Laboratory Audit Preparation

Spain May 2014

Paul Smith
paul_smith@agilent.com
Contents
• Audit Preparation – Thinking/ Organising ……………………….. 
• Common Compliance Questions…………………….. 
• FDA Warning Letters – Data Gathering…………………………. 
• Audit Letter………………………………………………………………………………….. 
• Types of Audit / Focus Areas….......…..……………………. 
• Prepare Your People……………………………………………….……….. 
• Instrument Qualification……………………………………..………. 
• Instrumentation………………………………………………………………………. 
• Data Integrity……………………………………………………………………….…….. 
• Laboratory Tour……………………………………………………………………… 
 CAG EMEAI FY14 | Agilent Restricted | Page 2
What Do You See?

• Camels
• Walking
• Same Direction

• 48 Camels
• Families
Shadow
• The More You Look, Human Condition
the More You See Camel
• People “see” what they “expect”
• The Greater the Expertise • Some auditors look in detail,
the Greater their “Resolution” for Looking
others & Understanding
don’t look or see Finer
what Detail…..
they expect.
• What is the expertise of your next auditor……. ?
• Specialists will Always look in detail

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Some Possible Laboratory Audits Audits Preparation is
a Strategic Priority !
Health & Environmental
Safety
Pharmaceutical Financial

ISO 17025 / 9001

Regulatory [FDA, MHRA]
Internal
Accreditation (Self-Audits)
Body
EU GMP Chapters
Customs &
Excise Customers
Laboratory

CORPORATE
(Sometimes the Hardest !)
Rules Applied
& Possible Actions….. … But, the same principles apply
Vary Between Audits.... to ALL AUDITS.

Prepare Well Once – Then Update / Apply

 CAG EMEAI FY14 | Agilent Restricted | Page 4
Managing The Audit – What to Expect

Strategic Official
Audit Role Audit Role
• “Reads” The • Broad
Inspector • Inspector Knowledge
• Host - stay with inspector

• Technical
• Believable • Fronter Experts
• Scribe - Subject

• Records • Records
- Actions • Runner - Time asked
issues….. supplied

• Spy • Gets what's

(In – Out) asked
(Info. / People)

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 Managing The Audit – What to Expect
The Control Room is Staffed
by experienced personnel who:
• Keep calm under pressure
• Know site & company systems well

• Inspector
• Host
Runner
• Fronter
• Scribe
• Runner
• Live – Software Vs.
Presentations / Simulated
Audit Decisions: FDA / EU Regulators – Now LIVE / INTERACTIVE Review
• Document Request System (Electronic or Paper) ?
 CAG EMEAI FY14 | Agilent Restricted | Page 6
Common
Compliance
Questions
Common Questions – Customers Ask Agilent (During their Audit !)
Audit Question How do we defend……

• Read the documentation

• Always understand – what you sign
• Ask for training / explanation…..
Audit Question

1. The auditor has asked why we don’t How do we defend……

perform a particular test (e.g. injection linearity).
Implications of Choice – WHY ?
The auditor found we qualify the How do we defend……
2.
instrument at different settings to our
methods (e.g. temperatures), what do we do.
Range of Use
The auditor has asked for our PQ, but How do we defend……
3.
we don’t perform one as we do System
Suitability, but the auditor rejected this !
Life Cycle Usage

4. The auditor is asking questions How do we defend……

we can’t explain…….. Fundamental Understanding
 CAG EMEAI FY14 | Agilent Restricted | Page 8
Data Integrity Questions – About Software ?

1. Do you have your source electronic data – or are your deleting them ?
- Electronic files should be retained – they are the source data, paper is not

2. Do you review your electronic source files ?

- Data integrity check – visibility of repeat work, integration and sequence files – data not reported

3. Does review include a review of meaningful metadata ?

- Authenticity of data

4. Does your system configuration include clear segregation of duties ?

- Independence of Administrator and User Roles, Shared Passwords… Etc.

5. If “COTS” software – Is it validated for your intended use ?

- Vendor documentation (including qualification) must be reviewed and may need augmenting

 CAG EMEAI FY14 | Agilent Restricted | Page 9

Do You Define Print Outs as “Raw Data” ?

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124787.htm

3. How do the Part 11 regulations and “predicate rule requirements” (in 21 CFR Part 211) apply to the
electronic records created by computerized laboratory systems and associated printed
chromatograms that are used in drug manufacturing and testing?

Industry Misinterpreted the 2003 Part 11 Scope & Applications Guidance !

