Regulatory 101 Putting AIQ to Use - Agilent · Regulatory 101 Putting AIQ to Use ... Functional tests - works as expected – in the Lab. ... Changes in Requirements . Related

Regulatory 101

Putting AIQ to Use

The difference between: - Operational Qualification (OQ) and - Performance Qualification (PQ)

Paul Smith

September 17, 2015

Confidentiality Label

1

September Seminar

July Seminar Focused On These areas

Previously: 10 Steps to a “New Instrument”….

DQ URS User Requirement Specification

• What you need the instrument to do • Purchasing decision

Design Qualification

• Why suitable • Range of use

Analytical Need

1.

Approval To Buy

2.

Instrument “Selection”

3.

Order Instrument

4. Delivery

5.

Install 6.

Review & Approval

8.

Release For Use

9. Maintenance 10.

PQ

Installation Qualification

• Installed correctly • Lab. is suitable

Operational Qualification

• Functional tests - works as expected – in the Lab. • Test range of use

Performance Qualification

• Application test – works with your applications

IQ

OQ

Qualification 7.

September 17, 2015


2

WebEx Structure Contents

A. The Instrument Life Cycle Changes in Requirements Related Regulatory Information

B. Regulations & Historical Interpretation

Operational Qualification (OQ) Performance Qualification (PQ) C. Examples of OQ & PQ

Questions ?

Divided into 3 sections. Within the time frame, can’t answer detailed questions about specific instrumentation……. However, if you have a specific Qualification 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 current regulatory information that can help laboratories make qualification and compliance decisions…..

September 17, 2015


3

The Instrument Life Cycle

Historical Perspective

Management of Evolution of Instrument Life Cycle

USP <1058> OQ/PQ

September 17, 2015


4

Purchase Qualify Train Maintain Use

Historical Instrument Compliance Requirements

September 17, 2015


5

Is the instrument suitable for its intended use ?

Might have been considered as a sequential series of activities….

Independent Roles………

What is Laboratory Compliance ?

September 17, 2015


6

Laboratory Compliance framework is used for:

• Justify - the Scientific validity of the results

• Defend - the Results & how they were generated

Complexities of Current Compliance Requirements

September 17, 2015


7

Is the instrument suitable for its intended use ?

1. Is the data you are generating Valid ? (and the decisions made on that data)

2. If the instrument developed a fault – would you detect it ?

3. If someone “cheated” in your lab. – would you detect it ?

4. What are the risks around what you do – how are you managing them ?

Historically, a rational, technical response has been used……

• Instrument Working

• Method Validated

• System Suitability • Ref. Samples

“Sensitivity” of your ability to detect faults ?

Data Integrity ……

Risk Management ……

Historical Instrument Compliance Requirements

September 17, 2015


8

Maintain Use

Maintain

Qualify

Use

Repair

Re-Qualify

All of these ensure instrument compliance status:

Qualify Qualify Maintain Use

“User” Maintenance

Planned Maintenance

GAMP 5 and USP <1058>

September 17, 2015


9

Historically, GAMP and USP <1058> have been perceived as being very different, but, complement each other and there are more similarities than differences……..

1. Infrastructure

GAMP Category (software focus)

3. Non-Configured Products

4. Configured Products

5. Custom Applications

<1058> Category (usage focus)

A. Apparatus – Document • No Calibration Requirement • No Measurement Capability

[Appendix M4, GAMP 5]

B. Instruments – Calibrate • Follow SOP • Calibrate

C. Systems - Qualify

2. No Longer Used

Same principles – increasing complexity = more work to test / document “suitable” Diverse interpretation - in industry The framework followed and actions taken – are more important

GAMP GPG USP Chapter <1058>

[21 CFR, FDA]

[USP, e.g. <1058>]

[Method, Process, Software]

[GAMP 5, ASTM E2500]….

Calibration 1 – Terms Used in Regulated Industries

September 17, 2015


10

1. Calibration

2. Qualification

3. Validation

4. Verification

May have a

“specific” meaning or

may be “label”

There is a need to “position” calibration - in the context of OQ / PQ [Qualification]

Calibration can mean something which is very specific to an action performed on a particular type of instrument, or, it can be a descriptive “label” to describe a kind of activity……. [e.g. “Calibration” = Qualification].

