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

Introduction to Laboratory Compliance

Sample Receipt and

Booking In

May 8, 2015

4

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

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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

Polling Question 1

May 8, 2015

12

Generating the Results

Scheduling Work and

Testing Samples

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13

• 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

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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

Polling Question 2

May 8, 2015

20

Validity of Data

Checking Work and

Reporting Results

May 8, 2015

21

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

Concentration and % RSD

May 8, 2015

28

Decreasing Concentration

Increasing % RSD

Horwitz Function

Polling Question 3

May 8, 2015

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Questions

May 8, 2015

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