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

 CAG EMEAI FY14 | Agilent Restricted | Page 10

Audit Preparation – Thinking Perspective
Stereotype Answer Potential Implications

“I Believe…….” Passion, but risk

• Scientist
“Yes, but…….” Calculated answer
• Manager

Strategic……. Minimise risk

• QC ( “avoid” justification )
(“economical” with answers)

Love a good argument

• R&D “Why…..” ( “love” justification )
( “scientific” with answers)

Implications for Technology Transfer……

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 Debarment………. (Updated March 2013)
To date, the FDA has applied the GDEA to debar over 132 people and lists these:
http://www.fda.gov/ICECI/EnforcementActions/FDADebarmentList/ucm2005408.htm

Legal details for each debarment are published in the federal register:

• Significant fines if debarred person employed

• FDA will not accept / review ANDA…..
18
18

16 Possible Fines:
14 13 Individual $250, 000
12 Company $1, 000, 000
10
8
8 7
6

4 3
2
2 1 1 1
April 5th 2012 0

“….Employed as a chemist in the

Quality Control Depart….”
Number of people FDA Debarred each year
 CAG EMEAI FY14 | Agilent Restricted | Page 12
FDA Warning A Compliance Data Tool
Letters
Google “FDA Warning Letters”

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

 Basic Search Engine

CAG EMEAI FY14 | Agilent Restricted | Page 14
How Many ? How Many Times are Techniques Cited ?

• HPLC – 68
• GC – 17 Updated: 31/Mar./2014

• KF – 2
• NMR - 2
• FTIR – 6
• FT-IR – 11
• Chromatography - 32
• Dissolution – 40
• UV – 44
• Infrared – 52
Manufacturing Process Qualification
• Qualification 348
Supplier Qualification
• Stability - 371
• Calibration 438
• Training > 1,000
 CAG EMEAI FY14 | Agilent Restricted | Page 15
FDA Audit Letter
FDA Letter Time Line…. For an Inspection - Reactive
Auditor
Mgt. Major Team
Meeting • Google Tidy Action Brief
• FDA Team
Audit • Other… Up Progress
Brief Daily
Notification (Specialist ?)
• Audit Actions Last
• Amnesty ! “Wash
• Action
• OOS Tour
Lab. Tour (e.g. Printed
• CAPA Up”
Plan Documentation)
• Qualification
• Ongoing • Validation • News
• News • Training
• Briefing Process • Timings
• Tour • Documentation • Bins .. Etc.
(Procedure) Findings • Change…. Etc.

Audit Preparation Time Line – From FDA Pharmaceutical Audit

• Presentations….. • Site
• Overview • Site or ?
• Validation • Global
• Changes and • DEMONSTRATION • Quality
Updates (last visit) (“Live System”) Company • Lists
Change • CAPA
• Annex 11 / Chapter 4 Systems
• Data Integrity Management
(“Audits”).........
Location OOS
Overview Self Complaints
Computer Ongoing Audits Trends
 Systems - Proactive CAG EMEAI FY14 | Agilent Restricted | Page 17
Types of Audit /
Focus Areas
How The Audit is Performed.…
• Records Trace (e.g. “Batch”) – Pedigree
Hierarchical • Examine the Manufacturing Records
• Examine the Lab. Results
• Examine the Analyst Training Records
Hierarchical • Examine the Instrument Details... etc

Emphasis – Identify areas of non-compliance in the INFORMATION

Scope – Limited by where the inspection “starts” (e.g. which batch)

System Based Inspection • Examine Your Quality System

• Examine Your - Analyst Training Process
• Instrument Selection and Qualification
Generic System • Batch Failures / Out of Specification Results
Questions: • Your Trending and Quality CAPA System

Emphasis – Identify areas of non-compliance in your QUALITY SYSTEM

Scope – Your whole quality system – everything – WIDER RANGING

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Kinds of Audit
• Quality Management System
Is it Effective ?
• Some Component
- Quality Mgt.
• Early Observation….
ISO 9001 • CAPA follow up
Emphasis – Evaluate if Quality System is Effective for - SCOPE of ACCREDITATION

Is it Valid…… • Technical Review of What You Do

• Examine Your Systems
- Technical Evaluation
• Uncertainty of Measurement (not just pass / fail)
ISO 17025 • CAPA
Accredited Calibration ISO 13485 – Medical Devices • Adverse Effects
Accredited Services • Change Control
Emphasis – Problems & Technical Evaluation of What You Do Scope of A..

• Now Assume - You Are Fraudulent

Date Integrity • Until You Can “Prove” otherwise
• Data Integrity (electronic data)
FDA / MHRA • Independent Data Integrity Auditing
Emphasis – We don’t Trust / Believe You – EVIDENCE to “Prove” Otherwise

 CAG EMEAI FY14 | Agilent Restricted | Page 20

 Audit
Hierarchical
Data Integrity
[e.g. MHRA]
How The Audit
is Performed

ISO Accreditation Supplier Pharmaceutical Data Integrity

Kinds of Audit

Supply Chain
[e.g. Approval of
Lab. Suppliers]

System Based Inspection

 CAG EMEAI FY14 | Agilent Restricted | Page 21
Principles of Data Quality Triangle – Apply to All

Emphasis (Relative Importance) Move ?

