Preparing Your Analytical Laboratory for a Regulatory Audit · PDF filePREPARING YOUR...

Preparing Your Analytical Laboratory for a Regulatory Audit

Live Webinar

Paul Smith

[email protected]

May 2, 2014

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PREPARING YOUR ANALYTICAL LABORATORY FOR A REGULATORY AUDIT

Possible Audits – You May Face

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Laboratory


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Health &Safety

Accreditation BodyISO:

13485 / 17025 / 9001

Customs &Excise

Financial

Internal(Self-Audits)

Customers

Environmental

Laboratory


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PharmaceuticalRegulatory

Health &Safety


13485 / 17025 / 9001

Customs &Excise

Financial


Customers

Environmental

Rules Applied& Possible Actions…..

Vary Between Audits.... Industries

Laboratory


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(Sometimes the Hardest !)


Health &Safety


13485 / 17025 / 9001

Customs &Excise

Financial


Customers

Environmental



CORPORATE

Laboratory


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… But, many of the same principles apply toALL AUDITS……………..



Health &Safety


13485 / 17025 / 9001

Customs &Excise

Financial


Customers

Environmental



CORPORATE

Laboratory


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… But, many of the same principles apply toALL AUDITS……………..



Health &Safety


13485 / 17025 / 9001

Customs &Excise

Financial


Customers

Environmental



CORPORATE

Prepare Well Once – Then Update / Apply

Audits Preparation is a Strategic Priority !

Run as a Project !

Laboratory

Compliance Drivers – All Industries

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Are Your Results Valid ? CommercialReasons

Analytical Service

Compliance Reasons

Compliance Drivers – All Industries

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Are Your Results Valid ? CommercialReasons

Analytical Service

Compliance Reasons

Pharmaceutical GXP ISO 9001 ISO 17025

Influenced by – Where you:

- Manufacture- Supply

National Pharmacopeia's• USP• EP• JP

Influenced by:- Scope of Accreditation

Quality Management System Testing & CalibrationLaboratories

Influenced by:- Scope of Accreditation

EU GMP

CFR(Code of Federal Regulations)

• 4.2.4 – Control of Records• 7.4.3 - Materials• 7.6 – Measurement

Equipment

• 8.5.2 - Corrective Actions• 8.5.3 - Preventative Actions

• 4.13.1.2• 5.2.1• 5.2.3• 5.3.1• 5.4.6.1• 5.4.7.1• 5.5.2• 5.5.4…….Etc.

- Manufacture- Supply

Clauses

How Do You Know Your Results are Valid ?

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• Instrument Was Qualified / Calibrated…. Etc.• Method Limits Were Validated

• Correct Reference Materials Were Used

• Training Records - The Analyst Was Trained

• System Suitability – The Method Was Working Correctly

How Do You Know Your Results are Valid ?

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• Instrument Was Qualified / Calibrated…. Etc.• Method Limits Were Validated

• Correct Reference Materials Were Used

• Training Records - The Analyst Was Trained

• System Suitability – The Method Was Working Correctly

The above align with United States Pharmacopeia (USP) general chapter 1058 on Analytical Instrument Qualification (AIQ).

The Principles of This Data TriangleApply to All Labs!

• Broad Knowledge - stay with inspector

• Technical Experts- Subject

• Records- Time asked

supplied

• Gets what's asked(Info. / People)

Managing The Audit – What to ExpectWho Has Been in an FDA Audit ?

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• Inspector

• Host

• Fronter

• Scribe

• Runner

Official Role


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• Inspector

• Host

• Fronter

• Scribe

• Runner

• ReadsInspector

• Believable

• Records- Actions

issues…..

• Spy(In – Out)

Strategic Role


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• Inspector

• Host

• Fronter

• Scribe

• Runner

AuditControlRoom

ExpertsDocumentation

Information

Runner

Suppliers

The Control Room is Staffedby experienced personnel who:• Keep calm under pressure• Know site & company systems well


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• Inspector

• Host

• Fronter

• Scribe

• Runner

AuditControlRoom

ExpertsDocumentation

Information

Runner

Suppliers


Audit Decisions: • Live – Software Vs. Presentations / SimulatedFDA – Now LIVE (Agilent is Supporting Customer FDA Audits)

• Electronic or Paper Request System


Managing Document Requests

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• Have to Remain Compliant During The Audit

• With some inspections, such as the FDA, there may be SEVERAL Inspectors

• Original Approved “Master” Document provided to Inspectors

Requests from Audit …..Requests from Control Room….• What is requested?• Time of Request• Who is required (to Front/Present the Information)

Pad’sOf

Request Forms

1.