Calibration 2

September 17, 2015


11

There are several references to Calibration in the CFR:

On Line eCFR:

21 CFR SECTION Calibration CFR Reference

58 (BIMO) 21 CFR 58.63(a)

110 (Food) 21 CFR 123.8(a)(2)(ii)

211 (Drugs) 21 CFR 211.68(a) 21 CFR 211.160(b)(4)

606 (Biologics) 21 CFR 606.60(a)

820 (Medical Devices) 21 CFR 820.72(a)

[1]

[57]

[54] [13]

[11]

21 CFR 820.72(b) [42] [3]

21 CFR 606.60(b) [6]

• These are the CFR references provided in the annual FDA 483 spreadsheet

• [57] = Number of 483 citations in 2014 [for this CFR]

• Search FDA FDA Warning Letters – [cut and paste the CFR from excel file into the Warning Letters search !]

FDA Warning Letter FDA 483 Inspectional Observations

Requirement General Requirements

http://www.ecfr.gov/cgi-bin/ECFR?page=browse

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

http://www.fda.gov/ICECI/Inspections/ucm250720.htm

Instrument Life Cycle

12

Design Qualification

(DQ)


(OQ)

Installation Qualification

(IQ)


(PQ)

Ongoing System

Suitability

Major instrument upgrade or New Analytical Method – DQ !

Regular or move or

major repair

OQ Verifies

DQ

Qualified State

Polling Question 1

September 17, 2015


13

Regulations and Historical OQ / PQ Interpretation

September 17, 2015


14

Evolution of Compliance

September 17, 2015


15

Qualification / Validation Time Line…..

PICSVF - 1994

GAMP 3 - 1998

GAMP 4 - 2001

GAMP 5 - 2008

PICSVF Formed - 1991

Pharmaceutical Industry Computer Systems Validation

Forum

Version 1 Validation

Management Paper

1994

AAPS

2008 AIQ <1058>

American Association of Pharmaceutical

Science

2003-4

Furman Paper Holistic Vs

Modular HPLC

2015

Draft <1058>

January 2002

May 1987 June1997

FDA Process Validation Guide

Lines General Principles

of Software Validation

(Draft)

General Principles

of Software Validation

(Final)

Impact of Diversification & History

September 17, 2015


16

• Manufacturers / Laboratories - Different Interpretation of Requirements • Laboratories Just Managed any Differences…… • Cost – Reduced Instrument Availability • Potential Risk – Justifying / Managing Different Approaches

• No Strong Compliance Driver for Harmonisation……….

May 1987

FDA Process

Validation Guide Lines

2008 AIQ <1058>

GAMP 5 - 2008

These were after diversification of Qualification…..

USP <1058> Analytical Instrument Qualification (Draft)

September 17, 2015


17

OQ Operational Qualification (OQ) is the documented collection of activities necessary to demonstrate that an instrument will function according to its operational specification testing in the selected environment. OQ demonstrates fitness of purpose for the user's ways of working, and should reflect the contents of the DQ document. Testing activities in the OQ phase may consist of these test parameters.


• Test the instrument in the environment • Operational Specification

• Demonstrate Fitness For Purpose

• Should Reflect the DQ Document

Key Messages


September 17, 2015


18

PQ Performance Qualification (PQ) is the documented collection of activities necessary to demonstrate that an instrument consistently performs according to the specifications defined by the user, and is appropriate for the intended use. The PQ verifies the fitness for purpose of the instrument under actual conditions of use. After IQ and OQ have been performed, the instrument's continued suitability for its intended use is demonstrated through continued performance qualification.


• Specifications Defined by User

• Conditions of Use

• Implies System Suitability

Key Messages


September 17, 2015


19

PQ PQ tests are usually based on the instrument's typical on-site applications and may consist of analyzing known components or standards. The tests should be based on good science and reflect the general intended use of the instrument


• Based on on-site application

• Reflect the intended use of the instrument Key Messages


September 17, 2015


20

What does this mean ? Relates to historical, diverse interpretation of what an OQ and PQ contain, but not necessarily helpful…

Performing the activity is far more important than phase under which the activity is performed.

