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Strategic QbD for the Analytical Laboratory

Paul Smith

EMEAI Laboratory Compliance

Productivity Specialist

[email protected]

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Agilent Technologies and QbD Support Tools

2

2D-LC

HDR - DAD

ISET

RA

Qualification

HPLC System

QbD

3

QbD Principles

Understand, reduce and control Sources of Variation

Example - Why Apply QbD Principles ?

4

Method Conditions [ Main Component ]

In this Illustration: • Temperature – Minimal Effect

• pH – Critical Effect

• Factor Interaction !

• Depends on Chemistry

FDA Warning Letter Search – “Stability”

5

0

5

10

15

20

25

30

35

40

45

2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998

39

30

25

41

32

22

17

22 19

34

23

29

39

1 2 1

68 Warning Letters

Mention “HPLC” [Highest]

376 Warning Letters

Mention “Stability” [> 5 times more]

6

Primary Cause – FDA - HPLC Warning Letters

0 2 4 6 8 10 12

Calibration Defeciency

No Calibration

N/A

OOS Problems

Problems With System Suitability

Chromatography - Unknown Peak

HPLC Method Validation

Defecient HPLC Method

Data Integrity - Data Deletion

Data Integrity - Incomplete Data

Data Integrity - Security

Data Integrity - Fraud

Stability Testing

Sterlity

Impact of Instrument Repair / Failure

9

8

8

7

2

2

11

5

1

3

4

3

1

1

1

Calibration: Biggest Single

Category

Decisions & Justification

Using the Method

Data Integrity

Capability of the Method

Poor HPLC Use / Training

Key Word Analysis of HPLC Warning Letters

7

71 % of HPLC warning letters

Include Reference to Stability

0 10 20 30 40 50 60 70 80

Calibration

Training

OOS

SSC

Method Validation

Defecient Methods

Data Integrity - Security

Data Integrity - Data Deletion

Data Integrity - Incomplete Records

Reaccurance

External Consultant Required

Data Review

Complete Data

Poor Response / CAPA

Stability

41

27

51

27

43

17

27

13

43

30

16

27

43

43

71

Detailed Analysis – HPLC Warning Letters - Stability

8

Solution Stability

Not Stability Indicating

Storage Temperature

Storage Excursion

Validation of

Deficiencies

Deviations

Specification Failure

Storage Not Supported

Calculation of Results

Stability Testing

Facilities

Protocol

Stability Results

37 %

16 %

38 %

38 %

17 %

78 %

50 %

50 %

40 %

67 %

21 %

54 %

29 %

21 %

71 % of HPLC

warning letters

Include Reference to

Stability

Analytical Methods in the Laboratory

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Develop Validate Transfer

Representation of Historic Approach

Define DOE /

Screen

Model / Optimise

Verify Validate Control

Representation of QbD Approach

• “Fixed” Method

• SSC Variation [e.g. pH, mobile phase]

• Variable Method [in Design Space]

• No Change [outside Design Space]

Examples of Potential “Uncontrolled” Variation:

• Poor Method – Not-Robust

• Instrument Specification – From Different Manufacturers

• Instrument Usage – Some Instruments

• Instruments Performance – Qualified in Different Ways / Human Judgement

• Instrument Life Cycle – Service Events and Return to Use

Example – Laboratory Lean Sigma Application

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How Many Days to Test

Product Batches of Material

Before

Mean Workflow Optimisation

After

Mean

Impressive Results:

• 50 % Reduction In Tests Times are “Common”

• Improved Testing Control

Moderately Robust

HPLC Method

• Sample Based

Testing

• Product Team [analysts perform all tests]

• Optimised for

Control / Speed

Less-Robust

HPLC Method

• Test Based

Testing

• HPLC Team [HPLC “specialists”]

• Designed to

Reduce Problems

What is Required for Analytical QbD ?

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• Automated Systems – Minimise Manual Activity

• Compliant Data Transfer – 21 CFR Part 11 Compliant

• Data Analysis Capability – Tools to Simplify Data Analysis

• Flexible – To Support Different Requirements

• Collaborative Approach – Between CDS, Instrument & QbD Tools

QbD

Software

/ Tool

Configurable

Laboratory

Instrument

Flexible

Instrument

Control

Software

Work Together…..