3.2.

4.

White Copy – Stays in Audit

Blue Copy – Stays in Control Room

Green Copy – Attached to Information

Pink Copy – Left in the Filing System(in case someone requests original)

Audit Preparation Focus Area…..

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Area Subject

People

Equipment

Methods

Data

Audits

Observations

• Suitable for Use ?• Life Cycle Management• Return to Use

A. DebarmentA. TrainingB. Demographics

• Validation / Change Mgt.• Training / Uncertainty (ISO)

• Data Integrity• Life Cycle

• Internal• Observations

• Actions from Audits• Customer Complaints

Comments

Audit Preparation Focus Area…..

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Area Subject Comments

People

Equipment

Methods

Data

Audits

Observations

• Suitable for Use ?• Life Cycle Management• Return to Use

A. DebarmentA. TrainingB. Demographics

A. FDA Web SiteB. Structure / “Proof”C. Justification of Resource

• Expected <1058> Changes• USP – General Chapters• GAMP – USP Harmonisation

• Validation / Change Mgt.• Training / Uncertainty (ISO)

• Data Integrity• Life Cycle

• Internal• Observations

• FDA Focus Area• 21CFR Part 11 • Chapter 4 / Annex 11

• Actions from Audits• Customer Complaints

• USP Stimulus Paper (QbD)(Method Validation & QbD

Pharmacopeiai Forum)

• Are you doing them ?• Resolution of Observations

• Have you resolved them?• HPLC – FDA Warning Letters (62)(28% Repeat, 38% Poor Response (CAPA)

Audit Preparation Focus Areas

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People

Analytical Methods

Analytical Equipment

Procedures

Infrastructure

Supplier Approval

• Job Description / Training Records• Demographics / Age / Qualifications• Expertise / Skills Map• Audit Risk ? • Validation “Status”

• Technology Transfer• Registration• Review (e.g. OOS)• Suitability for Use

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

• Approved• In Date• Is the Ink Wet !• Justification• Housekeeping

• Electricity• Location of Instruments • Audit

• Questionnaires• Lab. Supplier Approval• Quality Agreement

Software / Computer Systems• Validation /

Qualification• Configuration Mgt.

• Reviews• Change

Control

+ Data Integrity

What did You Mean ?

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What did You Mean ?

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Terms Used:

1. Calibration [21 CFR 211.160 (b) (4), FDA]

2. Qualification [USP, e.g. <1058>]

3. Validation [Method, Process, Software]

4. Verification [GAMP 5, ASTM E2500]

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TYPES OF AUDIT

How The Audit is Performed.…

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Hierarchical

Hierarchical

Emphasis – Identify areas of non-compliance in the INFORMATION

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

• Records Trace – Pedigree / History• Examine the Manufacturing Records• Examine the Lab. Results• Examine the Analyst Training Records• Examine the Instrument Details... Etc.

How The Audit is Performed.…

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Hierarchical

Hierarchical

Emphasis – Identify areas of non-compliance in the INFORMATION

System Based Inspection

Generic SystemQuestions:

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

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

Hierarchical Some Element of Luck(depending on where it “starts”)

System-Based Inspection

Prepare, Prepare, Prepare

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

Scope – Your whole quality system – everything – WIDER RANGING

• Records Trace – Pedigree / History• Examine the Manufacturing Records• Examine the Lab. Results• Examine the Analyst Training Records• Examine the Instrument Details... Etc.

Kinds of Audit

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ISO 9001

• Quality Management System• Some Component• Early Observation….• CAPA follow up

Is it Effective ?- Quality Mgt.

Emphasis – Evaluate if Quality System is Effective for - SCOPE of ACCREDITATION

Kinds of Audit

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ISO 9001




Is it Valid…… - Technical Evaluation

ISO 17025Accredited CalibrationAccredited Services

Emphasis – Problems & Technical Evaluation of What You Do Scope of A..

• Technical Review of What You Do• Examine Your Systems• Uncertainty of Measurement (not just pass / fail)

ISO 13485 – Medical Devices• CAPA• Adverse Effects• Control

Kinds of Audit

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ISO 9001




Is it Valid…… - Technical Evaluation

ISO 17025Accredited CalibrationAccredited Services

Emphasis – Problems & Technical Evaluation of What You Do Scope of A..

