Post on 06-Jul-2018
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Inna Ben-Anat, Senior Engineer,Research and Development, Teva Pharmaceuticals USA
PQRI-FDA Workshop on Process DriftDecember 1-3, 2010
Process Drift Affects Specifications and Shelf-Life
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The Boiling Frog Story…
“The boiling frog story is awidespread anecdote describing a
frog slowly being boiled alive. Thepremise is that if a frog is placed inboiling water, it will jump out, but if
it is placed in cold water that is
slowly heated, it will not perceivethe danger and will be cooked todeath…”
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The Boiling Frog Story…
“The boiling frog story …”
“Process Drift” is the change of “normal process behavior” over time
http://www.google.com/imgres?imgurl=http://www.vaniercollege.qc.ca/international-education/images/vefa/question-mark-red.png&imgrefurl=http://www.vaniercollege.qc.ca/international-education/projects/vefa/resources/mdg.html&usg=__fiWACsUXAGSspLfy5fipQjltwSs=&h=300&w=300&sz=7&hl=en&start=12&sig2=H6brt7LDGHnKK76X6HiAOQ&zoom=1&tbnid=MWyQHgAnywFrVM:&tbnh=116&tbnw=116&ei=ILCTTIa4E4SclgfQnIynCg&prev=/images%3Fq%3Dquestion%2Bmark%26um%3D1%26hl%3Den%26tbs%3Disch:1&um=1&itbs=1http://www.google.com/imgres?imgurl=http://www.payrollcheck.co.uk/graphics/warning-sign.gif&imgrefurl=http://www.payrollcheck.co.uk/scam.htm&usg=__yxc7spYAjWy_iu9TbN3Y0xIbtZM=&h=216&w=245&sz=4&hl=en&start=2&sig2=Shbrwz0qC1puQ_BlNRNlYQ&zoom=1&tbnid=rE76B2orThNzcM:&tbnh=97&tbnw=110&ei=7K-TTNHTAsGBlAfJxN2mCg&prev=/images%3Fq%3Dwarning%2Bsign%26um%3D1%26hl%3Den%26tbs%3Disch:1&um=1&itbs=1
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Presentation Outline
Process Drift: Potential Causes
Statistical Tools for Monitoring and Detecting ProcessDrift
Shelf-Life Re-Evaluation Illustration
Process Drift Affects Dissolution Dissolution Test Specifications
Potential root-causes for Dissolution change
Detecting and Monitoring tools and techniques
QbD, PAT and Specifications Setting
Summary and Conclusions
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Process Drift: What Is Causing It?
Raw materials: physical and chemical properties vendors change
Manufacturing equipment: upgraded/downgraded machinery
equipment models/outputs
Operators: knowledge gain and lost recourses availability
Environment
Drift within measurement equipment
Analytical Methods...and many more factors potentially changing the process conditions…continuously
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Process Drift: How Can We Monitor andDetect It?
Control Charts
Data Modeling/DOE
Statistical Tools for Monitoring and Trending
Capability Analysis
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Process Drift: How Can We Monitor andDetect It?
Distribution ANOVA (Analysis Of Variance)
Regression Analysis
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Shelf Life Re-Evaluation
Shelf-Life of a product might be re-evaluated throughoutproduct life-cycle
24 months Shelf-Life is commonly defined based on 12
weeks Accelerated Conditions stability data of thesubmission batch
A longer Shelf-Life might be considered based on actualobtained stability data
“Statistical design andanalysis of stability
studies”
by Shein-Chung Chow
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Generic R&D – CONFIDENTIAL
Product Shelf-Life Determination
Definition of Shelf-Life (ICH Q1A): “The time period duringwhich a drug product is expected to remain within the
approved Shelf-Life specification, provided that it isstored under the conditions defined on the container
label”
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Product Shelf-Life Prediction(ICH Q1A(R2))
Shelf-Life will be determined based on stability data evaluation ofminimum three batches
The degree of variability of individual batches affects the confidencethat a future production batch will remain within specification
throughout its Shelf-Life If the batch to batch variability is small, it is advantageous to
combine the data into one overall estimate – slope and interceptequivalence test
If it is inappropriate to combine data from several batches, prediction is
based on the batch with shortest Shelf-Life
Shelf-Life will be determined based on the time at which the 95%confidence limit for the mean curve (CI) intersects the acceptancecriteria
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Calculation example for Shelf-LifeRe-evaluation: pooled lots data
All the batches can bepooled together for one
overall Shelf-Life estimate:slope and intercept
equivalence p-value is largerthan 0.25
Poolability test: Slope and Intercept equivalence model
Intercept p-value
Slope p-value
All the data presented in thisexample is fictitious in sake
of illustrating the calculationprocedure
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Generic R&D – CONFIDENTIAL
Calculation example for Shelf-LifeRe-evaluation: pooled lots data
Shelf-Life determination based on 95% confidence limit forthe mean curve
Recommended Shelf-Life is 34 months
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Calculation example for Shelf-LifeRe-evaluation: based on the „worst‟ lot data
Shelf-Life determination based on one lot with shortest Shelf-Life(not required in this case)
