Reduce Risks and

Costs for Laboratory

Equipment Qualification Gary Powers
Global Compliance Program Manager

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Aspects of
Instrument Qualification
4 Q Model for Instrument Qualification

Does it Does it
Meet your USER WORK as YOU
REQUIREMENTS Installation EXPECTED Performance
Qualification Qualification

DQ IQ OQ PQ
Design Operational
Qualification Has it been Qualification Will it
INSTALLED CONTINUE to
CORRECTLY work
CORRECTLY

But there are no set rules, and people do not agree on:

WHAT content is in each of the stages

HOW often an OQ should be performed
WHO performs the stages (OQ / PQ)
WHAT needs to be done during the lifecycle

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Instrument Lifecycle Audit Focus
What about

the future?  Is the instrument
What do you want Re-Qualification suitable for use?
the system to do? (Justification)

- Write it down   Is it installed
- Why is it suitable? Maintenance
correctly?
 IQ 
DQ Use  Is there an SOP?
OQ Are people trained?
 Calibrated?
Breakdown Validated method?
Does it work?

- Installed correctly Re-Qualification Repair
 Failure management
- In your laboratory (Justification) Impact of failure
CAPA?

 Maintenance
Routine?
Justification:

Frequent Questions
OQ – How Often  Re-Qualification
RQ – What to include / Calibration

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Search “FDA Warning Letters”

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

Basic Search Engine

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Search for “HPLC”

A
B
C
D
E

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FDA Warning Letters by Technique

• KF – 2
• NMR - 2 • Pharmaceutical Manufacture
• FTIR – 3 • Medical Devices
• FT-IR – 7 • Food Imports (3,000, 128,000, 48,000,000)
(Updated M. Hamburg Speech, 4th Oct. 2011)
• Infrared – 47
• GC – 14 • Neutraceuticals (Fundamental cGMP)
• Chromatography - 26 • Cosmetics
• Dissolution – 38 • Tobacco Products
• UV – 43
• HPLC – 60 Manufacturing Process Qualification
• Qualification – 303 Supplier Qualification
• Calibration – 405
• Training – > 1,000
• Agilent - 0 Searched 26 Feb 2013

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 FDA Audits: 97 % of US
FDA Warning Letters FY 2004-2012 Facilities [pharmaceutical, every 2 years]

3000
FDA Audits: 7 % of Non US
Facilities [pharmaceutical every year]
2800
[Source: Journal of Validation Technology;
2600 D. W. Vincent, Winter 2012 edition]
www.fda.gov/downloads/ICECI/EnforcementActions
2400
2767
2200
2000 Trend sharply up Mutual recognition
1800 1720 audits [Tougher “National” Audits]
FDA Warning Letters

1600 Risk-based audit

1400 triggers……
1200
Trend down to flat
1000 Whistle blowers….
800 725 673
535 538
600 471 445 474
400
200
0
2002 2004 2006 2008 2010 2012 2014
Margaret Hamburg joins FDA

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 FDA HPLC Warning Letters
Most concern validity of analytical results
92% related to Data Integrity
1 Would you trust these data ?
No HPLC - But Chromatograms !

Calibration Defeciencies 10 Calibration: Biggest Single

No Calibration 8 Category (30 %)

No Data Backup 1

N/A 4

OOS Problems 2

Repair Impact Assessment 2 Poor Compliance SOP’s Decisions & Justification

Repeat Work - No Justification 1

Problems With System Suitability 3

Poor HPLC Use / Training Using the Method
Chromatography - Unknown Peak 3
HPLC Method Validation 8
Capability of the Method
5 HPLC Methods
Deficient HPLC Method

Data Integrity - Data Deletion 1

Would you trust these data ?
Data Integrity - Incomplete Records 3
Data Integrity
Data Integrity - Security 7

Data Integrity - No Electronic Review 1 From 2001

0 1 2 3 4 5 6 7 8 9 10 11 12

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FDA “HPLC” Warning Letters last 12 years
More HPLC warning letters issued than any other year!
9
9

7
6
6
FDA HPLC 5 5 5
Warning 5
4 4 4
Letters 4
3 3
3
2 2
2

Year

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FDA GC Warning Letters
Most concern validity of analytical results
86% related to Data Integrity
Evaluate
Read Categorize Knowledge
Risks

No GC 1
1 Would you trust these data ?

