Process Capability: More than Just a Quality Metric: It is ...€¦ · Process Capability: More than Just a Quality Metric: It is a Quality Behavior 28October2015 16 The original

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


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


a Quality Behavior

8 28October2015

A condition in which the set of controls

consistently provides assurance of

continued process performance and product

quality.

State of Control ICH Q8


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


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


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


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


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


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


IPAC-RS DDU Working Group Member

AAPS CMC Statistics FG Members

Acknowledgements

Documents

Process Capability: More than Just a Quality Metric: It is ...€¦ · Process Capability: More than Just a Quality Metric: It is a Quality Behavior 28October2015 16 The original