• Technical Review of What You Do• Examine Your Systems• Uncertainty of Measurement (not just pass / fail)

FDA

• Now Assume - You Are Fraudulent• Until You Can “Prove” Otherwise• Data Integrity (electronic data)• Independent Data Integrity Auditing

Is it Fraudulent ?

Emphasis – We don’t Trust / Believe You - EVIDENCE

ISO 13485 – Medical Devices• CAPA• Adverse Effects• Control

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PREPARE YOUR PEOPLE

Prepare Your People

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Some inspectorsare HOSTILE,

“The Future ofthis site depends.. ”

ALL inspectors can be Intimidating…….

Prepare Your People

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• BE CONFIDENT in what they say• ONLY answer questions on what they are knowledgeable• ONLY answer QUESTIONS ASKED (don’t provide additional information)

• SOME PEOPLE find audits very stressful and/or FIND 1 to 3 difficult

People who talk to the auditor must:

An inspector will:

• ASK you to describe…in your own words (to check you understand)• CHECK what you say Vs. the Standard Operating Procedure (SOP)• OBSERVE YOU doing the work• CHECK records of previous examples• CROSS-CHECK – with other departments• ASK QUESTIONS…

Prepare Your People

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Everyday phrase …. Inspectors impression….

“I think this is what happens …”

“Normally, we would…..”

“That’s too expensive……”

“That’s not my problem…”

“To be honest…..”

Prepare Your People

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Everyday phrase …. Inspectors impression….

“I think this is what happens …”

“Normally, we would…..”

“That’s too expensive……”

“That’s not my problem…”

“I would expect you to know whathappens …”

Care – this implies you don’t care

“So what happens when it’s notnormal …”

“If you can’t afford to have proper controls,you shouldn’t be doing this…”

“To be honest…..” Suggests you are not alwayshonest !

Provide a rational reason !

Training

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Personnel – TrainingDocumented (Training File)Background / Experience (CV / Resume)GMP (Annual)Job / Task SpecificTraining Certificates“Testing” of Knowledge (Demonstration of Understanding)

Personnel must have the proper education, background, training and experience to perform their job function….

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INSTRUMENTATION

4 Q Model for Instrument Qualification

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DQ IQ OQ PQDesign Qualification

Performance Qualification

Operational Qualification

Installation Qualification

4 Q Model for Instrument Qualification

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DQ IQ OQ PQDesign Qualification

Performance Qualification

Operational Qualification

Installation Qualification

Does itWORK as YOU EXPECTED?

Has it beenINSTALLED

CORRECTLY?

There are no “Set Rules” on:

• WHAT – Some of The Stages Contain• HOW – Often an OQ should be Done• WHO – Performs Some of The Stages (OQ/PQ)

Does itMeet your USER

REQUIREMENTS?

Will itCONTINUE to work

CORRECTLY?

What will an Auditor Look at ?

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DQ UseOQ

IQ Maintenance

Re-Qualification(Justification)

Breakdown

RepairRe-Qualification(Justification)

What do you want it to do:

- Write it down- Why is it suitable

Does it Work:

- Installed correctly- In your laboratory

What about:- The future

What will an Auditor Look at ?

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DQ UseOQ

IQ Maintenance

Re-Qualification(Justification)

Breakdown

RepairRe-Qualification(Justification)

Is the Instrument Suitable for useAccuracy / UncertaintySensitivity / Science

Is it installedCorrectly

Is there an SOPAre people TrainedIs it Calibrated Method Validation

MaintenanceRoutine ?

Failure Mgt.Impact of FailureCAPA ?

Re-Qualification/ Calibration “As Found”

What do you want it to do:

- Write it down- Why is it suitable

Does it Work:

- Installed correctly- In your laboratory

What about:- The future

Audit Focus

Laboratory Instrumentation …..

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Inventory Critical Instruments List

System URS DQ IQ OQ PQ Rationale Problems ActionsFT-IR

GC

HPLC

Dissolution

LC-MS

NIR

KF

pH Meters

Balances

……. etc • List all your “Critical Instruments” • Review the Qualification Status /

History (Maintenance / System Log Book) of Each Instrument


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GC

HPLC

Dissolution

LC-MS

NIR

KF

pH Meters

Balances



QualificationRationale

AnyProblems ?

What is YourStrategy ?

User Requirements Specification/ Design Qualification


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GC

HPLC

Dissolution

LC-MS

NIR

KF

pH Meters

Balances



QualificationRationale

AnyProblems ?