No Calibration 4
Calibration: Biggest Single
Calibration Deficiencies 22 Category (43 %)

System Suitability 1 Poor GC Use / Training Using the Method

GC Method Validation 1
GC Methods
Capability of the Method
Defecient GC Method 1

N/A 2

Data Integrity - Security 1

Would you trust these data ?
Data Integrity
Data Integrity - No Raw Data 1

0 1 2 3 4 5 6

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HPLC/GC FDA Warning Letters vs. Lifecycle

Method Use 7

Data Integrity 14

Calibration 24 Method Capability 15

Impact Assessment 2

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 What are the most
common deficiencies in
calibration / qualification?
Review of FDA Warning Letters
what OQ / Calibration Problems does FDA Find ?
• OQ not good enough - Critical parts of system not qualified adequately or did not
qualify range of use [27 % HPLC, 36 % GC of warning letters on these techniques] Example:
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2009/ucm183410.htm [Ion Labs. 2009]

• People not adequately trained – FDA observe people doing the work
[High feature in EIR Data Review]
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm298187.htm [UNAM, 2012]

• No raw data for the work – Firm could not show inspectors the raw data
[More common in India and China] Example:
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm249641.htm [Nanjing Pharmaceuticals, 2010]

• Tools used were not calibrated – Tools used in an OQ must be calibrated. Example:
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm236841.htm [Yuki Gosei Kogyo, 2010]

• OQ failures not detected – By person doing the work or managers checking it. Example:
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2009/ucm136661.htm [Time-Cap Labs., 2006]

• Data integrity – Data not assured or not secure - could have been tampered with
[Most significant area, includes all the above]. Example:
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/ucm249641.htm [Nanjing Pharmaceuticals, 2010]
Laboratory Compliance Risk
• Cost of “Cost Savings”
• What are “Real Costs” Laboratory Compliance Risk is about
Many companies don’t know “getting it right ”

“Too Much”
Compliance
(High Cost) Laboratory
Compliance

“Too Little” • Damage to reputation

Compliance • Loss of accreditation
(High Risk)

Risk Implications to consider:

• High “visibility” of non-compliance + “risk rating”
• Low Risk – Faster Review / High Risk - AIP (FDA - Application Integrity Program)
• Now much wider than laboratory cost savings……

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 Data Integrity • ALCOA…. (understand)
• Build lab workflow
• Compare results to electronic
• Data Integrity audits

Data

• All electronic
Prove your data are not fraudulent • Not tampered with
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• Implement reviews
Confidentiality Label
May 15, 2014
 • FDA Part 11 “add-on” Audits • Data Integrity has always
• Jan. 2011 been an FDA focus

Part 11 Add on Audits

Fundamental
Data Integrity

• 1997 Implementation FDA focus

• 2003 Guidance
on data
integrity
21 CFR Part 11 [ PAI, Consent Decree,
Data Integrity Training… etc. ] Science Based
GMP Decisions
(e.g. cGMP for 21st
Century)

• Scientific “Validity”
• ICH Q9, Q10, Q11 support

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Data Integrity drives Harmonization
Sample Receipt “21 CFR Part 11 = Good Document
1.
Practice for Electronic Data”

Booked into LIMS

2. A ttributable Electronic Log Vs. Ink Signature
[Who did it]

Schedule Tests
3. L egible Print Vs. Handwriting
[Can you read it]

Sample Preparation
4. C ontemporaneous Electronic Log Vs. Written Data
[Done in “Real Time”]

5. Chromatograph Sample O riginal Secure Electronic File Vs. Paper “Photocopy”

[Is it original]

6. Calculate Results A ccurate Validated Electronic Output Vs. Paper….

[Is it Accurate]

Check / Report Results More Secure Electronic Greater Risk

7.
(harder to manipulate) ? Vs. Paper (easier to manipulate) ?
Compare Against Specification
8.

