Equipment Qualification Considerations When Purchasing, Designing,

or Qualifying Storage Units

Robert Craig MillerSenior Validation SpecialistVaLogic, LLC

Purpose of Today’s Meeting

• Discuss the regulatory requirements driving our processes and the relationship to test scripts.

• Discoveries encountered in Validations.

• Q & A

Receipt Storage Distribution

Shipper Qualification Temperature Monitoring Shipper Qualification

Equipment Certification Preventive Maintenance Document Control

Equipment Qualification Equipment Certification

Document Control Change Control

Equipment Qualification

Document Control

Cradle To Grave

Definitions• Acceptance Criteria – The standards a product or process must meet to

successfully complete a test phase or to meet delivery requirements.

• As-Found-Data – Data comparing the response of an instrument to known standards, as determined without adjustment, after the instrument is made operational.

• Calibration: The process of adjusting an instrument or compiling a deviation chart so that its reading can be correlated to the actual value being measured.

• Certification – A documented statement, by authorized and qualified individuals, that an equipment/system validation, revalidation, qualification, re-qualification, or calibration has been performed appropriately with acceptable results.

• Change Control – A formal monitoring system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status.

Definitions (Continued)• Corrective Action – An action, specified in Standard Operating Procedures, that is

taken in response to information gathered from environmental monitoring data. This may be implemented when Alert or Action Limits are exceeded or when Trend Analysis indicates a developing problem.

• Critical – Of or pertaining to a condition causing an abrupt change in the quality or property of an environment, process or product.

• Critical Component – Any component of a critical device that’s failure to perform can be reasonably expected to cause the failure of a critical device, or to affect the device’s safety or effectiveness.

• Critical Instrumentation – Those instruments which are pertinent to the proper operation, control, and recording of critical process parameters.

• Critical Process Parameter – A control parameter that has a direct relationship to the quality, safety, effectiveness, or performance of the intermediate or final product.

Definitions (Continued)• Final Report – A document summarizing the results derived from the execution of a

protocol. The final report shall include a conclusion, which indicates validation success or failure and designates proven acceptable ranges for all critical process parameters as determined by the execution of the validation protocol.

• Installation Qualification – The performance of documented verification that an equipment/system installation adheres to approved contract specification and achieves design criteria.

• Operational Qualification – The documented verification that the equipment/system performs per design criteria over all defined operating ranges.

• Performance Qualification – Documented verification that equipment, systems, or processes operate the way they are purported to do. This operation must be reliable and reproducible within a specified, predetermined set of parameters under normal production conditions and must be in a state of control.

Definitions (Continued)• Protocol – The written and approved document of an experimental sequence of tests that, when

executed as prescribed, are intended to produce documented evidence that the equipment or system does what it is designed or claims to do reproducibly.

• Qualification – Operation aimed at proving, with regard to materials, equipment, or personnel, that the required conditions are met and that they actually provide the expected results.

• Trend Analysis – Periodic review and analysis of environmental monitoring program results that can be related to time, shift, facility, etc. for patterns that may suggest underlying or developing problems.

• Validation – The overall term for establishing documented evidence through defined tests and challenges, that a system, manufacturing process, analytical method, and/or piece of equipment meets design criteria and that adequate provisions have been established to keep it in a state of control so it will produce a product that meets predetermined specifications and quality attributes. Validation can be performed prospectively, concurrently, or retrospectively.

• Validation Master Plan – The establishment of a dynamic written plan that defines the overall approach to a validation project.

So . . . what is Validation?

• Legal responsibility?• Ethical responsibility?• Sound Business Practice?

Regulatory Requirements Validation and Documentation

The FDA’s 1987 guideline defines validation as:

• Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.

Key Validation Documents

• Validation Master Plan (VMP)

• User Requirements

• Functional Specifications

• Validation Protocols

• Standard Operating Procedures (SOPs)

• Validation Final Reports

• Change Control System

User Requirements

• Can you identify your needs– In writing?

