Cleanroom Validation:Key Learnings and

Case Studies

Kelly Thomas and Rich Yeaton

Atlantic Technical and Validation Services

1Copyright 2015 by Atlantic Technical and Validation Services, LLC.

Agenda

• Review full Validation effort (IQ, OQ, PQ, OngoingMonitoring) for a new ISO 7/8 Cleanroom Suite– Discuss E/M related water issues

• Review followup modifications and Validation efforts for thisCleanroom Suite under Change Control

• Discuss current FDA expectations for integrating CleanroomEnvironmental Monitoring with Risk Management

• Review a Cleanroom “War Story”/Case Study

2

Cleanroom Suite Validation:Background

• A Medical Device manufacturer built a new facilitythat included a Cleanroom suite consisting of fiveISO Class 7 and Class 8 rooms

• The new facility was built in response to FDAconcerns with the client’s existing cleanrooms

• We knew that the FDA would be looking veryclosely at the Cleanroom validation

3

Cleanroom ValidationApproach

• Installation Qualification (IQ)

– We’re showing that we know what we have

– We’re showing that we know that the suite was builtproperly

• Operational Qualification (OQ)

– We’re showing that the suite works

• Performance Qualification (PQ)

– We’re showing that the suite meets our needs on anongoing basis

4

Cleanroom Validation Step 1

• Developed a User Requirements Specification

• Stated client’s requirements for control of:

– Temperature

– RH

– Total Airborne Particulates (TAPs)

– Airborne and Surface Viables

5

Cleanroom URS (continued)

• Outlined what the IQ, OQ and PQ would betesting

• Listed what was required in the TurnoverPackage (TOP)

6

Cleanroom URS

• Kept it to 13 pages in length

– Including the Approval, TOC and Revision Historypages

– We focused on stating what performance we needed,not how to achieve the performance

– KISS principle

7

Cleanroom IQ Verifications

• Identified critical components; verifiednameplate information

• Engineering drawings

• TOP contents

• Cleanroom MOC

• Cleanroom entered into client support systems

• Utility connections

• HEPA Filter Certifications

• BMS Configuration (controlled document)

8

Cleanroom OQ Verifications

• Client SOPs for:

– HVAC equipment operation

– HVAC equipment PM

– Gowning

– Cleanroom access control

– Cleanroom cleaning

– ΔP Monitoring

– Environmental Monitoring

9

Cleanroom OQ Verifications

• Critical and Test Instrument Calibration

• Air Balance Report Review

– Air Changes per Hour (ACH)

• Smoke studies

– Visual confirmation of ΔPs

• Alarm and Interlock Operation

• Baseline E/M Study

– Demonstrated that the Cleanrooms could achieverequired conditions in the At Rest state

10

Cleanroom Baseline OQ Study

• Monitored temperature at three setpoints; keptRH setpoint constant

– Demonstrated RH control over temperature changes

• Collected TAP, Airborne and Surface Microbial dataat all three temp/RH setpoint combinations

• All E/M data collected At Rest

– Demonstrated what the suite HVAC system was capableof

11

Cleanroom Baseline OQ Study

• Sampling locations determined by ISO 14644

– ܮ

• Where A is the area of the Cleanroom in square meters

• A standard geometric grid was used:

12

Cleanroom PQ

Demonstrated that the Cleanroom suite worked as asystem, that when:

• trained personnel

• follow approved procedures

• to operate qualified equipment

the Cleanrooms reliably maintained the requiredEnvironmental Conditions

13

Cleanroom PQ

• Phase 1

– Three 2-hour sessions of simulated manufacturingactivities

– Performed E/M at all sampling locations

– This was a SIGNIFICANT effort• Trained Temps were brought in for PQ execution

• We exhausted our E/M technician (who is a GREAT person,BTW)

14

Cleanroom PQ

• Phase 2

– Performed weekly E/M for one quarter

– Rotated through sampling locations

– Established E/M Alert and Action levels

15

Cleanroom PQ

• Phase 3

– Performed weekly E/M for three additional quarters

– Rotated through sampling locations; concentrated on“challenge” spots

• High traffic areas

• Areas more difficult to clean

– Determined Ongoing Monitoring sampling plan and E/MAlert and Action levels based on this full year’s data

– My client was very careful in using significant figures• Certain less significant locations were designated with the “K” units

16

Validation ReportOrganization

• Concise Summary Report

• Executed protocol

• Deviations and Discrepancies

• Associated documentation/exhibits

– HEPA Certification Reports

– Calibration documentation

– Air Balance Reports

17

Cleanroom ValidationOutcome

The FDA Inspector “was bored”.

In this case, we’re glad to be boring.

18

Key Lessons

• A prospective, concise specification is extremelyvaluable

– During startup

– During Validation

– During an Inspection

• Wherever feasible, include copies of documentsreferenced during execution with the ValidationReport

– “The inspectors don’t have a lot of time or patience”Paul Strouth, Organogenesis Validation Manager

19

Water System(Cleanroom PQ) Issues

• Cleanroom Gowning procedure specified thatOperators should wash their hands at a sink inthe Gowning room

– PQ called for sampling the handwashing sink waterfor bioburden

– Results were 9X what we specified

20

Water System(Cleanroom PQ) Issues

• Investigation determined that the industrial parkin which the client’s facility was located wasoriginally meant to house > 12 companies

• Plans changed; it housed 2 companies

• The 12” tie-in to the Main had become a microbialincubator

• The client installed a chlorinator for the entirefacility 21

Water System(Cleanroom PQ) Issues

• We reviewed microbial E/M data for thecleanroom suite and confirmed that the highmicrobial counts in the handwashing sink waterwere NOT reflected in our data

