computer based instrument validation - ipheb...

Computer Based Instrument Validation

April 2012Brendan Somerville

[email protected]

mailto:[email protected]

Content

Terms of Reference & OQ DriversFDA Warning Letters (OQ) Instrument Compliance ChoicesCompliance Trends & QuestionsAgilent ACE – Partner Edition

FDA Focus on Data Integrity…..

• Differences Between ComputerRecords and Paper Print Outs

Difference

• High Profile Cases (e.g. Able Laboratories – Passed 11 PAI Inspections, but …. ) “Whistle Blower”

Terms of Reference – FDA PAI

FOOD AND DRUG ADMINISTRATIONCOMPLIANCE PROGRAM GUIDANCE MANUAL PROGRAM 7346.832

Chapter 46 – New Drug ApplicationPRE-APPROVAL INSPECTIONS

3.3 INSPECTION / AUDIT STRATEGY

There are three primary inspectional objectives of this PAI program. These objectives are:

Objective 1: Readiness for Commercial ManufacturingObjective 2: Conformance to ApplicationObjective 3: Data Integrity Audit

• Data Integrity – is a core objective of FDA PAI !• FDA – is conducting Part 11 Audits during GMP Inspections• FDA – is being trained in Data Integrity by Monica Cahilly

Compliance Drivers.....

• How do you keep up to date with compliance ?• Newsletters?• When Company Policy Changes ?• When You Are Told To ?• When “found out” in an Audit

• What is the “role” of the FDA ?• Historical Influence• Do You Supply to the USA ?• Mutual Recognition

• How do you know what is “good enough” ?

FDA Warning Letters

Review of FDA Warning Letters - What OQ Problems do FDA Find ?

• OQ not good enough - Critical parts of system not qualified adequately

• People not adequately trained – FDA observe people doing the work

• No raw data for the work – Firm could not show inspectors the raw data

• Tools used were not calibrated – Tools used in an OQ must be calibrated

• OQ failures not detected – By person doing the work or managers checking it

• Data integrity – Data not secure and could have been tampered with

Google FDA Warning Letters….

Review of FDA Warning Letters - What OQ Problems do FDA Find ?

Agilent ACE satisfies ALL requirements, including FDA warning letters.....

• OQ not good enough - Critical parts of system not qualified adequately

• People not adequately trained – FDA observe people doing the work

• No raw data for the work – Firm could not show inspectors the raw data

• Tools used were not calibrated – Tools used in an OQ must be calibrated

• OQ failures not detected – By person doing the work or managers checking it

• Data integrity – Data not secure and could have been tampered with

No Audit Problems / FDA 483 Warning Letters after > 150,000

Annual GMP Training / Retraining

Raw Data Electronically Added, No Customer Checking

Calibration Data Added to EQR

Management of Deviations is a CORE Feature of ACE

Scientific ACE Development – Guarantee Points & Limits

Facts:1.Agilent has never been cited in an FDA warning letter for qualification2.More warning letters are issued to “in house” OQ solutions !

Examples – HPLC (Use the Warning Letter Search)

A

B

C

D

Instrument Compliance

Choices

Don’t Do IT !

Do It Yourself (DIY)

Justify – what you don’t Do

Balance Control Vs RisksSpecialist / Supply ChainHidden Costs Not “Core” Lab. Business(May not be as “cheap” as it appears)

Justify – Alternative Interpretation

Customer – People Leaving......Risks – Training & Parts (Repair)

– Getting it WRONG !

Customer OQ and Compliance Choices......

Use the Original Equipment Manufacturer (OEM)

Possible Inflexible ApproachDifferent Qualification Strategy

Use Harmonised Approach All OQ’s are the same

Easier to DefendSimpler to Understand

How Was The OQ Report Generated ?

Qualification Delivery

PaperManual process (cheap labour)Changeable, but not Flexible, Risk of errorManual processes - data integrity

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FDA Direction on Paper Records

Industry Misinterpreted the 2003 Part 11 Scope & Applications Guidance !

“Printed chromatograms do not satisfy the predicate rules…..”