• Musts vs. Wants

• Simple, yet has a large impact on the design and validation processes

• Provides basis for PQ acceptance criteria

Functional Specifications

• The “How To’s” of meeting the User Requirements

• Other Terms– User Requirement Specification– Purchasing Specification– Technical Specification

• Provides basis for OQ and PQ acceptance criteria

Detailed Design

• The hard specifics of the design

• Detailed specifications and drawings– Cut sheets– Technical specs– P&ID’s– Manufacturer’s documentation

• Provides the basis for IQ

Design / Validation Relationship

User Requirements PQ

Functional Spec OQ

Detailed Design IQ

Build

Typical Things Done – Summary Reports

• Completed following protocol execution– Following completion of each protocol– May “lump” IQ / OQ together

• Content– Defined by Validation Master Plan / SOPs– Clearly states whether equipment met acceptance criteria as

stated in the approved protocols– Clearly states user limitations on the equipment, if any– Provides raw data obtained during the studies, along with

information regarding performance of the unit during the studies, for example:• How long the unit maintained acceptable temperatures following

power loss?• Hot and Cold spots in the unit

GMP Relevance & Risk AssessmentSection

21 CFR Relevance

Product Equipment Section21 CFR

RelevanceProduct Equipment

Installation Qualification Performance Qualification

Purchase Order Verification 211.63N/A Moderate

Operational Qualification Verification

211.22, 211.63, and 211.100

High Low

Manufacturer’s. Documentation Verification

211.67, 211.68, and 211.100 N/A Moderate

Equipment Set-up and Thermocouple Placement Verification

211.68 and 211.100 Low Low

Environmental Conformance Verification

211.63N/A High

Operating Temperature Thermal Mapping

211.63, 211.68,

211.100, and 211.142

High N/A

Electrical Utilities Verification Same as aboveN/A High

Thermocouple Calibration Verification

211.68 and 211.100 Low N/A

Standard Operating Procedure Verification

211.67, 211.68,

211.100, and 211.142

N/A ModerateValidation Test Equipment Verification

211.68Low Moderate

Operational Qualification Re-qualification

Installation Qualification Verification

211.22, 211.63, and 211.100

Low ModeratePreventive Maintenance Verification 211.67, 211.68,

and 211.100Low High

Validation Test Equipment Verification

211.68Low Moderate

Critical Instrumentation Calibration/Certification Verification

211.68 and 211.100 High Low

Critical Instrumentation Calibration/Certification Verification

211.68 and 211.100 High Low

Electrical Utilities Verification 211.63N/A High

Equipment Set-up and Thermocouple Calibration

Same as aboveModerate N/A

Validation Test Equipment Verification

211.68Moderate N/A

Temperature Distribution Thermal Mapping

211.63, 211.68,

211.100, and 211.142

High N/AEquipment Set-up and Thermocouple Calibration

211.68 and 211.100 Moderate N/A

Open Door Analysis Thermal Mapping

Same as aboveModerate N/A

Operating Temperature Thermal Mapping

211.63, 211.68,

211.100, and 211.142

High N/A

Power Failure Analysis Thermal Mapping

Same as aboveModerate N/A

Thermocouple Calibration Verification

211.68 and 211.100

Moderate N/A

Alarms and Controls Testing 211.68, 211.100, and 211.142

High LowAlarms and Controls Testing 211.68, 211.100,

and 211.142High Low

Re-qualification

• Event Driven– Replacement of

critical components – Change in process or

procedures– Change in personnel– Failure Investigation

• Time Driven– Change of “the little

things” over time– Poorly maintained

systems– Routine system

failure– Environment

dependent

Change Control

• The modification, relocation or decommissioning of any equipment that has been tested under validation conditions must be documented.

• Change Control is necessary to perpetuate validation

• When should Change Control begin?– After the validation report is approved?– Before qualification begins?