Emphasis (Relative Importance)
- Qualification - Verification

Is
part of

System Working

Shewhart Chart
Must be Suitability of Method
done before

Must be
done before Know Instrument is Working

Data Quality Triangle

From USP <1058> ISO 17025
Pharmaceutical
• Pass / Fail Decisions Principles Apply • Uncertainty of Measurement
• Qualification Protocol - Story • Verification / Calibration - Certificate
To ALL
• Data Integrity • Proficiency Studies
Laboratories

 CAG EMEAI FY14 | Agilent Restricted | Page 22

 Audit Preparation Focus Areas + Data Integrity
• Job Description / Training Records
People
• Demographics / Age / Qualifications
• Expertise / Skills Map
•
exclusion
Validation “Status”
• Audit Risk ? (+ Debarment)
• Technology Transfer
Analytical Methods • Registration
idoneidad

• Suitability for Use • Review (e.g. OOS)

• Maintenance
Analytical Equipment • Qualification / Calibration
• Training (Technique / Instrument / SOP)

• Validation / • Reviews
Qualification Software / Computer Systems • Change
• Configuration Mgt. Control

• Approved
Procedures • In Date
• Is the Ink Wet !
• Justification
• Housekeeping
Infrastructure • Electricity • Audit
• Location of Instruments • Questionnaires
• Lab. Supplier Approval
Supplier Approval • Quality Agreement
 CAG EMEAI FY14 | Agilent Restricted | Page 23
Prepare Your
People
Prepare Your People

Some inspectors
are HOSTILE,

“The Future of
this site depends.. ”

ALL inspectors
can be
Intimidating…….

 CAG EMEAI FY14 | Agilent Restricted | Page 25

Prepare Your People
People who talk to the auditor:
• NEED training to answer AUDIT Questions:
 BE CONFIDENT in their answers
 STRUCTURE their answers When asking questions,
• MUST ONLY answer questions on…… an inspector will ASK,
WHICH THEY ARE KNOWLEDGEABLE Then wait for your answer
• ONLY answer.…. THE QUESTION ASKED After Your ANSWER, they
then wait ………
When people are nervous,
An inspector will: they will talk…............ to fill
the LONG SILENCE …….
• ASK you to describe…..
• CHECK Understanding Vs. SOP
RAPPORT……. !
• OBSERVE, then CHECK……
• CROSS-CHECK…. & ASK QUESTIONS…..

 CAG EMEAI FY14 | Agilent Restricted | Page 26

Prepare Your People
Everyday phrase …. Impression….

“I think this is what happens …” “I would expect you to know what

happens …”

“Normally, we would…..” “So what happens when it’s not

normal …”

Suggests you are not always

“To be honest…..”
honest !

“That’s not my problem…” Care – this implies you don’t care

“If you can’t afford to have proper

“That’s too expensive……” controls, you shouldn’t be doing
this…” Provide a rational reason !

 CAG EMEAI FY14 | Agilent Restricted | Page 27

Instrument
Qualification
 HPLC Qualification – History of Divergence
1990’s
People Applied
FDA PROCESS
VALIDATION GUIDE
to…. • Approach Not Harmonised
[ different approaches ]

FDA Company B

Process Company A
• Conflicting Content
[ for laboratories to defend ]
Validation
Guide
Lines Company A
• Paper Based
[ storage, access, risk ]

May Company C
• Compliance Risks
1987 Company A [ manual calculations ]
[ paper protocols ]
[ data integrity ]
To LABORATORY
INSTRUMENTS

 CAG EMEAI FY14 | Agilent Restricted | Page 29

Suitability for Use – Fundamental 4Q Life Cycle
Does it Does it
Meet your USER WORK as
REQUIREMENTS Installation EXPECTED Performance
Qualification [in the lab] Qualification

DQ IQ OQ PQ
Design Has it been Operational Will it
Qualification INSTALLED Qualification Work with
CORRECTLY Customer
User METHODS
User

Pharmaceutical Companies & Service providers don’t agree…

• WHAT - An OO or PQ Contains
• WHO - Should perform it
• HOW - Often an OQ should be Done

do you want to use it for ?

What CAG EMEAI FY14 | Agilent Restricted | Page 30
What will an Auditor Look at ?
Audit Focus
 Is the Instrument
Suitable for use
What about: Accuracy / Uncertainty
Sensitivity / Science
- The future

What do you
  Is it installed
Re-Qualification Correctly
want it to do: (Justification)

- Write it down   Is there an SOP
- Why is it suitable Maintenance
Are people Trained
 IQ  Is it Calibrated
Method Validation
DQ Use
OQ
  Failure Mgt.
Breakdown Impact of Failure
Does it Work: CAPA ?

