPI

DegradedAPI

FormulationShelf-life

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API stressed-process offraction totalingmanufactur of endat API altered-process undegraded of (%)fraction

ingmanufactur of endat API degraded chemically of (%)fraction

00

0

0

FLFFL

total

Page 22: Strategy for Design Space/stability Considerations

Key research questions: linking DS to stability prediction models

• What are effective methods for incorporating the output of design space models (stability-relevant material characteristics) into shelf-life prediction models ?– Application of Bayesian approaches to estimate parameter

distributions rather than single-point estimation– Development of biomolecule and small molecule stability models

based on isoconversional concepts– Determination of key manufacturing –induced physical changes

that form the basis for subsequent physical and chemical instability under environmental stress

– Assessment of excipient roles in shelf-life prediction models : Do they catalyze/stabilize chemical or physical transformations

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Page 23: Strategy for Design Space/stability Considerations

What is a meaningful stability specification?

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• Is 90 or 95 % potency relevant for the therapeutic use of all drugs irrespective of therapeutic use and index, population variability, pharmacokinetics or pharmacodynamics?

• Is 1% or 2% level of a specific related substance meaningful irrespective of the drug-like properties, pharmacokinetics, dosage regimen, or toxicokinetics of that related substance?

• Does it make sense from a QbD-standpoint to fix the impurity profile of a drug product based on toxicology studies on pre-clinical drug product batches?

• How can we meaningfully address the potential safety and efficacy issues that relate to drug product stability as determined by product design, manufacturing and storage?

Page 24: Strategy for Design Space/stability Considerations

Simplified model

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Degradationproduct profile

Dosage RegimenRanges

ClearanceVariation

AverageSteady-state

Concentration

ResponseModel

Variation

Probabilityof Mild

AdverseEffects

Page 25: Strategy for Design Space/stability Considerations

Monte-Carlo simulation and logistical regression

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0.00

0.25

0.50

0.75

1.00

0 .01 .02

Prob

abili

ty o

f MA

E

fraction of degradation product

Maximum acceptable risk

Meaningful Degradation Product Specification

Page 26: Strategy for Design Space/stability Considerations

Summary of Suggested Stability Research Investments1. Molecular basis of instability pathways for complex

molecules or for simple molecules in complex formulation milieus

2. Development of quantitative frameworks for relating the effects of product design variation and manufacturing stress on stability-relevant material characteristics

3. Methodologies for incorporating the output of design space models shelf-life prediction models

4. Design and development of population-based clinical product performance models to link design space-stability models to clinical performance in relevant patient populations based on intended therapeutic use regimens

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