Paper Protocols……

Are hard to do wellAre more prone to human errorsDifficult to include calculationsNeed checking……



PaperManual process (cheap labour)Changeable, but not Flexible Risk of errorManual processes - data integrity

ExcelData TranscriptionVersion ControlValidation

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Monica Cahilly – Training the FDA in Data Integrity

From Monica Cahilly, ISPE Conference – New Brunswick, USA – September 2011



Paper

Hybrid

Manual process (cheap labour)Changeable, but not Flexible Risk of errorManual processes - data integrity

Potential Data integrity concerns ?FDA Publication 60052Manual Checking


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Many People Now Believe…….

From Monica Cahilly, ISPE Conference – New Brunswick, USA – September 2011



Paper

Hybrid

Fully Electronic

Manual process (cheap labour)Changeable, but not Flexible Risk of errorManual processes - data integrity

Potential Data integrity concerns ?FDA Publication 60052Manual Checking

Remove Transcription ErrorsSecure Report GenerationMeta Data Preserves:“Content and Meaning”Electronic Data IndexingElectronic Storage


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Data Integrity – An Increasing Area of FDA Focus“There is a paradigm shift in the way FDA thinks about part 11”

Monica Cahilly, ISPE Conference on Risk-Based Systems ValidationNew Jersey, USA, 12-13th September 2011

Agilent ACE OQ satisfies the latest definitions required for data integrity:

FDA “ALCOA” requirements: Attributable

Legible

Original

Accurate

Contemporaneous

Complete

Consistent

Enduring

Available

“Engineer” Securely Logged OnDate / Time Stamps

Real Time Results Recording

Electronic Report

Secure PDF EQP Report

Secure Error Management / GMP

Monica is training FDA in Data Integrity

EQR is Full OQ Report

Full data transfer log

CDS, PDF, Print

On CD / Print....

Data Integrity Example

Update on GAMP and AIQ <1058>

GAMP and USP <1058>

CommonGoals Good Issues

• Too Complex ?

• Software Focus

• Verify Vs Qualify

• Category 2 (gone)

• Over Simplified ?

• What AboutSoftware

• What AboutGroup C ……

• DQ “Ownership”

Trends

• IQ / OQ in USPGeneral Chapters

• PharmacopeiaForumStimulus Paper

• GAMP GPG(Validation of LaboratoryComputerized Systems)

• Risk Based( 7 Categories Gone !)

GAMP 5- 2008

AIQ <1058>- 2008

ISPE

USP

• Simplify Process

• Risk by Categorisation

• Roles andResponsibilities

• Maximise use of SupplierDocumentation

• 5 pages !

• Easy to Follow

• A and B Simple

• Flexible

• Better Than 4

• Very Comprehensive

• Great For CustomSoftware

GAMP 4- 2001

Harder to Answer Questions

Laboratory QualitySystem

HPLC (A)IQ / OQ

HPLC (B)IQ / OQ

Prep HPLCIQ / OQ

LC-MSIQ / OQ

Metals AnalysisIQ / OQ

Instrument Qualification Is An Integral Part of Your Quality System

• Different Definitions for IQ / OQ / PQ• Conflicting OQ / PQ Interpretation• Different Documentation:

- IQ / OQ / PQ Detail- Look & Feel

• Fixed Qualification - Relevance to your Application ?- Does it cover Your Range of Use ?

To Defend Lab. Results, Companies Must Defend the Instrument QualificationWell !

Where there is a Difference:Qualification Strategy and Rationale is Fragmented,

Time Consuming to Understand & Defend (Cost) + Risk....

Explaining Your Instrument Qualification in an Audit……

ALL REGULATORY

inspectors can be Intimidating…….

Fragmented Qualification is Harder to Defend……

Scientific Data Integrity ? - Prove the INTEGRITY of your Results

Did the Qualification Cover theRange of Use ?

Has the Qualification StatusBeen Maintained ?

• The Instrument was Qualified…. Etc.

• The Method Limits Was Validated

• The Correct Reference Materials Were Used

• Training Records - The Analyst Was Trained

• System Suitability – The Method Was Working Correctly

Can You Explain The QualificationRationale & Justify The Set Points & Limits ?

Prove that the data has not beentampered with….. ?

Compliance Trends

How Many ? How Many Times are Techniques Cited ?

• KF – 2• FTIR – 3• FT-IR – 4• Infrared – 40• GC – 9• Dissolution – 35• UV – 36• HPLC – 51• Qualification – 247• Calibration – 336• Training – 895• Agilent - 0

• Pharmaceutical Manufacture• Medical Devices• Food Imports

• Neutraceuticals (Fundamental cGMP)

• Cosmetics• Tobacco Products

2767 ?