- Installed correctly Re-Qualification Repair  Maintenance
- In your laboratory (Justification) Routine ?

 Re-Qualification
/ Calibration

 CAG EMEAI FY14 | Agilent Restricted | Page 31

Instrumentation
Laboratory Instrumentation ….. Status
Decisions – What do you do about……
What is Your
Does Your Laboratory Have These Rationale Any
[or their equivalent steps ?] Strategy ?
- Monitoring Problems ? [about problems]

System URS DQ IQ OQ PQ Rationale Problems Actions

Calib. SSC
FT-IR      B test site…. Too Good !! Avoid in Audit ?
GC X X X   USP, SSC URS, DQ, IQ Do OEM

HPLC X  X   Caffeine GAPS Do IQ Review

Dissolution      OEM, USP Sets Std… USE in Audit

LC-MS X X X X X Non Routine From R & D Move

NIR X     Calibration No URS Retrospective

KF X X  X  Daily Test IQ, PQ only System Suit.

pH Meters X X X X  In House PQ only Hide !

Balances      OEM Calib. Fail Review Results

……. etc ! ! X  X Fragmented Mixture Panic !

 = Present X = Absent
 CAG EMEAI FY14 | Agilent Restricted | Page 33
Laboratory Instrumentation ….. People / Contacts
With “Live” System
System “Owner” “User” “Expert” 2nd Expert Supplier (s)

FT-IR (1) Paul John Paul Derek A

GC (4) Clare Peter Ted Mark B

HPLC (11) James Mark Carole Mike A

Dissolution (1) Dave R John Derek Rob C

LC-MS (1) James R&D Mike Rob D

NIR (1) Paul Paul Paul Derek A

KF (3) James Andy Derek Mark E

pH Meters (2) Dave R Mark Mark Andrew E

Balances (6) Clare Richard Derek Andrew F

……. Etc…… Manager 7 5 4 7

Holiday Too Busy Company Closed !

Relationship with supplier – in an Audit…. (what would yours do ?)

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Data Integrity
 So, What is Data Integrity
Data Integrity ?
• ALCOA +…. (understand)
• Build lab. workflow
• Check results to electronic
• Data integrity audits

Data
Data Traceability is Essential
In Data Integrity….

• You have it electronically

Prove Your Data is Not Fraudulent ! • It is not tampered with
 CAG EMEAI FY14 |
• Implement reviews
Agilent Restricted | Page 36
 Example Sample Workflow….
Electronic Vs. Paper

Sample Receipt
1.
A
A ttributable
[Who did it]
Electronic Log Vs. Ink Signature

Booked into LIMS

2.
LL egible
[Can you read it]
Print , Secure Electronic File or Handwriting

Schedule Tests
3.
C
C ontemporaneous
[Recorded in “Real Time”] Electronic Log Vs. Date Written

Sample Preparation
4. O
O riginal
[Is it original]
Secure Electronic File Vs. Paper “Photocopy”

Chromatograph Sample
5. AAaccurate Validated Electronic Output Vs. Paper….
[Is it Accurate]

Calculate Results
6.
More Secure ? Electronic Greater Risk ?
(harder to manipulate) (easier to manipulate)
Check / Report Results (simpler to detect) Vs. Paper (very difficult to detect)
7.

Compare Against Specification

8.
 CAG EMEAI FY14 | Agilent Restricted | Page 37
The Laboratory
Tour…..
Plan The Lab. Tour How Do You Plan Yours ?

KF
Office
Area

Sample Storage / Weighing

LIMS
HPLC

Fume

Write Up
Hoods

Write Up
Write Up

 Clipboard – with Flow Charts

 Sample Receipt – Paperwork Etc… Sample
Receipt
 CAG EMEAI FY14 | Agilent Restricted | Page 39
Strategy For The Laboratory Tour
 Plan the Lab. Tour
 Walk the route…..
 Where would you “like” to stop ?
 Where will you explain your Instrument Control(Calibration). ?
 What did your audit reveal ?
 Look in cupboards…… !
 What is Visible – Housekeeping ….Etc.
 Before the Audit – EMPTY Tree CYCLERS / Bins … Etc.
 Empty PC Recycle Bin !
Empty the Bins !
“…found unofficial batch records for approximately 75 batches of injectable
finished drug products torn in half in the waste are” Wockhardt – ucm361928

“ The investigator found a certificate of analysis (COA) for (b)(4) oz, lot number
(b)(4), dated January 19, 2011, in a trash container in the office
used by QC personnel ” Compania – ucm311326

 CAG EMEAI FY14 | Agilent Restricted | Page 40

Questions ?

 CAG EMEAI FY14 | Agilent Restricted | Page 41