Recommended Shelf-Life is20 months based on the lot
with shortest Shelf-Lifeprediction
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Process Drift Affects Specifications:Dissolution Test Example
Dissolution/Drug Release Rate is one of the most critical
quality attributes in product development
Used as a quality control tool to ensure batch –to –batch
consistency of predicted performance
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Dissolution Specifications Setting –Current Practice Deficiency
Specifications are set to fit the available, often limiteddata
May not be discriminative or sensitive enough to reflectthe ‘true’ product quality and performance
Absolute Q values based on Mean and do not reflectStandard Deviation
Based on empirical approach – lack of product andprocess understanding
OOS results’ Root Cause is unknown
Variability source is unknown
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Process Drift May Affect Specifications:Dissolution Test Example
Dissolution is one of the most critical quality attributes that can bepotentially affected by process drift
Possible root-causes:
Specifications setting deficiency (previous slide)
Excipients
API
Equipment
Processing parameters
Packaging
Analytical Method
Statistical tools and instrumentation can be utilized in order tomonitor and detect process drift impact on dissolution
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Generic R&D – CONFIDENTIAL
Process Drift May Affect Specifications:Dissolution Test Example
Statistical Tools
Control Charts
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Process Drift May Affect Specifications:Dissolution Test Example
Dissolution AVG: Grouped by manufacturing year
Dissolution Range (Max-Min): Grouped by manufacturing year
Year X Year Y Year Z
Year X Year Y Year Z
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Process Drift May Affect Specifications:Dissolution Test Example
Dissolution AVG: Grouped by manufacturing year
Year X Year Y Year Z
Date Tested??
Lab Error??
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Process Drift May Affect Specifications:Dissolution Test Example
Statistical Tools ANOVA
Is Year Ysignificantlydifferent??
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Process Drift May Affect Specifications:Dissolution Test Example
Statistical Tools
Regression and Trendanalysis
Is Year Zstability trendsignificantlydifferent??
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Process Drift May Affect Specifications:Dissolution Test Example
The FT4 Powder Rheometer ( ) is a universalpowder tester that can measure dynamic flow, shear and bulk
properties of powders and granules:
Instrumentation
http://www.freemantech.co.uk/
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Process Drift May Affect Specifications:Dissolution Test Example
Lot C
Lot D
Lot B
FT4 Powder Rheometer Granulation Testing
T o t a l E n e r g y ( m J )
Lot A
FT-4 powder tester is discriminative enough toobserve the granulation differences and correlate
it with dissolution values
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Specifications Setting –QbD Approach
Drug Development process understanding and control:
Design Specifications early in development-target product profile Root Cause analysis
Gauge R&R to identify source of variability
Specifications as continuous "real time" assurance of product quality,
should evolve during development as process knowledge andexperience increases
Life Cycle Management – data collection and trending using statisticaltools
Raw MaterialsProperties
Effect Of Formulation onmanufacturing process
Effect Of Manufacturing Processon critical quality attributes
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In Process Testing – PAT
PAT – Process monitoring tools needed to analyze criticalattributes: on-line monitoring (NIR, FBRM)
Detecting errors or process deviations and correcting
them while the product is being made Continuous Improvement and control of design space
Impact on Specifications Setting: Quality control testing
will evolve from testing against a discrete specification(pass/fail) to real-time comparison of process/productsignatures against a reference
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In Process Testing – PAT
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Summary
Don‟t become a "boiled frog": be proactive – look fortrends, be a detective – explore your data
"Traditional" Specifications based on process
experience; "QbD" specifications leverage processunderstanding: increased ability to control the processand eliminate the drift in the future
Specifications as continuous "real time" assurance ofproduct quality: life cycle management, data collectionand trending using statistical tools
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References
ICH Q6A – Specifications: Test Procedures and Acceptance Criteriafor New Drug Product
ICH Q8 – Pharmaceutical Development
ICH Q9 – Quality Risk Management
ICH Q10 – Pharmaceutical Quality System
ICH Q1A (R2) – Stability Testing of New Drug Substances andProducts
ICH Q1E – Evaluation of Stability Data – Comments
„Establishing Drug release/Dissolution Specifications – QBD Approach‟, Moheb M. Nasr, Ph.D., ACPS, 2005
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Questions?
Thank you!