Difficulties in Validation

• Inadequate definition of system requirements / specifications

• Poor protocols

• Inadequate resolution / explanation of failures / deviations

• Poor planning

• Poor communication

Success in Validation

• Getting Validation personnel involved early in the process

• Well defined user requirements and specifications

• Good Communication

• Integrating Validation into design-build-test-use cycle

Discoveries

• What we have learned in our supporting role to Operations.– Identifying hot and cold spots.– Affects of TC placement on loaded upright,

ultra-low storage unit.– Same is often different.– Hidden costs of being economical.– Helping is sometimes hurting.– When up is down and when down is up.

Typical TC Placement Diagram

TC 01

TC 02

TC 06

TC 04

TC 05

TC 07

TC 08

TC 09

TC 10

TC 11

TC 12

TC 03

TC Shelf Location Suspension

01 Top Back Left Liquid

02 Top Front Right Airborne

03 Second Front Left Airborne

04 Second Controller Airborne

05 Third Back Left Airborne

06 Third Center Airborne

07 Third Front Right Airborne

08 Fourth Front Left Airborne

09 Fourth Back Right Airborne

10 Bottom Center Liquid

11 Bottom Front Right Airborne

12 External Filter Airborne

Probe Placement on a Walk-in

FRONT OF UNIT

RTD

8.8'

8.5'

7.4'

Probe 01Back

Back

Back

Front

Front

Front

Back

Middle

Probe 02Front

Probe 03Middle

Probe 04

Probe 05

Probe 11

Probe 06

Probe 07

Probe 09

Probe 10

High Level6' from floor

Mid Level4' from floor

Low Level2' from floor

MiddleProbe 08

MiddleProbe 12

Affects Upon Temperature During TC Placement

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

11:42:40

12:20:00

13:00:00

13:40:00

14:20:00

15:00:00

15:40:00

16:20:00

17:00:00

17:40:00

18:20:00

19:00:00

19:40:00

20:20:00

21:00:00

21:40:00

22:20:00

23:00:00

23:40:00

0:20:00

1:00:00

1:40:00

2:20:00

3:00:00

3:40:00

4:20:00

5:00:00

5:40:00

6:20:00

7:00:00

7:40:00

8:20:00

9:00:00

9:40:00

10:20:00

11:00:00

11:40:00

Time

Tem

per

atu

re

201A-T13 202A-T14 203A-T15 204A-T16 205A-T17 206A-T18

207A-T19 208A-T20 209A-T21 210A-T22 211A-T23 Ambient

TC placement

Temperatures below -70C

Undocumented entry by Operations

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

11:42:40

12:20:00

13:00:00

13:40:00

14:20:00

15:00:00

15:40:00

16:20:00

17:00:00

17:40:00

18:20:00

19:00:00

19:40:00

20:20:00

21:00:00

21:40:00

22:20:00

23:00:00

23:40:00

0:20:00

1:00:00

1:40:00

2:20:00

3:00:00

3:40:00

4:20:00

5:00:00

5:40:00

6:20:00

7:00:00

7:40:00

8:20:00

9:00:00

9:40:00

10:20:00

11:00:00

11:40:00

Time

Tem

per

atu

re

101A-T01 102A-T02 103A-T03 104A-T04 105A-T05 106A-T06

107A-T07 108A-T08 109A-T09 110A-T10 111A-T11 Ambient

TC placement

Temperatures below -70C

• Same model; same set point; same TC diagram.• Different load; different age; different ambient.• Recovery time: 8 hours and 16 hours, respectively.

All units of same model are created equal; some operate more efficiently

than others.

