Computer Based

Instrument Validation

April 2012
Brendan Somerville
brendan_somerville@agilent.com

Page 1

Content

Terms of Reference & OQ Drivers

FDA Warning Letters (OQ)
Instrument Compliance Choices
Compliance Trends & Questions
Agilent ACE Partner Edition

Page 2

FDA Focus on Data Integrity..

Difference

Differences Between Computer

Records and Paper Print Outs

High Profile Cases (e.g. Able Laboratories

Passed 11 PAI Inspections, but . ) Whistle Blower

Page 3

Terms of Reference FDA PAI

FOOD AND DRUG ADMINISTRATION
COMPLIANCE PROGRAM GUIDANCE MANUAL

PROGRAM 7346.832

Chapter 46 New Drug Application

PRE-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 Manufacturing

Objective 2: Conformance to Application
Objective 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

Page 4

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

How do you know what is good enough ?

What is the role of the FDA ?

Historical Influence
Do You Supply to the USA ?
Mutual Recognition

Page 5

FDA Warning
Letters

Page 6

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.

Page 7

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

; Agilent ACE satisfies ALL requirements, including FDA warning letters.....
No parts
AuditofProblems
/ FDA 483
Warning Letters after > 150,000
OQ not good enough -;
Critical
system not qualified
adequately
GMP Training
/ Retraining
People not adequately trained ;
FDAAnnual
observe people
doing the work
Raw
Data
Added,
No Customer Checking
No raw data for the work ;Firm
could
notElectronically
show inspectors the
raw data
Calibration
Data
Added
to EQR
Tools used were not calibrated ;
Tools
used in an OQ
must
be calibrated
ofwork
Deviations
is achecking
CORE Feature
of ACE
OQ failures not detected ;
ByManagement
person doing the
or managers
it

Data integrity Data

not secure ACE
and could
have been tampered
with Points & Limits
Development
Guarantee
; Scientific

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

Page 8

Examples HPLC (Use the Warning Letter Search)

A
B
C
D
Page 9

Instrument
Compliance
Choices

Page 10

Customer OQ and Compliance Choices......

Justify what you dont Do

Dont Do IT !

Do It Yourself

(DIY)

Justify Alternative Interpretation

Customer People Leaving......

Balance Control Vs Risks

Specialist / Supply Chain
Hidden Costs
Not Core Lab. Business

Risks

Training & Parts (Repair)

Getting it WRONG !

(May not be as cheap as it appears)

Use the Original Equipment Manufacturer (OEM)

Possible Inflexible Approach
Different Qualification Strategy

Use Harmonised Approach

All OQs are the same

Easier to Defend
Simpler to Understand

Page 11

How Was The OQ Report Generated ?

Paper

Manual process (cheap labour)

Changeable, but not Flexible, Risk of error
Manual processes - data integrity

Reduced Compliance Risk

Qualification Delivery

Page 12

FDA Direction on Paper Records

Industry Misinterpreted the 2003 Part 11 Scope & Applications Guidance !

Printed chromatograms do not satisfy the predicate rules..

Page 13

Paper Protocols
Are hard to do well
Are more prone to human errors
Difficult to include calculations
Need checking

Page 14

How Was The OQ Report Generated ?

Paper

Manual process (cheap labour)

Changeable, but not Flexible Risk of error
Manual processes - data integrity

Excel

Data Transcription
Version Control
Validation

Reduced Compliance Risk

Qualification Delivery

Page 15

Monica Cahilly Training the FDA in Data Integrity

From Monica Cahilly, ISPE Conference New Brunswick, USA September 2011
Page 16

How Was The OQ Report Generated ?

Paper

Manual process (cheap labour)

Changeable, but not Flexible Risk of error
Manual processes - data integrity

Excel

Data Transcription
Version Control
Validation

Hybrid

Potential Data integrity concerns ?

FDA Publication 60052
Manual Checking

Reduced Compliance Risk

Qualification Delivery

Page 17

Many People Now Believe.

From Monica Cahilly, ISPE Conference New Brunswick, USA September 2011
Page 18

How Was The OQ Report Generated ?

Paper

Manual process (cheap labour)

Changeable, but not Flexible Risk of error
Manual processes - data integrity

Excel

Data Transcription
Version Control
Validation

Hybrid

Potential Data integrity concerns ?

FDA Publication 60052
Manual Checking

Fully Electronic

Remove Transcription
Errors
Secure Report Generation
Meta Data Preserves:
Content and Meaning
Electronic Data Indexing
Electronic Storage

Reduced Compliance Risk

Qualification Delivery

Page 19

Data Integrity An Increasing Area of FDA Focus

There is a paradigm shift in the way FDA thinks about part 11

Monica is training FDA in Data Integrity

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

Agilent ACE OQ satisfies the latest definitions required for data integrity:
FDA ALCOA requirements:
Attributable ;
Legible

Engineer Securely Logged On

Date / Time Stamps

; Electronic Report

Contemporaneous ; Real Time Results Recording

Original

; Secure PDF EQP Report

Accurate

; Secure Error Management / GMP

Complete ;

EQR is Full
OQ Report

Consistent ;

Full data
transfer log

Enduring

CDS, PDF, Print

Available

On CD / Print....

Page 20

Data Integrity Example

Page 21

Update on GAMP
and AIQ <1058>

Page 22

GAMP and USP <1058>

USP
Common
Goals

AIQ <1058>
- 2008

Good

Issues

Trends

Over Simplified ?
5 pages !
Simplify Process

Maximise use of
Supplier
Documentation

IQ / OQ in USP
General Chapters

What About
Group C

Pharmacopeia
Forum
Stimulus Paper

Easy to Follow

Risk byGAMP 4
A and B Simple
Categorisation
- 2001
Roles and
Responsibilities

What About
Software

Flexible

DQ Ownership

GAMP GPG

Better Than 4
Very
Comprehensive
GAMP
5

- 2008

(Validation of Laboratory
Computerized Systems)

Too Complex ?
Software Focus

Great For Custom

ISPE
Software

Risk Based
( 7 Categories Gone !)