Historical OQ/ PQ Interpretation 1.

September 17, 2015


21

Interpretation of process validation guidance - 3 Validation batches…… (for process).

For an instrument such as a pH Meter, calibration is the is the key test (matching USP <1058> Group B).

May 1987

FDA Process

Validation Guide Lines

OQ Perform Test Once (e.g. pH Meter Calibration)

PQ Perform Test 3 Times (e.g. pH Meter Calibration)


September 17, 2015


22

So, the results of testing reference samples are evaluated against acceptance criteria…….

Diagnostic Tests Are Built into

The Instrument

OQ “Turn the instrument on, if no error messages are reported, the instrument has passed the OQ”

PQ “Proceed to test the PQ of the instrument with reference samples.”


September 17, 2015


23

Implies that the OQ is a periodic evaluation (documenting the instrument is working correctly at the time of testing) and the PQ is an ongoing evaluation………..

OQ “Tests performed to document & evaluate that the instrument works as expected in the laboratory,…”

PQ “Tests performed to document & evaluate that the instrument will continue to work as expected in the Laboratory….”

FDA Method Validation Guidance….

Trend Analysis on Method Performance (system suitability ?)…..


September 17, 2015


24

This interpretation has it’s “roots” in the 1994 Furman paper, based on HPLC instruments that were available 21 years ago. In principle, an instrument could pass a series of “module tests”, but fail an “overall test”. Therefore, an injector precision test, could be a module or holistic test (some companies define an injection test of a Chromatography system as a PQ).

HPLC OQ “During an OQ, the performance of each module or component is evaluated”

PQ “During the PQ, the “Holistic” or overall performance of the instrument is evaluated”

Where Does Calibration Fit In ?

September 17, 2015


25

Although calibration can have a very specific meaning (which is not within the boundary of Qualification), some of the “common ways” CALIBRATION might be used, include:

1. Adjust – the response of an instrument based on external measurement or reference source

3. Check – the response of the instrument is within performance limits

2. Use – the response of a reference material to calculate values

For 1, before any adjustment is made, a test of the measurement device should be made, to highlight the performance “as found”. Some auditors have requested as found measurements for systems as complex as HPLC, FT-IR, LC-MS.. Etc. Impact assessment required…….

For 2, this represents “standardisation” or System Suitability type tests

For 3, this is a control test before using an instrument. A balance check weight is used to document acceptable performance before use.

What is the Role of Metrology Tests ?

September 17, 2015


26

Where an instrument performs what could be classifies as a “Metrology Function” (where the functional performance can be evaluated independently, such as flow, rotation, temperature… Etc.), it is good practice to test the functionality in an equivalent (Metrology) way. Results of holistic tests do not provide 100 % assurance of the performance of the instrument (IMO) !

HPLC instruments for example, should include a mixture of metrology and holistic tests……..

Polling Question 2

September 17, 2015


27

OQ and PQ Possibilities….

September 17, 2015


28

Laboratory Instrument: Compliance Framework

September 17, 2015


29

Who can Perform Installation, Qualification, Maintenance and Repair ?

There are no regulatory barriers about who “Should” perform qualification:

FDA# Friendly Compliance

# [and other Regulators]

• Pharmacopeia's • GMP (CFR, EU or other) • FDA Warning Letters

• How to “Justify” the Qualification ? [Are documents designed to support this ?]

• Are the people Trained ? [How do you know the quality of the training ?]

• How is Data Integrity Assured ? [Electronic data traceability ?] [Is repeat work “tracked” and visible ?]

• Is it Scientifically Valid ? [Can you explain / “defend” it ?]

• Does it Meet Your Requirements ? [Configured to your analytical range of use ?]

But….. you need to consider….

The regulations do not specify how often qualification should be performed !

How Different is Your Use of the instrument ?

