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Process Capability: More than
Just a Quality Metric: It is Quality
Behavior
Helen Strickland 28October2015 AAPS Annual Meeting Orlando, FL
Promote Statistical Thinking
The long-range contribution of Statistics depends not so
much upon getting a lot of highly trained statisticians into
industry as it does in creating a statistically minded
generation of physicists, chemist, engineers and others who
will in some way have a hand in developing and directing
the production processes of tomorrow.
Process Capability: More than Just a Quality Metric: It is a Quality Behavior 2
Walter A. Shewhart
1890 -1967
W. Edwards Deming
1900-1993
28October2015
Process Capability: More than Just a Quality Metric: It is
a Quality Behavior
3 28October2015
Intent of Process Capability Indices
Basic Equations
Probability Distributions—Normal and Skewed
State of Control
Control Strategy
Statistical Measures from Control Charts
SPC, SQC Control Charting
Summary
Additional Acceptance Sampling & Process Capability
Outline
Process Capability: More than Just a Quality Metric: It is
a Quality Behavior
4 28October2015
Are a measure of the process’s ability to produce product that
complies with specification.
Provide an estimate the amount of product outside specification—
the proportion of individual units/items/entities outside numerical
limits in the case of quantitative variables.
Process Capability Indices
Process Performance Indices
Basic Intent of Performance and Capability Indices
Process Capability and Process Performance Equations
28October2015 Process Capability: More than Just a Quality Metric: It is a Quality Behavior 5
Computations for Non-Specified
Distribution Computations for Normal Distribution
Process Capability
Process Performance
Process Capability-Normal Distribution—Tail Behavior
6
Process Capability-Skewed Distribution—Tail Behavior
7
Process Capability: More than Just a Quality Metric: It is
a Quality Behavior
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A condition in which the set of controls
consistently provides assurance of
continued process performance and product
quality.
State of Control ICH Q8
Process Capability: More than Just a Quality Metric: It is
a Quality Behavior
9 28October2015
Product Characteristic in Control Distribution of the CQA
Does not practically change, or
Changes in a known manner or
within known limits
Stable Process Process in a state of statistical
control
A production in control is a
production with processes in control
Samples taken at any time during
the manufacture are simple random
samples from the same population
Variation Inherent—Predictable
Special Cause—Not Predictable
State of Control--ISO 22514
State of Statistical Control Considerations
Process Capability: More than Just a Quality Metric: It is a Quality Behavior 10 28October2015
Traditionally, when the probability distribution of the characteristic of
interest is constant over time.
“Generalized” extends to cases for which an underlying statistical
model of the quality characteristic is stable over time (Woodall:
2000).
Statistical model could included autocorrelation and multiple
variance components related to batch effects?
Control Strategy & Process Capability
11
Image from L. Yu., et.al, Understanding Pharmaceutical Quality by Design, 2014, The AAPS Jourrnal, Vol. 16, No. 4, July DOI:10.1208/s12248-014-99598-3
What type of Control Strategy will you
develop to support Batch Release
decisions during routine commercial
manufacture?
Minimal Control Strategy
Traditional Development Approach
Product Based Inferences of Quality
Conformance to Specification
utilizes SQC of lagging Product
Quality Indicators
Enhanced Control Strategy
QbD Development Approach
Process Based Inferences of Quality
Conformance to Specification relies
more on SPC of Leading Process
Indicators and less on SQC of
lagging Quality Indicators
Process Capability: More than Just a Quality Metric: It is a Quality Behavior 28October2015
Control Strategy: Use of SPC & SQC
Process Capability: More than Just a Quality Metric: It is a Quality Behavior 12 28October2015
SPC Process Based Inference
Uses Control Charting to analyze process
INPUTS
Critical Material Attributes
Critical Process Parameters
Leading Indicators
Identifies Process Drift before
Product Quality Drift
SQC Product Based Inference
Uses Control Charting to analyze process
OUTPUTS
Critical Quality Attributes
Product Quality Characteristics
Lagging Indicators
Detects Product Quality Drift after
Process Drift
28October2015 13 Process Capability: More than Just a Quality Metric: It is a Quality Behavior
During Process Performance Qualification and Continued Process Verification 3A
1) Confirm probability distribution,
2) Obtain statistical measures of the process output (CQA mean and variation)
3) Compute initial estimates of process capability or process performance
4) Determine Control Chart Limits for routine release
Process Capability: More than Just a Quality Metric: It is a Quality Behavior 14 28October2015
0.6 %<85, CpkL=0.83 1.33 % >115, CpkU=0.73
0.135 %<85, 0.135 %>115,Cp=1.0 ≈0 % Units<85, ≈ 0 %>115,Cp=2.0
Example: Distribution for Capability Indices
Process Capability: More than Just a Quality Metric: It is a Quality Behavior 15 28October2015
Capability and Performance are about making examinations of the
natural variation pattern a process produces during a given period of
time.
Capability and Performance ISO Acknowledges large shifts in opinion
and they addresses through firm distinction between capability
conditions & performance conditions.
If the process is in a state of statistical control, the pattern of the
distribution should be predictable. Product Data and Process Data
After you have demonstrated that the process is capable, and that it
has operated in a state of statistical control,
The Cpk value is only valid for a process under statistical control, and
therefore, can only be used in connection with SPC methods that
ensure an ongoing verification of the process stability.
Process Capability: Quality Behavior before Quality Metric
Summary
Process Capability: More than Just a Quality Metric: It is
a Quality Behavior
16 28October2015
The original intent of process capability and process performance indices
was not to determine how often we would fail our acceptance sampling
procedure, it was to represent the quality of the product provided to the
consumer. And that is how many sub or super potent doses are being sent
to market.
How does one reconcile the intent of the acceptance sampling plan, if
6.25% is the quality level at which there is a 5% probability of accepting and
sending to the patient based on the individual sampled batch.
Process Capability & Acceptance Sampling of UDU
Process Capability: More than Just a Quality Metric: It is
a Quality Behavior
17 28October2015
If a single dose less than LSL %label claim can be considered sub-potent
and a single dose greater than USL %label claim can be considered super-
potent, which limit is to be used?
Uniformity Tests (Acceptance Sampling Plans) concerned with ensuring
there is not an excessive percentage of sub-potent or super-potent doses in
the product released to the patient.
A 95% confidence/87.5% coverage PTI-TOST acceptance sampling plan
corresponds to the a priori claim: there is at least a 95% probability of failing
the L-value limit if >=6.25% of the doses are sub-potent or >=6.25% of the
doses are super-potent.
Process Performance/Process Capability & UDU
P(A
cce
pt
)
0.05
0.95
Quality Indicator—Proportion Outside Specification Limits
Quality Demonstration Test A:
Quality Demonstration Test B:
Quality Demonstration Test C:
Region Where In Vitro
Quality Level Negatively
Impacts In Vivo
Performance
ACCEPTANCE SAMPLING PLAN PERFORMANCE
18 28October2015 Process Capability: More than Just a Quality Metric: It is a Quality Behavior
Process Capability: More than Just a Quality Metric: It is a Quality Behavior 19 28October2015
IPAC-RS DDU Working Group Member
AAPS CMC Statistics FG Members
Acknowledgements