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Regulatory 101 Core Elements of Laboratory Compliance
Paul Smith
Global Strategic Compliance
Program Manager
Agilent Technologies, Inc.
May 8, 2015
May 8, 2015
1
What Influences Laboratory Compliance ?
May 8, 2015
2
Where
Export
Quality System
Activity Occurs (e.g. country)
of Products / Services (e.g. country)
ISO Accreditation (scope),
What ? Activity (of Laboratory / Organisation)
Sample Receipt
Logging In (LIMS)
Plan Work
Test Sample
Check Results
Report Results
A B C
Analytical Life Cycle
Laws
&
Regulations
WebEx Structure
Contents
A. Introduction to Laboratory Compliance
Sample Receipt & Booking In
B. Generating The Results
Scheduling Work & Testing
Samples
C. Validity of Data
Checking & Reporting Results
Questions ?
Can’t answer detailed questions about specific analytical methods, or accreditation…….
However, if you have a specific compliance question you would like an answer to - use the on-line system to ask, and we will provide reference information.
A key part of this WebEx is to highlight similarities and differences across industries for exchanging information and sharing best practice. In the future, further convergence and sharing of best practice is expected.
May 8, 2015
3
What is Laboratory Compliance ?
May 8, 2015
5
General framework used for:
• Justifying - the validity of the results
• Defending - the Results & how generated
Framework Applied
& Content depend on:
• Industry
• Company
• Function
• Drug Screening (e.g. Olympics)
• Pharmaceutical Testing
• Food Testing
• Environmental Testing
• Tobacco Testing
• Cosmetics Testing… Etc.
ISO Vs GMP
May 8, 2015
6
17025
13485
• Technical Standard
• Medical Device Standard
• Uncertainty of Measurement
• Adverse Effects Reporting
• Change Management
GMP • Good Manufacturing Practice • Pharmaceutical Products
The Quality principles that must be applied to the manufacture
and testing of Pharmaceutical Products.
9001 • Quality Management Standard
• 4.2.4 – Control of Records • 7.4.3 - Materials • 7.6 – Measurement Equipment
• 8.5.2 - Corrective Actions • 8.5.3 - Preventive Actions
ISO Standards Contain
Specific Clauses:
Legal
Framework
GMP
Guidance • CFR or PIC/S or ….
• Pharmacopeia
Policy &
Procedures
Quality Systems
May 8, 2015
7
Where Laboratories test to Different
Requirements - What Standards Apply ?
• GxP / ISO 17025 (testing and calibration)
• GxP / ISO 13485 (medical device)
• Makeup / Topical Pharmaceuticals
• Human Health / Animal Health
• Trace / Bulk Analysis
• Food Analysis / Environmental
• Raw Materials / API…etc.
Segregation Raw Materials
API
Bulk Analysis
Trace Analysis
But, segregation may not be possible and it is simpler,
lower risk and more efficient to adopt a single compliance
standard across a laboratory – at the higher level!
+ Quality Agreement
Risk Based Contract Laboratory Approval
May 8, 2015
8
Supplier Questionnaire
+ Specific ISO Accreditation
+ Physical Audit
Formal Technology Transfer
• Tech. Transfer Protocol
• Training
• Cross-Validation
• Approval
• Monitoring
Simple Analysis
Complex Analysis
Customised / Bespoke
Analysis
Low Intrinsic Risk
High Intrinsic Risk
Analysis Type Analysis “Risk” Approval Options
Sampling & Logging In
May 8, 2015
9
Some analytical samples (e.g.
environmental) can have strict
time limits applied.
If 8:20 was the time limit for sample
receipt, but it arrived at 8:22
– the analyst may practice time travel !
Data Integrity – Has Implications
for ALL Laboratories !
The Sample should be representative
of the material it represents !
• C of A – Approval, Mgt. & ID
• Travelling
Sample - Hazard
• Stabilize
• Food / Environmental - Sample Preparation….
• How Many - √N +1 ?
Chain of Custody
May 8, 2015
10
Chain of Custody Form
Request for
Analysis Form
What decisions will be made
from the analytical results ?
• Tamper - seal
• Controlled - access
• Access - log
• Label - can you read it ?
• Bottle - Contamination ?
• Who - Sampled ?
• Sufficient - Sample ?
Legal “Evidence” ?
“Routine Analysis”
“Non-Routine Analysis”
“Protocol Analysis” • Know – the protocol
• Follow – the protocol
• Why – testing
• Correct – question
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]….
Confusion Over Terms – Different Terms, Different Industries
May 8, 2015
11
USA: Code of Federal Regulations – Uses Calibration,
USP <1058> uses term Qualification (Agilent aligned)
1. Calibration
2. Qualification
3. Validation
4. Verification
May have a “specific” meaning
or may be a name / “label”.
Different auditors can use
different names…….