What is YourStrategy ?

User Requirements Specification/ Design Qualification

USP <1058> Includes Definitions of:• Roles:

• User• QA• Supplier

• Responsibilities• DQ / IQ / OQ / PQ

Work Flow Mapping / Data Integrity – Output to Source File…Independent “Data Integrity” Review – sample / checkData Integrity Detection Training

Laboratory Instrumentation…. Status

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System URS DQ IQ OQCalib.

PQSSC

Rationale Problems Actions

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

Rationale- Monitoring

AnyProblems ?

What is YourStrategy ?[about problems]

Does Your Laboratory Have These[or their equivalent steps ?]

Laboratory Instrumentation…. Status

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Decisions – What do you do about…

System URS DQ IQ OQCalib.

PQSSC

Rationale Problems Actions

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

Rationale- Monitoring

AnyProblems ?

What is YourStrategy ?[about problems]

Does Your Laboratory Have These[or their equivalent steps ?]

Laboratory Instrumentation …

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People / Contacts

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 Company Closed !Too Busy

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

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DATA INTEGRITY

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So, What is Data Integrity ?Data Integrity

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Prove Your Data is Not Fraudulent !• You have it electronically• It is not tampered with• Implement reviews

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Data

Prove Your Data is Not Fraudulent !

• ALCOA…. (understand)• Build lab workflow • Check results to electronic • Data integrity audits

• You have it electronically• It is not tampered with• Implement reviews

Data Traceability is EssentialIn Data Integrity….

Example – Identification by FT-IR

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Sample

FT-IR SamplePreparation

InfraredSpectrum

SpectrumComparison

Result


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• ATR• Nujol Mull• KBr Disk• Film … Etc.

Only compare spectra recorded under the “same” conditions[equivalent scan and sample preparation

defined by Pharmacopeia Requirements]

Sample Preparation Influences:1. Spectrum Appearance2. Variability [Skill]3. Quality of Spectrum

[subjective decision]

• USP• EP• Registration• Procedures

Sample


InfraredSpectrum

SpectrumComparison

Result


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Spectrum Quality:[of the sample preparation – not the identification]

1. Is the Quality of the sample prep good enough ?

2. How managed / documented ?[ OOS for sample prep. or procedure explaining poor spectrum quality & how documented ]

Instrument Performance:[How Do You Manage It ?]1. Wavenumber [Accuracy]2. Resolution [of Instrument]3. Interference [contamination or water

vapour]4. Reproducibility [of Spectra – JP]5. % T [Scale – Not Linear]6. EP / JP / USP / IP / CP .. Etc.




Spectra – Do You:1. Saved electronically or2. Define print out as raw data[ FDA Data Integrity, Tamper Evident, Print Scan Conditions, Analyst… cGMP, Etc.]

Complete Data

Sample


InfraredSpectrum

SpectrumComparison

Result


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SpectralComparison:1. Electronically or2. Using Print Outs[ Reference material or Spectra ]






Reference Spectra:1. Approval of FT-IR Identification Test2. Management of Suitability[ of the Reference spectra & Materials Used ]

File Management:Can Files Be:1. Re-named ?2. Manipulated ?3. Deleted ?





Complete Data

Sample


InfraredSpectrum

SpectrumComparison

Result


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SpectralComparison: 1. Electronically or2. Using Print Outs[ Reference material or Spectra ]




Validation[for intended use]



Reference Spectra:1. Approval of FT-IR Identification Test2. Management of Suitability[ of the Reference spectra & Materials Used ]

Differences:1. How Manage and 2. Documented[ What level is significant ]

Training[& SOP]

File Management:Can Files Be:1. Re-named ?2. Manipulated ?3. Deleted ?





Complete Data

Sample


InfraredSpectrum

SpectrumComparison

Result

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THE LABORATORY TOUR

Plan The Lab. Tour

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Sample Receipt

Fume Hoods

LIMS

HPLC

KF

Sam

ple

Stor

age

/ Wei

ghin

g

Writ

e U

p

Writ

e U

p

Writ

e U

p

OfficeArea

Plan The Lab. Tour

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Sample Receipt

Fume Hoods

LIMS

HPLC

KF

Sam

ple

Stor

age

/ Wei

ghin

g

Writ

e U

p

Writ

e U

p

Writ

e U

p

OfficeArea

Plan The Lab. Tour

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Sample Receipt

Fume Hoods

LIMS

HPLC

KF

Sam

ple

Stor

age

/ Wei

ghin

g

Writ

e U

p

Writ

e U

p

Writ

e U

p

OfficeArea

Clipboard – with Flow Charts Sample Receipt – Paperwork Etc…

Strategy For The Laboratory Tour

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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.

