Process Capability Session

(CpK/PpK)IFPAC Conference – Washington DC

January 23, 2014

Brian Eden / Kenneth Coté

Process Capability Applications

• What we’re hearing in the Industry

• APR/ PQR

• Metric Selection

• Analytical Process

• Capability Examples

• Proceduralization

What we’re hearing in the industry

• Top 10 metrics - FDA

• ICH references

• Recent World Health Organization observations

related to CpK

APR / PQR

• Current State

– APR / PQR documents are prepared in accordance with cGMP

– However…..Presentation of data tends to be tabular without statistical analysis.

• Future State

– Standardizing across sites and affiliates

– Use of Control Charts, CpK calculation and graphs

– More detailed understanding of Product trends

• Proactive vs. Reactive

Metric SelectionParameter Diagram

• API

• Excipient

• Labor

• Energy

• Sterility

• Blend Uniformity

• Content Uniformity

• Stability

• Residual Solvents

• Assay

• Dissolution

• Related Substances

• Foreign Material

Production

Process

• Ambient temp. and humidity

• RM particle size, polymorphism

• Random human errors

• Normal variation in Xc factors

• Specified Formulation

• Equipment choices

• Analytical methods

• Handing techniques

Inputs Outputs (Y’s)

Controllable Factors (XC)

Noise Factors (XN)

To what metrics do

we apply this?

Analytical Process

Source Raw data

Refine Data

Statistical Analysis

Prepare Report

• Analytical Software• Outsourced

Laboratories• Manual Collection

• Filter / sort data in MS-Excel®

• Gaps in data?• Incorrect formats• Pooling considerations

• Copy to Minitab ®

• Verify Assumptions• Control Charts• Capability Analysis

• Report in MS-PowerPoint®

• Analysis• Business Decision

Oral Solid Dose Content Uniformity Example

Year

Month

201120112011201120112011201120102010

8765321129

750.0%

500.0%

250.0%

0.0%

Sa

mp

le M

ea

n

__X=290.2%

UCL=424.0%

LCL=156.4%

2010 2011

Year

Month

201120112011201120112011201120102010

8765321129

400.0%

300.0%

200.0%

100.0%

0.0%

Sa

mp

le S

tDe

v

_S=151.1%

UCL=248.7%

LCL=53.4%

2010 2011

Xbar-S Chart of CU Acceptance Value by Year

Tests performed with unequal sample sizes

3.01.50.0-1.5-3.0-4.5

transformed dataLB* USL*

Sample Mean* -0.0986806

StDev (O v erall)* 1.05564

LB 0

Target *

USL 15

Sample Mean 2.90185

Sample N 54

StDev (O v erall) 1.64437

LB* -5.74322

Target* *

USL* 3.08505

A fter Transformation

Process Data

Pp *

PPL *

PPU 1.01

Ppk 1.01

C pm *

O v erall C apability

PPM < LB 0.00

PPM > USL 0.00

PPM Total 0.00

O bserv ed Performance

PPM < LB* *

PPM > USL* 1280.93

PPM Total 1280.93

Exp. O v erall Performance

Process Capability of CU Acceptance ValueJohnson Transformation with SU Distribution Type

-3.357 + 1.465 * Asinh( ( X - 0.853 ) / 0.348 )

Control charts – 2 Stages by year Capability Analysis

Injectable Assay Example

105.0103.5102.0100.599.097.596.0

LSL USL

LSL 95

Target *

USL 105

Sample Mean 100.677

Sample N 35

StDev (Within) 0.800373

StDev (O v erall) 0.758902

Process Data

C p 2.08

C PL 2.36

C PU 1.80

C pk 1.80

Pp 2.20

PPL 2.49

PPU 1.90

Ppk 1.90

C pm *

O v erall C apability

Potential (Within) C apability

PPM < LSL 0.00

PPM > USL 0.00

PPM Total 0.00

O bserv ed Performance

PPM < LSL 0.00

PPM > USL 0.03

PPM Total 0.03

Exp. Within Performance

PPM < LSL 0.00

PPM > USL 0.01

PPM Total 0.01

Exp. O v erall Performance

Within

Overall

Process Capability of Average Composite Assay

Control charts – All Stages Capability Analysis – Stage 3

Sustainability

• Documentation

– Global directives

– APR / PQR templates and Standard Operating Procedures

• Education

– Workshops – Intro to Stats and Minitab ®

– Workshops- APR / PQR stability

– Lean / Sig Sigma Green Belt/Black Belt training

– Minitab ® software Enterprise License