FDA Warning Letters – Trends…..

www.fda.gov/downloads/ICECI/EnforcementActions

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http://www.fda.gov/downloads/ICECI/EnforcementActions

GAMP

USP <1058>

Part 11 / Annex 11

Data Integrity

GAMP 5 – Risk Based

GAMP Computer System Validation(7 Categories – Removed – Now Risk Based)

• FDA Surveillance Audits• Implementation (e.g. Network Qualification)

Risk BasedThinkingFlexibility

Mandatory Chapters - Qualification

Optional Chapters – Best Practice

Bob McDowallStimulus Paper- AAPS 2010

Monica CahillyISPE 12/13 September

Profound Implications for Compliance !

“In each case, we recommend that the copying process used produces copies that preserve the content and meaning of the record” [2003 Scope and Applications Guide]

Compliance Trends

Agilent ACE

Evolution of Agilent Thinking….

Chromatography Data System (CDS)Or Instrument Software

• Instrument Control• Collect / Store Chromatograms• What YOU USE when you generate results

Qualification

CDS

Network

Instruments

(Annex 11)

Agilent ACE uses TNF (technology neutral format)

•Reads native file format or

•AIA output•Original and Meta Data Retained

(ACE)

So, How Does ACE Work ?

ACE Runs from Spinning Hard Disc

ACE 2.1 is Client Server Enabled

• Engineer controls instrument in CDS• Engineer Sets ACE up For The Work• Engineer Uses ACE to browse for data • Compliance Data (file transfer details) Partner

Edition.....

Enterprise Compliance Standardized Qualifications Across

Multi-vendor –Enterprise Compliance Delivery

2-wire analog detector output

NetworkInstrument

Control

Customer’s CDS

Empower

Enterprise EditionDelivery Model

Digital output

• Audit-ready paperless deliverables with electronic signatures

• Streamlined approval from equipment qualification plan to final report

• Robust vendor-neutral qualification platform

• Configurable testing conditions providing flexible delivery

• Chromatography Data System (CDS) agnostic

Global Solution providing Reproducible, Quality Deliverables with Full Traceability

ACE 2.0

• Universal Protocol• Paperless Execution• Paperless Report• Audit Ready

ACE 2.0 Overview Designed for Efficiency

Multiple sessions

Agilent Software Look

& FeelConfigurable

UI

Task instructions

Workflow based task

list

Attachment window

Work Type

ACE ExampleWork Type

PM, IQ, OQRequalification,Software OQ

Select Technology- HPLC- GC - MS (GC-MS, LC-MS, (UPLC-MS)

- Dissolution- UV ….. Etc.

Ref. / Name

Configure(Software usedto Collect Data)

Test Limits You Approveare Included

Integrated Graphic Functions:- Software- EQR

ACE Computer Based Help – To Support Engineers & Partners

Partner Edition.....

Context Work Instructions

DetailedExplanations

Instrument Photographs

Agilent Paperless Automated Compliance Engine

ACE efficiently enforces complianceWorkflow and rule based (simple to use, flexible to develop)

Enables electronic “execution” of Paper DocumentsReports free of transcription errorsElectronic chromatograms with meta dataPDF reports for efficient storage and reviewIntegrated GMP compliance:

Test execution counter (reports how many times a test was run)

Deviation justification and managementValidated calculationsAutomated Pass / Fail report.. Etc.

Company Life Cycle - Compliance Maturity Curve

Time

Companies With High cGXP Expertise

Companies WithLower cGXPExpertise

Mature Pharmaceutical• Risk Management• Life Cycle Compliance• Aligned Compliance

Chemical Supplier, Start Up Company or ISO 9001• Avoidance Risk• Low Experience in Qualification • Need Qualification & Compliance Support

Agilent Compliance Solutions Support the Needs of these two differentapproaches

ACE

Partner Edition

Harmonised Approach

ACE

Standards / Limits + Compliance Delivery

Summary

• Agilent is Closely Involved in Lab. Compliance

• Changes are Coming:• USP <1058> , GAMP, Data Integrity • Agilent is Closely Involved

• Move to Electronic and Away from Paper

• RISK Based Thinking NEEDSGreater Flexibility….. In Qualification

• ACE 2.0 + is Designed to Support These Needs

• Simple, Intuitive Interface

• Through our Partner program – we can train you !

Questions ?