Customer Collaboration and Agilent Partnerships……

Instrument Contribution – Potential QbD Paradigm

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Execute the Method = Run the Process

Gradient

Slope (14.5%/min)

pH (3.0)

Measurement

(Detector)

RS

2.00

Failure Threshold

1.50

Column Oven

Temperature (35º C)

Instrument Contribution – Potential QbD Paradigm

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Gradient

Slope (14.5%/min)

pH (3.0)

Measurement

(Detector)

2.00

Failure Threshold

1.50

Column Oven

Temperature (35º C)

= variation around setting

RS

Execute the Method = Run the Process

Instrument Contribution – Potential QbD Paradigm

14

Execute the Method = Run the Process

Gradient

Slope (10.0%/min)

pH (2.7)

Measurement

(Detector)

2.00

Failure Threshold

1.50

Column Oven

Temperature (30.0º C)

= variation around setting

RS

QbD Output ?

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Target Conditions

Verification

Variation

Failure Threshold

Failure Threshold Example

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Automated, Audited

Data Exchanges

Automated one-click analysis,

graphing, and reporting.

Report formats: RTF, DOC, HTML, PDF.

• Full Support for 21 CFR 11 Compliance

• Scalable from Standalone to Enterprise

Fusion AE

Dataflow

QbD-aligned

Experimental

Design

Automatically

Builds Sequence

and All Methods

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Fusion AE Automatically

Retrieves All

Chromatogram Results Data

ChemStation or Other CDS

Know Instrument is Suitable for Use [ Update Proposed to USP <1058> ]

Instrument Performance – Qualification and QbD

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• Independent of Manufacturer – Consistent Performance

• Independent of CDS – Harmonised Across Laboratories

• Technology Neutral – Harmonised Across Technologies

• Controlled Flexibility – Configurable Compliance

• Qualify Range of Use – Match Usage

Agilent (Automated) Compliance Engine

Designed and Validated to be:

Data Quality Triangle

4Q Qualification Model

USP <1058> AIQ [Analytical Instrument Qualification]

Qualification Space

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Wavelength (nm)

Oven Temperature (oC)

Flow Rate (mL/Min.)

245 nm

45 oC

1 mL/min.

Min. Flow

Max. Flow

Lo

west

Wav

ele

ng

th

Hig

hest

Wav

ele

ng

th

Highest Temp.

Lowest Temp.

Qualification

Space

• Qualify Range of Use

• Simpler to “Defend” in an Audit

• Qualification Equivalent to Design Space

Where Does Instrument Performance “Fit In” ?

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Pharmaceutical

QbD

Analytical

QbD

(Process Operability)

Sharmista Chatterjee

Jan. 2013

EQP (Equipment

Qualification Plan)

Instrument

Qualification

Analytical Instrument

(Range of Use)

QTPP = Quality Target Product Profile ATP = Analytical Target Profile MODR = Method Operable Design Region EQP = Equipment Qualification Plan EQR = Equipment Qualification Report

Instrument Variability – Usage / Utilisation

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Diagnostic Instrument Usage Functions – e.g. Injections

Remote Advisor – Example “Built In” Reports

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Instrument

Availability

Error

History

System

Usage Service

History

Capacity

Planning Instrument

Diagnostics

Usage Based

Management

Automated Data Gathering

Across Secure Gateway

Uses of Utilisation and Instrument Usage

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• Instrument Usage Functions

• Workflow Optimisation

• Resource Planning

• Instrument Life Cycle Management

• Automated Data Gathering – For Alternative Maintenance Models

• Accelerates Instrument Repair – Reduces Down Time

• Tool to Reduce “Unknown” Sources of Variation – Why Some Systems Not Used ?

Agilent & Non-Agilent HPLC

• Volume of Mobile phased Pumped

• Number of Injections

• Lamp Hours

Longer Term – Laboratory Business Intelligence – Utilise Instrument Data

Example – Method Transfer Problems – Instrument Impact

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Minimizing Method Transfer Problems Example of Intelligent System Emulation Technology (ISET)

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Instrument A

Instrument B

ISET – Works With Transfer to Non-Agilent Systems

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