1. Calibrate – Instrument or measurement device prior to use
2. Qualify – Analytical instrument
3. Validate – Analytical method & manufacturing
4. Verification - Procedure
• Do All Analysis [“Sample Based” Testing]
• Team / “Cell” [analysts perform all tests]
• Optimised for
Control / Speed
of Prioritised
Analysis
Robust Methods
HPLC, LC-MS
Problem Methods
HPLC, LC-MS
• Only Do HPLC ! [“Test Based” Testing]
• Specialists [e.g. HPLC “Team”]
• Designed to
Reduce Problems
& Their Impact
May 8, 2015
14
How Many Days to Test
Product Batches of Material
Before
Mean Laboratory Layout &
Workflow Optimisation
Lean Sigma - Impressive Results:
• 50 % Reduction In Tests Times are “Common”
• Improved Testing Control
After
Mean
Ways of Working – Work Flow & Test Scheduling
Analysts Must be Trained !
May 8, 2015
15
There are 2 Basic Overlapping Training Needs
Need:
• Document Training
• Demonstrate Competency
Need:
• Train People
• Develop Competency
Required for Audits Required to Do The Job
Required to Do a Good Job
Different
Business
Drivers !
May 8, 2015
16
Preparing For a Laboratory Audit
• The Laboratory Is Too Busy…….
• We Have a Lot of Audits
• This Audit is No Different……
• We’ve Passed Them All Before
• We Have a Good Track Record…..
• …… Similar Approach (New Risk)
Used to “Get Ready !”
Audit Notification Period
Design Laboratory
Workflow
Re-Think Your
Approach to Audits
• Lab. Productivity • Data Integrity • Informed Decisions
• Replacement Plan • Instrument Utilisation • Reliability….
• Reduce Business Risk
• Partners to Help • Collaboration • Share Knowledge • Best Practice
Scheduling
May 8, 2015
17
Complex – If Prioritisation is Required
People
Computers Prioritisation
Workload
Priorities
Instrument Capacity
Trained Analyst
Project - Routine
Reference Materials
Work Sequence
Ways of Working – Work Flow & Test Scheduling
May 8, 2015
18
How do you know the “Capacity” of
a complex busy testing laboratory ?
Example Instrument
Usage Graph (e.g. Injections)
• Instrument Counters
• Set Counter triggers [Align maintenance & use !]
• Real time monitoring
• Level load instruments
• Right size laboratory
Productive Use
Ready (Consuming)
Maintenance
Not Ready (Standby)
Instrument Utilisation
In The
Laboratory
Ways of Working – Work Flow & Test Scheduling
May 8, 2015
19
What “Work Sequence” is appropriate
for your laboratory ?
Continuous
Run Dedicated Instrument / Method
Mon. Tue. Wed. Thur. Fri.
A B HPLC Method D C A Daily
Prioritisation
A - Mon. & Thur.
B – Tue. & Fri.
Fixed Schedule A B A C B HPLC Method
Are Your Results Valid ?
May 8, 2015
22
What Things Contribute
to a Laboratory:
Having Confidence in Their Data ?
Being Able to “Defend” Their Data ?
Ind
ep
en
de
nt
of
Ind
ustr
y
• Method – Validated for Use
• Method – Traceable Reference Materials Used
• Analysts – Trained, trained to follow instructions, professional
• Analysts – Can’t “Cheat”…..
• Procedure Test Sequence – “System Suitability Tests”
• Instrument – “Calibrated” (response vs Std.)
• Audited – Never Had a Problem
• Instrument – SOP – Instrument Used Consistently
What Effects the Quality of my Results
May 8, 2015
23
• Each Level Depends on Other Levels
• All Levels are Required !
• Quality of Instrument Performance &
Correct Functionality is Foundation
Hierarchy:
Instrument Suitable For Use
Quality of Performance & Functionality
Control
Samples
Method Validated
Controlled Use
Run System Suitability
Sequence
Data Quality Triangle – Principles of Good Science
May 8, 2015
24
Emphasis
(Relative Importance)
Emphasis
(Relative Importance)
Pharmaceutical ISO 17025
Fundamentally –Each level is required for Good Science, but:
• Different Approach: ISO 17025 and Pharmaceutical Companies
Different
Company
Emphasis
Instrument Suitable For Use
Quality of Performance & Functionality
Control
Samples
Method Validated
Controlled Use
Run System Suitability
Sequence
Different Approaches to The Data Quality Triangle
May 8, 2015
25
Instrument Suitable For Use
Quality of Performance & Functionality
Control
Samples
Method Validated
Controlled Use
Run System Suitability
Sequence
Pharmaceutical
• Report Pass / Fail Decisions
• Data Integrity
ISO 17025
• Uncertainty of Measurement
• Proficiency Studies
Shewhart Chart Quality by Design
Instrument
Result Calculation - Options
May 8, 2015
26
Inc
rea
sin
g
Se
cu
rity
of
Da
ta Paper Forms /
Worksheets ! [Paper Documents / Protocols]
• Low Set Up Cost
• Manual Calculations
• 100% Checking
• Risk of Manipulation !
Excel or
PDF [Design Your Own]
• Automated Calculations
• Report
• Manual Data Entry / Checking
• Why – “write your own software”
e.g. Performing Impurity Calculations In Excel
Working
Electronically • Security of Data
• Reduced Checking
• May Need Help (vendor)
• Expertise (to set up) Chromatography System
LIMS
Samples Results
Instrument Failure
May 8, 2015
27
Verify Instrument Performance
Verify Method Performance
“Restore” Method
Samples Results
Repair
Impact
Assessment
Breakdown
Samples Results
Validated
Method