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YSPharma 1
Introduction
to
PROCESS
CAPABILITY
Ram Nyshadham AAPS, New Orleans, LA
November 17, 1999
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YSPharma 2
CONTENTS
Rationale
Process Capability Overview
Philosophy
Literature Review
Assumptions
Process Capability Indices
Example
Summary
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YSPharma 3
RATIONALE
Why do Validation ?
Why apply Process Capability to
Validation ?
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YSPharma 4
Why Do Validation ?
Why ? Common sense and good science requires it.
cGMP mandates it !
How ? Qualify facility and equipment train.
Establish extremes and limits of manufacturing
process in development through scale-up.
Process validation batches on target.
If done right, should be the easiest exercise ? !
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YSPharma 5
Why Process Capability?
Provides a means for common and
easily understood language for
quantifying the performance of
manufacturing process.
Provides a measure for “High Degree of
Assurance”, a key requirement for
process validation.
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YSPharma 6
PROCESS CAPABILITY OVERVIEW
Philosophy
Literature Review
Assumptions
Process Capability Indices
Example
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YSPharma 7
Philosophy
Quantification of process location (mean) and variation(standard deviation) is central to product quality.
Process capability provides a means to compute unitless indices (PCIs) using process location and variation relative to pre-established specifications (target & limits).
Process capability is the measured reproducibility of the manufacturing process.
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YSPharma 8
Non-Pharmaceutical Literature
J.M. Juran (1974). Quality Control Hand Book, 3rd edition. McGraw-Hill, New York, NY.
V.E. Kane (1986). “Process Capability Indices.” Journal of Quality Technology, 18, pp 41-52.
Journal of Quality Technology
Quality Progress
B.H. Gunter (1989). “The Use and Abuse of Cpk, part 2 and 3. Quality Progress, March and May, 1989.
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YSPharma 9
Pharmaceutical Literature
J.A. Daley. “A Practical Guide to Sample Selection
for Cpk Determinations”. Journal of Validation
Technology, Volume 2, Number 1, pp 25-28.
L. Torbeck. “Validation and Process Capability”,
Pharmaceutical Technology, June 1998, pp 66-76.
R. Nash. Pharmaceutical Process Validation, 2 nd
edition, Marcel Dekker, Volume 57.
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YSPharma 10
Assumptions
The process is in a state of statistical control.
The data are normally distributed.
The data collected are collected from independent random samples.
The data are truly representative of the process.
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YSPharma 11
Process Capability Indices (PCI)
First Generation PCI - Focus of this
session Cp, Cpu, Cpl, k, Cpk
Second Generation PCI: Cpm
Third Generation PCI Cpmk
Robust PCI: Cq
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YSPharma 12
Summary of Capability Indices
Index Term Equation Usage
Cp Potential USL - LSL process potential for two-
Capability 6s sided specification limits
CPU Upper USL - process performance relative to Capability Index 3s upper specification limit
CPL Lower - LSL process performance relative to Capability Index 3s lower specification limit
k Non-centering 2| m - | deviation of process mean
Correction USL - LSL from midpoint (m) of
specification limits
Cpk Demonstrated Min { CPL, CPU} process performance for two-
Excellence = Cp( 1 - k) sided specification limits
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YSPharma 13
Interpretation
Potential Capability - Cp (V. Kane)
Using a 3s spread, for a process with normal
distribution:
Cp=1.0 0.27% of parts are beyond specification
limits.
Cp=1.33 0.007% of parts are beyond specification
limits.
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YSPharma 14
Interpretation (continued)
Demonstrated Excellence - Cpk (L. Torbeck)
For Assuming normal distribution:
Cpk for potency should be targeted at 1.33.
To consistently achieve a Cpk of 1.33 during routine
production, Cpk > 1.33 should be obtained in
validation.
Units Outside of Specifications
Cpk (Billion) (Percentage)
0.5 70,000,000 7
1.0 1,300,000 0.13
1.33 30,000 0.003
1.67 1000 0.0001
2.0 1 0.0000001
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YSPharma 15
Example
OTC Product; B.S: 500.0 kg
Drug Loading: 4.65%; Compression Stage
Collect random sample of tablets
representing the entire compression run
Test 5 tablets/sample; 40 tablets/batch; 4 batches (overall n=160)
Check Process Capability for 85-115 % CU limits
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YSPharma 16
4321
102.5
101.5
100.5
99.5
X b a r a n d R C h a r t
Subgr
Means
19
14
9
4
Ranges
4321
L a s t 4 S u b g r o u p s
11010510095
Subgroup Number
Valu
es
115 85
109.500 92.728
C a p a b i l i t y P lo t
Process Tolerance
Specifications
C p k : 1 .6 6
11110395
N o r m a l P r o b P lo t
11110395
C a p a b i l i ty H i s to g r a m
X=101.1
U C L = 1 0 2 . 4
L C L = 9 9 . 7 9
R = 1 0 . 9 9
U C L = 1 6 . 9 3
L C L = 5 . 0 4 3
IIIIII
Content Uniformity - Compression Run
Example (continued)
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YSPharma 17
1151059585
U p p er S p ecL o w er S p ec
A c t i v e
s
Mean-3s
Mean+3s
Mean
n
k
LSL
USL
Targ
Cpm
Cpk
CPL
CPU
Cp
0
0
0
0
0.00
0.00
0.00
0.00
Obs
PPM<LSL Exp
Obs
PPM>USL Exp
Obs
%<LSL Exp
Obs
%>USL Exp
2.795
92.728
109.500
101.114
160.000
0.074
85.000
115.000
100.000
1.64
1.66
1.92
1.66
1.79
C o n t e n t U n i fo r m i t y - C o m p r e s s io n R u n
Example (continued)
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YSPharma 18
SUMMARY
Knowledge of
Pharmaceutics,
Manufacturing
Processes, etc.
Process
Validation
Apply Process
Capability Prerequisite
High
Degree of Assurance