-90

-88

-86

-84

-82

-80

-78

-76

-74

-72

-70

-68

-66

12:16:05

12:55:00

13:35:00

14:15:00

14:55:00

15:35:00

16:15:00

16:55:00

17:35:00

18:15:00

18:55:00

19:35:00

20:15:00

20:55:00

21:35:00

22:15:00

22:55:00

23:35:00

0:15:00

0:55:00

1:35:00

2:15:00

2:55:00

3:35:00

4:15:00

4:55:00

5:35:00

6:15:00

6:55:00

7:35:00

8:15:00

8:55:00

9:35:00

10:15:00

10:55:00

11:35:00

12:15:00

Tim e

Tem

p

TC 01 TC 02 TC 03 TC 04 TC 05 TC 06 TC 07 TC 08 TC 09 TC 10 TC 11

-90

-88

-86

-84

-82

-80

-78

-76

-74

-72

-70

-68

-66

12:16:05

12:55:00

13:35:00

14:15:00

14:55:00

15:35:00

16:15:00

16:55:00

17:35:00

18:15:00

18:55:00

19:35:00

20:15:00

20:55:00

21:35:00

22:15:00

22:55:00

23:35:00

0:15:00

0:55:00

1:35:00

2:15:00

2:55:00

3:35:00

4:15:00

4:55:00

5:35:00

6:15:00

6:55:00

7:35:00

8:15:00

8:55:00

9:35:00

10:15:00

10:55:00

11:35:00

12:15:00

Tim e

Tem

p

TC 01 TC 02 TC 03 TC 04 TC 05 TC 06 TC 07 TC 08 TC 09 TC 10 TC 11

-90

-88

-86

-84

-82

-80

-78

-76

-74

-72

-70

-68

-66

12:16:05

12:55:00

13:35:00

14:15:00

14:55:00

15:35:00

16:15:00

16:55:00

17:35:00

18:15:00

18:55:00

19:35:00

20:15:00

20:55:00

21:35:00

22:15:00

22:55:00

23:35:00

0:15:00

0:55:00

1:35:00

2:15:00

2:55:00

3:35:00

4:15:00

4:55:00

5:35:00

6:15:00

6:55:00

7:35:00

8:15:00

8:55:00

9:35:00

10:15:00

10:55:00

11:35:00

12:15:00

Tim e

Tem

p

TC 01 TC 02 TC 03 TC 04 TC 05 TC 06 TC 07 TC 08 TC 09 TC 10 TC 11

-90

-88

-86

-84

-82

-80

-78

-76

-74

-72

-70

-68

-66

14:56:15

15:30:00

16:05:00

16:40:00

17:15:00

17:50:00

18:25:00

19:00:00

19:35:00

20:10:00

20:45:00

21:20:00

21:55:00

22:30:00

23:05:00

23:40:00

0:15:00

0:50:00

1:25:00

2:00:00

2:35:00

3:10:00

3:45:00

4:20:00

4:55:00

5:30:00

6:05:00

6:40:00

7:15:00

7:50:00

8:25:00

9:00:00

9:35:00

10:10:00

10:45:00

11:20:00

Tim e

Tem

p

TC 01 TC 02 TC 03 TC 04 TC 05 TC 06 TC 07 TC 08 TC 09 TC 10 TC 11

Cost of Quality Acceptance Criteria: -195°C to -135°C

Slot Brand X - Economical Brand Y – Top of the Line

1 -88.5°C -178.6°C

2 -94.5°C -182.1°C

3 -118.3°C -186.4°C

4 -127.0°C -187.8°C

5 -154.9°C -188.8°C

6 -159.5°C -189.8°C

7 -171.1°C -190.9°C

8 -187.9°C -192.2°C

9 -192.2°C -192.6°C

10 -194.6°C -192.8°C

11 -194.8°C -193.5°C

12 -196.5°C -194.1°C

13 -196.6°C -194.3°C

Quick “Fix” Acceptance Criteria: -195°C to -135°C

Slot Temperature – High Fill Set Point of 7” Temperature – High Fill Set Point of 10”