Verify Vs Qualify
Category 2 (gone)
Page 23

Harder to Answer
Questions

Page 24

Instrument Qualification Is An Integral Part of Your

Quality System
To Defend Lab. Results, Companies
Must Defend the Instrument Qualification
Well !

HPLC (B)
Different Definitions for IQ / OQ / PQ

HPLC (A)

IQ / OQ

IQ / OQ

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 ?

Laboratory
QualityPrepIQ /HPLC
OQ
LC-MS System
IQ / OQ

Metals Analysis
IQ / OQ

Where there is a Difference:

Qualification Strategy and Rationale is Fragmented,
Time Consuming to Understand & Defend (Cost) + Risk....
Page 25

Explaining Your Instrument Qualification in an

Audit

ALL
REGULATORY
inspectors can be
Intimidating.

Fragmented Qualification is Harder to Defend

Page 26

Scientific Data Integrity ?

- Prove the INTEGRITY of your Results
The Correct Reference Materials Were Used
Training Records - The Analyst Was Trained
System Suitability The Method Was Working Correctly
The Method Limits Was Validated
The Instrument was Qualified. Etc.

Did the Qualification Cover the

Range of Use ?
Has the Qualification Status
Been Maintained ?

Can You Explain The Qualification

Rationale & Justify The
Set Points & Limits ?
Prove that the data has not been
tampered with.. ?

Page 27

Compliance Trends

Page 28

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

Page 29

FDA Warning Letters Trends..

www.fda.gov/downloads/ICECI/EnforcementActions

Number of FDA Warning Letters

2767 ?

Page 30

Compliance Trends
GAMP 5 Risk Based

GAMP
GAMP Computer System Validation

Risk Based
Thinking
Flexibility

(7 Categories Removed Now Risk Based)

Mandatory Chapters - Qualification

USP <1058>
Optional Chapters Best Practice

Part 11 / Annex 11

Bob McDowall
Stimulus Paper
- AAPS 2010

FDA Surveillance Audits

Implementation (e.g. Network Qualification)

Profound Implications for Compliance !

Data Integrity
Monica Cahilly
ISPE 12/13 September

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]

Page 31

Agilent ACE

Page 32

Evolution of Agilent Thinking.

Qualification

Chromatography
Data System (CDS)

CDS

(ACE)

Or Instrument Software

Network

(Annex 11)

Instruments

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

Agilent ACE uses TNF (technology neutral format)

Reads native file format or

AIA output
Original and Meta Data Retained

Page 33

So, How Does ACE Work ?

ACE 2.1 is Client Server Enabled

ACE Runs from Spinning Hard Disc

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.....
Page 34

Enterprise Compliance
Standardized Qualifications Across
Audit-ready paperless
deliverables with electronic
signatures
Streamlined approval from
equipment qualification plan to
final report

Multi-vendor
Enterprise Compliance Delivery
Network
Instrument
Control

2-wire analog
detector output

Customers
CDS
Empower

Digital output

Robust vendor-neutral
qualification platform

Enterprise Edition
Delivery Model

Configurable testing conditions

providing flexible delivery
Chromatography Data System
(CDS) agnostic
Global Solution providing Reproducible, Quality Deliverables with Full Traceability

Page 35

ACE 2.0

Universal

Protocol
Paperless Execution
Paperless Report
Audit Ready

Page 36

ACE 2.0 Overview

Designed for Efficiency
Work Type

Workflow
based task
list

Task
instructions

Multiple
sessions

Agilent
Software Look
& Feel
Configurable
UI

Attachment
window

Page 37

ACE Example
Work Type
PM, IQ, OQ
Requalification,
Software OQ

Ref. / Name

Select Technology
- HPLC
- GC
- MS (GC-MS, LC-MS, (UPLC-MS)
- Dissolution
- UV .. Etc.

Configure
(Software used
to Collect Data)

Page 38

Test Limits You Approve

are Included

Page 39

Integrated Graphic Functions:

- Software
- EQR

Page 40

ACE Computer Based Help

To Support Engineers & Partners

Context Work Instructions

Detailed
Explanations

Instrument Photographs

Partner
Edition.....
Page 41

Agilent Paperless Automated Compliance Engine

ACE efficiently enforces compliance
Workflow and rule based (simple to use, flexible to develop)
Enables electronic execution of Paper Documents
Reports free of transcription errors
Electronic chromatograms with meta data
PDF reports for efficient storage and review
Integrated GMP compliance:
Test execution counter (reports how many times a test was run)
Deviation justification and management
Validated calculations
Automated Pass / Fail report.. Etc.

Page 42

Company Life Cycle - Compliance Maturity Curve

Agilent Compliance Solutions
Support the Needs of these two different
approaches

Companies With High

cGXP Expertise
ACE Partner Edition

Harmonised Approach
Standards / Limits

Mature Pharmaceutical
Risk Management
Life Cycle Compliance
Aligned Compliance

Compliance Delivery

Chemical Supplier, Start Up Company or ISO 9001

Companies With
Lower cGXP
ACE
Expertise

Avoidance Risk
Low Experience in Qualification
Need Qualification & Compliance Support

Time

Page 43

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 NEEDS
Greater Flexibility.. In Qualification
ACE 2.0 + is Designed to Support These Needs
Simple, Intuitive Interface
Through our Partner program we can train you !
Page 44

Questions ?

Page 45