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How to Balance – Costs Vs. Risks
As long as laboratory compliance is perceived as
a cost burden, a cost saving mind set will prevail
Costs
Generally, compliance risks are based on perceptions,
while costs savings are based on a spreadsheet

Compliance
Costs

Costs

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Laboratories that Follow Compliance Best Practice:
Good Defense
Robust, well structured, understood, rehearsed
“why are your results valid”?
this is the starting point….

Are Aware and Manage

Any gaps around their history, use, origins,
qualification, problems “show me…..” ?
Can explain and defend instrument control strategy

Are Proactive
Prepared for future compliance trends that will
affect them “what if…..”?
Perform gap analysis against those trends

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Laboratories that Follow Compliance Best Practice:
Minimize
Instrument down time using efficient, coordinated
maintenance and qualification processes
such as Agilent Enterprise Edition
ROI for LC-MS, GC-MS and UHPLC

Range of Use
Qualify the range where their instruments are used
no additional awkward qualification or justification
Linked to the methods they use

Understand
Traceability of raw data in their qualification reports
and can demonstrate this
Supported by fully integrated electronic reports

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Agilent Enterprise Edition
Innovation in Compliance

Agilent Enterprise Edition analytical instrument

qualification is automated, paperless and compatible
with instruments from all leading vendors

Enterprise Edition reduces regulatory risk:

• Harmonization across instruments
• Flexibility to configure testing to SOP requirements
• Full automation to assure adherence to protocol
• Electronic reports and signatures

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Equipment Qualification Plan – Universal Protocol

Harmonization
• Single protocol per technique
• Protocols compatible with systems from all leading vendors –
Waters, PerkinElmer, Thermo, Shimadzu, Dionex, many more
• One protocol for QA to approve saves time

Testing Flexibility
• Specify set points/limits, add/remove tests without interfering
with test design
• Specify testing based on your SOP requirements

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Configurable Testing

Agilent Enterprise Edition Innovation

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Paperless Reports

Agilent Enterprise Edition Innovation

Single locked .pdf report

• More secure GxP record
• One single signature required

All-electronic information
• Legible data entries, results and signatures
• Electronic Routing for review
• Export to external ECM and data bases

Reports burned to CD-ROM

• Total integrity, 21 CFR Part 11, ISO compliant format
• Less storage space and lower archival costs

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Automated Compliance Engine

Agilent Enterprise Edition Innovation

ACE efficiently enforces

compliance to procedure
• Fully automated protocol
• Validated calculations
• Simultaneous qualification
• Results fully traceable to raw data
• Reports free of transcription errors
• Automated pass/fail report

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ACE Partner Edition
Agilent Compliance Innovation

• Access to all Agilent-developed and -tested

protocols: (IQ, OQ, RQ, MQ, PQ, FV, PM)
• Assurance of auditability following approved
and locked test methodology
• Customize protocol using the EQP Editor
• ACE qualifies the latest technologies
including GC, LC, MS, Disso, UV, ICP-MS,
AA, more
• Training and support for more effective
teams
• Agilent-mentored deliveries help ensure
success
• Far more robust compared to smart pdf’s
and spreadsheets, especially in an audit

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ACE Partner Edition
Agilent Compliance Innovation

• Simple OQ setup typically takes less than 10 minutes  move

immediately to protocol execution
• Multiple sessions run simultaneously  easy to duplicate, restore
• Previous session recall without fear of losing past work
• Parallel services  run multiple simultaneous compliance services
• Parallel processes  complete documentation while running OQ
• Task-based working instructions now include GC and GC/MS
• Direct data retrieval from PC

Run Qualification

Process Data

Documentation

Attachments

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Agilent Compliance
Agilent Compliance Innovation

Questions?
For more information
please visit us online at

www.agilent.com

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