1 -88.5°C -125.3°C

2 -94.5°C -134.7°C

3 -118.3°C -139.3°C

4 -127.0°C -149.2°C

5 -154.9°C -153.4°C

6 -159.5°C -160.9°C

7 -171.1°C -167.5°C

8 -187.9°C -184.3°C

9 -192.2°C -192.1°C

10 -194.6°C -196.8°C

11 -194.8°C -196.9°C

12 -196.5°C -196.9°C

13 -196.6°C -197.1°C

Criticality of Temperature Set Point

Temperature Control Set Point at -85.0C

-90

-88

-86

-84

-82

-80

-78

-76

-74

-72

-70

-68

-66

-64

-62

-60

12:50:00

12:55:00

13:00:00

13:05:00

13:10:00

13:15:00

13:20:00

13:25:00

13:30:00

13:35:00

13:40:00

13:45:00

13:50:00

13:55:00

14:00:00

14:05:00

14:10:00

14:15:00

14:20:00

14:25:00

14:30:00

14:35:00

14:40:00

14:45:00

14:50:00

14:55:00

15:00:00

15:05:00

15:10:00

15:15:00

Time

Tem

per

atu

re (

Deg

C)

Min Max Avg

Temperature Control Set Point at -80.0C

-90

-88

-86

-84

-82

-80

-78

-76

-74

-72

-70

-68

-66

-64

-62

-60

12:50:00

12:55:00

13:00:00

13:05:00

13:10:00

13:15:00

13:20:00

13:25:00

13:30:00

13:35:00

13:40:00

13:45:00

13:50:00

13:55:00

14:00:00

14:05:00

14:10:00

14:15:00

14:20:00

14:25:00

14:30:00

14:35:00

14:40:00

14:45:00

14:50:00

14:55:00

15:00:00

15:05:00

15:10:00

15:15:00

Time

Tem

per

atu

re (

Deg

C)

Min Max Avg

Affects of Dynamic Testing

-2

-1

0

1

2

3

4

5

6

7

8

9

10

11

11

:00

:00

12

:10

:00

13

:20

:00

14

:30

:00

15

:40

:00

16

:50

:00

18

:00

:00

19

:10

:00

20

:20

:00

21

:30

:00

22

:40

:00

23

:50

:00

01

:00

:00

02

:10

:00

03

:20

:00

04

:30

:00

05

:40

:00

06

:50

:00

08

:00

:00

09

:10

:00

10

:20

:00

11

:30

:00

12

:40

:00

13

:50

:00

15

:00

:00

16

:10

:00

17

:20

:00

18

:30

:00

19

:40

:00

20

:50

:00

22

:00

:00

23

:10

:00

00

:20

:00

01

:30

:00

02

:40

:00

03

:50

:00

05

:00

:00

06

:10

:00

07

:20

:00

08

:30

:00

09

:40

:00

10

:50

:00

Time

Te

mp

era

ture

(D

eg

C)

B090 B131 B135 B145 B277 B353 B354 B403 D002 D003 D685 D686

D687 D691 D692 D693 D694 D695 D697 D698 D699 D700 D701 D703

D704 D705 D706 D707 D709 D710 D711 D712 D713 D714 D721 D722

Open Door Test #1

Open Door Test #2 Open Door Test #3

To Summarize

• As the User, know your requirements and processes.

• Validation is a lifecycle approach. It’s not a one and done.

• Be cognizant of change control.• Have a thorough TC/logger placement diagram to

detect hot and cold spots.• Understand the functionality of the units being

qualified.• But, above all, the most import thing to remember

is that . . .

OUR PRIMARY OBLIGATION IS TO THE END USER

• Family• Friends• Co-workers• Strangers

Thank You For Your Participation

Questions, comments, complaints?

About the Presenter

Robert “Craig” Miller has over twenty years experience working in the pharmaceutical and biotech support industry. Starting off as a Repository Technician at the National Cancer Institute Clinical Repository, he has held increasing key positions and recently left Fisher BioServices (formerly McKesson BioServices, Ogden BioServices) after ten years as the Validation Manager to join VaLogic, LLC, a calibration and validation consulting firm supporting life sciences.

Contact Information:

Email: cmiller@valogic.us

Office: 240-529-1673

Cell: 240-602-1424

Fax: 240-529-1678

Web: www.valogic.us