Strategy For The Laboratory Tour

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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.

“…found unofficial batch records for approximately 75 batches of injectablefinished drug products torn in half in the waste area”

“ 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 ”

Care Over Material in Waste Bins !

ucm361928

ucm311326

Questions ?

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Thank You!

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APPENDIXADDITIONAL INFORMATION

During The Audit…

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As the audit progresses…… Concerns are documented by the Auditor (s):

• OOS• CAPA• …Etc

Flip ChartWall Chart…..

TheseAre Discussed

At the Daily “Wash Up”

The site will WORK on theseIssues - to try and get them

off the chart….

EstablishmentInspection

Report (EIR)Form 483

WarningLetter

2 Tier “Wash up” System

Inspector (s)• Valuable – if they will do• Limited the no of people• Plan Next Day• Clarify Concerns

Site / Company• Brief site management• Communication update – off site• What Went Well• Plan Next Day• Work on Concerns …..overnight

Compliance - A Service Providers Perspective….

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We don’t supply to the US, so wedon’t have to worry about the FDA…..

Customer Statement Comments

We are an R&D laboratory, so wedon’t have to work to GMP

We have never had a problem withour paper qualification in audits before, so why should consider moving toelectronic now ?

Lab. Managers Will Often Say:

• Actually, you may have to…..• How familiar are you with the term “Mutual Recognition”

• Is your company involved in manufacturing generics• How is your company implementing QbD• Did you know QbD will be applied to methods• Appropriate GMP in R&D

• Data Integrity is a different kind of audit• A good audit is good news for a site, but a “perfect”

audit may not be ideal - as it’s harder to justify investment – do you ever find that a problem ?

• How do you justify new equipment / improvements

We use System Suitability, so wedon’t have to perform Qualificationor Calibration !

“Routine analytical tests do not constitute OQ testing”USP <1058>

- Justification Over Result Validity

Partnership Relationship Required….

Who Owns The Audit Preparation ?

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IN OUR AUDITPLAN

• You NEED everyone to CARE about AUDIT PREPARATION ….• Motivation of Managers and all Personnel is Critical• The ability to motivate and inspire others is a Leadership Quality……

• The AUDIT PLAN is owned by the TEAM – NOT the MANAGER

Example Sample Life Cycle….

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Electronic Vs. Paper

Sample Receipt

Booked into LIMS

Schedule Tests

Sample Preparation

Chromatograph Sample

Calculate Results

Compare Against Specification

Check / Report Results

“21 CFR Part 11 = Good Document Practice for Electronic Data”

Attributable[Who did it]

Legible[Can you read it]

Contemporaneous[Recorded in “Real Time”]

Original[Is it original]

Accurate[Is it Accurate]

Electronic Log Vs. Ink Signature

Print Vs. Handwriting

Electronic Log Vs. Written Data

Secure Electronic File Vs. Paper “Photocopy”

Validated Electronic Output Vs. Paper….

ElectronicVs. Paper

Greater Risk (easier to manipulate) ?More Secure

(harder to manipulate) ?

A

L

C

O

A

1.

2.

3.

4.

5.

6.

7.

8.

Laboratory Instrument Check List

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• Qualificationo URS – Current Useo Vs Range of Useo Talk Through (VMP)

• Life Cycleo PMo Repairo Change

• Gap Analysis

• CAPA

• Impact

• Documentationo SOPo Calibrationo Trainingo USP Statuso Method Validation

• Appearanceo Clean – Leaks / Powdero Reagent Labelso Waste Containero Excessive Stickers

• Definitionso Dateso Critical Int.o Grace.....

•Day

•Week

•Month

• User / Expert

• Fail

• Holiday

• “Calibration” Historyo Status Labelling ?o On time / Gapso Recordso Log Book

Knowledge Management

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Data

Data

Data

Data

Data

Data

Structure

Experience

• Store• Search • Organise

• Meaning

of the Audit Preparation Process

• Apply• Decisions

Information

Knowledge

What Questions Will The FDA Ask – Software ?

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1. Do you have your source electronic data – or are your deleting it ?

2. Do you review your electronic source files ?

3. Does review include a review of meaningful metadata ?

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

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

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

- Authenticity of data

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

- Electronic files should be retained – they are the source data, paper is not

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

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