[from the OQ]

How Complex is the instrument ?

Is a PQ Required ?

September 17, 2015


30

pH Meter

HPLC / GC

Balance

Titrator

UV-Visible

Hyphenated

OQ Metrology Test [External Agent]

PQ System Suitability

[Equivalent]

OQ Functional

Use Test

PQ Application Based Test

Manage Auditors Expectations…

What About HPLC / GC

September 17, 2015


31

In some companies: The Qualification Policy is PQ = System Suitability

Is this a Risk ?

“The auditor requested our PQ for the instrument. We advised that we include system suitability test and that is how we evaluate the ongoing performance of the instrument”

One of the risks associated with any audit are in part, how well the lab. Can “defend” their policy……

The auditor stated: “Routine tests do not constitute Qualification”…..

HPLC Example – Modify System Suitability….

September 17, 2015


32

• Detected in OQ ?

• Detected in SST ?

• Detected in Enhanced SST

Failure

Risk – Some Instrument Failures Not Detected !

http://images2.advanstar.com/PixelMags/lcgc-eu/digitaledition/02-2015.html

Implications for USP <1058> OQ

September 17, 2015


33

Associate the DQ documents to the analytical testing………. Review Analytical Methods To List:

Maximum and Minimum Range of Use (in the Methods).

Configure the OQ testing to COVER the RANGE of USE. Feedback Loop: Update DQ & OQ – NEW METHODS Ensures Range of Use Tested

OQ Verifies

DQ

If the OQ is “Fixed”, the range of use Cannot be tested !

September 17, 2015


34

HPLC OQ and PQ PQ OQ

Does the Instrument Work as Expected In the Laboratory :

• Tested Under Standard Conditions • OQ Service • Linked to RANGE of USE

Does the Instrument Work as Expected With the Analytical Methods:

• Tested with Method Conditions • Representative Method

OQ Parameter Min. Max.

Column Temp. 25 55

Wavelength 205 nm 273 nm Pump Flow 1 mL/Min. 2.5 mL/Min.

Autosampler Temp. 4 oC 8 oC

Gradient Step. 10 % 85 %

% RSD (Inj. Precision) 1.00 % (UV-Vis)

% Carry Over 0.20 % (UV-Vis)

PQ Parameter Value

Column Temp. 45

Wavelength 264 nm

Pump Flow 1.5 mL/Min.

Autosampler Temp. 4 oC

Gradient Prog. 10 to 65 %

% RSD (Inj. Precision) 0.5 %

% Carry Over 0.1 %

OQ Verifies: Functionality Range of Use

Technical Justification Vs Explanation

September 17, 2015


35

Where justification is provided for not including / performing a functional test of an instrument.

The auditor may have a different Interpretation ……. RISK

For example, the principle of operation of an FT-IR Instrument: - Internal He-Ne Laser Therefore, in principle, because of the internal Laser, no wavelength calibration is required….

In Practice: it is a much lower risk to test the Wavenumber accuracy !

FDA Warning Letter Search – 10 Years

September 17, 2015


36

21 CFR 211.68 21 CFR 211.160(b) 50 103

Some of the most common qualification problems that come up in FDA warning letters include:

• Calibration not performed or parts of the system missed (Justification) • No electronic raw data for the work • The tools included in the calibration were not calibrated • The people performing the work were not suitably trained

Relationship Between 483 Observations….

September 17, 2015


37

Correlation Between: Complete test data included in records

Calibration/Inspection/Checking not done

21 CFR 211.194(a)

21 CFR 211.68(a)

Over 2006 to 2014

This graph shows that there is a

correlation between “Complete Data” and

instrument calibration !

Drive for Harmonisation ?

September 17, 2015


38

Increased Regulatory Focus on Data Integrity: Is expected to motivate companies towards harmonised compliance!

Polling Question 3

September 17, 2015


39

Questions

September 17, 2015


40

Documents

Regulatory 101 Putting AIQ to Use - Agilent · Regulatory 101 Putting AIQ to Use ... Functional tests - works as expected – in the Lab. ... Changes in Requirements . Related