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Teva Generics System

PQRI-FDA Workshop on Process Drift


December 1-3, 2010

Process Drift Affects Specifications and Shelf-Life


Inna Ben-Anat, Senior Engineer,
Research and Development, Teva Pharmaceuticals USA
Teva Pharmaceutical USA.
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The Boiling Frog Story


The boiling frog story is a
widespread anecdote describing a
frog slowly being boiled alive. The
premise is that if a frog is placed in
boiling water, it will jump out, but if
it is placed in cold water that is
slowly heated, it will not perceive
the danger and will be cooked to
death
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The Boiling Frog Story


The boiling frog story

Process Drift is the change of


normal process behavior over time

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Presentation Outline
Process Drift: Potential Causes
Statistical Tools for Monitoring and Detecting Process
Drift

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 conditionscontinuously
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Process Drift: How Can We Monitor and


Detect It?
Statistical Tools for Monitoring and Trending
Control Charts

Data Modeling/DOE

Capability Analysis

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Process Drift: How Can We Monitor and


Detect 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 throughout
product life-cycle
24 months Shelf-Life is commonly defined based on 12
weeks Accelerated Conditions stability data of the
submission batch
A longer Shelf-Life might be considered based on actual
obtained stability data
Statistical design and
analysis of stability
studies
by Shein-Chung Chow
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Product Shelf-Life Determination


Definition of Shelf-Life (ICH Q1A): The time period during
which a drug product is expected to remain within the
approved Shelf-Life specification, provided that it is
stored under the conditions defined on the container
label

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Product Shelf-Life Prediction


(ICH Q1A(R2))

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Shelf-Life will be determined based on stability data evaluation of


minimum three batches
The degree of variability of individual batches affects the confidence
that 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 intercept
equivalence 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 acceptance
criteria
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Calculation example for Shelf-Life


Re-evaluation: pooled lots data

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Poolability test: Slope and Intercept equivalence model


All the batches can be
pooled together for one
overall Shelf-Life estimate:
slope and intercept
equivalence p-value is larger
than 0.25

All the data presented in this


example is fictitious in sake
of illustrating the calculation
procedure

Intercept p-value
Slope p-value
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Calculation example for Shelf-Life


Re-evaluation: pooled lots data

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Shelf-Life determination based on 95% confidence limit for


the mean curve

Recommended Shelf-Life is 34 months


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Calculation example for Shelf-Life


Re-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 is
20 months based on the lot
with shortest Shelf-Life
prediction

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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 batchtobatch
consistency of predicted performance

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Dissolution Specifications Setting


Current Practice Deficiency

Specifications are set to fit the available, often limited


data
May not be discriminative or sensitive enough to reflect
the true product quality and performance
Absolute Q values based on Mean and do not reflect
Standard Deviation
Based on empirical approach lack of product and
process 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 be


potentially 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 to
monitor and detect process drift impact on dissolution
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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
Year X

Year Y

Year Z

Dissolution Range (Max-Min): Grouped by manufacturing year

Year X

Year Y

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Year Z

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Process Drift May Affect Specifications:


Dissolution Test Example
Dissolution AVG: Grouped by manufacturing year

Year X

Year Y

Date Tested??
Lab Error??
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Year Z

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Process Drift May Affect Specifications:


Dissolution Test Example

Statistical Tools
ANOVA

Is Year Y
significantly
different??

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Process Drift May Affect Specifications:


Dissolution Test Example

Statistical Tools
Regression and Trend
analysis

Is Year Z
stability trend
significantly
different??

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Process Drift May Affect Specifications:


Dissolution Test Example
Instrumentation

The FT4 Powder Rheometer (


) is a universal
powder tester that can measure dynamic flow, shear and bulk
properties of powders and granules:

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Process Drift May Affect Specifications:


Dissolution Test Example

Total Energy (mJ)

FT4 Powder Rheometer Granulation Testing

Lot D
Lot B

Lot C

Lot A

FT-4 powder tester is discriminative enough to


observe the granulation differences and correlate
it with dissolution values
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Specifications Setting
QbD Approach

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Drug Development process understanding and control:


Raw Materials
Properties

Effect Of Formulation on
manufacturing process

Effect Of Manufacturing Process


on critical quality attributes

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 and
experience increases

Life Cycle Management data collection and trending using statistical


tools

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In Process Testing PAT


PAT Process monitoring tools needed to analyze critical
attributes: 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/product
signatures against a reference

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In Process Testing PAT

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Summary
Dont become a "boiled frog": be proactive look for
trends, be a detective explore your data
"Traditional" Specifications based on process
experience; "QbD" specifications leverage process
understanding: increased ability to control the process
and eliminate the drift in the future
Specifications as continuous "real time" assurance of
product quality: life cycle management, data collection
and trending using statistical tools

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References

ICH Q6A Specifications: Test Procedures and Acceptance Criteria


for 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 and


Products

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!

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