• Stated this in the CAPA closeout

22

Cleanroom Modifications -Physical Layout

• A year and a half later, the client decided toimplement some serious modifications to one ofthe suite’s Class 7 rooms and turn it into aProduct Development Laboratory

• They added a separate Gown Room to servicethe PD Lab and sealed off access from theoriginal suite

23

Cleanroom Modifications –Airflow and RH

• An additional (secondary) AHU and chiller wasadded to draw air from the original AHU Supplyand further reduce its RH

• Separate Reheat and Exhaust units were alsoadded

• Goal was to control conditions in the PD Labindependent of the original suite’s environment

24

PD Lab Intended Use

• Provide a controlled ISO Class 7 environment toallow Product Development activities to beconducted independent of the original Cleanroomsuite

– Antibiotic coatings were being applied to surgicallyimplanted Class III Medical Devices

– The specific coating process had a pretty tight RHrequirement (35% - 45%)

– Antibiotics were NOT beta lactams

25

Antibiotic Contamination

• 21 CFR 211.42 (d) states that “Operationsrelating to the manufacture, processing, andpacking of penicillin shall be performed infacilities separate from those used for other drugproducts for human use”

• The antibiotics in question were not betalactams, but we knew that this would be asensitive subject with the FDA

26

Antibiotic Contamination

• The FDA now has a Guidance for PreventingCross Contamination with non-Penicillin Drugs

• This became official in 2013, which was too late

• The FDA’s concerns had to be addressed

27

Additional CleanroomValidation Concerns

• Demonstrate Temperature/RH “Cascade” control

– RH spec was 35% - 45%

– If RH exceeded 40%, the BMS increased the room’stemperature setpoint from 68°F to 70°F, and then to72°F

• Demonstrate environmental isolation betweenPD Lab and original Cleanroom suite

28

RH Cascade Control

• Allowed PD Lab to operate at normal setpoints(68°F, 35-40% RH) for > 1 hour

• Used Building Management System to forcePD Lab Humidifier to increase RH to 44%

• Monitored room conditions for > 1 hour

29

RH Cascade Control

• Released Humidifier forced setpoint; monitoredroom conditions until Critical Process Parametersreturned to normal for at least 15 minutes

• Results: RH remained between 35% - 45%throughout the test

30

PD Lab Isolation Testing

• Monitored original Cleanroom Suite Total AirborneParticulate levels at 20 locations At Rest

– In other words, as clean as it could be

– Data set “A”

• We then injected a steady stream of HEPAcertification aerosol into the PD Lab Return register

– Measured to be over 17,000,000/m3 (particles ≥ 0.3µ)

• Maintained this aerosol injection for over an hour

31

PD Lab Isolation Testing

• Re-monitored the original Cleanroom Suite TAPlevels at the same 20 locations At Rest, butwhile the challenge aerosol was being injected

– Data set “B”

• We wanted to demonstrate that TAP levels in theCleanroom suite did not significantly increase

32

PD Lab Isolation TestingAcceptance Criteria

• The hypothesis that Data set B for particles≥ 0.3µm in diameter represents a population with a statistically greater mean than Data set A forparticles ≥ 0.3µm in diameter cannot be supported by the data

• Statistical conditions to be used for above analysis:

33

Confidence level 95%

Level of significance p > 0.05

Allowable variance 1 SD of Data Set A

PD Lab Isolation TestingResults

• TAP levels actually improved in theCleanroom suite

• We concluded that they didn’t get worse

34

Potential Cleanroom ValidationIssues

• Do not forget to:

– Qualify the media selected for use in the EM program.Must show the media that is used is the MOSTappropriate (i.e. comparison recovery studies). Mostcompanies use TSA contact plates by default, but thatmight not be right for your facility.

• Monitor for yeast and mold isolates.

– Requires separate media and incubation temperatures

35

Cleanroom PQ Testing

• Continued original Cleanroom E/M OngoingMonitoring

– Modified sampling locations and Action/Alertlevels based on the E/M data

• Monitored PD Lab as a separate system

– Separate Action/Alert levels

36

Routine Testing• Modified Cleanroom E/M program utilized during

validation

– Routine program is data based:

• reduced number of sampling locations from thevalidation:

– Risk based approach: sample locations include high traffic areasand areas more difficult to clean (i.e. under tables)

– Removed sites based on consistent results below alert levels

– Set Action/Alert levels based on the E/M data

• Monitored PD Lab as a separate system

– Separate Action/Alert levels 37

Routine Testing andRisk Management

• Once your At Rest testing is done, we recommendchanging your sampling locations based on what’sgoing on in each room:

– Manufacturing activities

– Routine personnel access

• Look at the “problem” locations, not the “good” ones

• Have a documented rationale for your PQ/PV samplingplan based on what is actually going on in yourcleanroom

– This will gain you credibility with the FDA

38

On the Horizon

• ISO 14644 has been about to be revised for severalyears

– God only knows when this will actually happen

• has been replaced by a table

• Somewhat “denser” sampling will be required

• OQ/Certification only – base your PQ/PV sampling on whatactually occurs in your cleanroom

39

On the Horizon

• Sampling using 1 m3 samples will be required forISO 14644 certification

• Will require new TAP monitoring equipment or much longersampling times

• NOT required for ongoing E/M Monitoring

• We recommend keeping ISO 14644 certificationseparate from Ongoing Monitoring for the time being

• Consider documenting a Comparability Study

40

On the Horizon

• Sampling using 1 m3 samples will be required forISO 14644 certification

• Will require new TAP monitoring equipment or much longersampling times

• NOT required for ongoing E/M Monitoring

• We recommend keeping ISO 14644 certificationseparate from Ongoing Monitoring for the time being

• Consider documenting a Comparability Study

41

Mold War Story - Background

• Acme Biotech built a new manufacturing facilityto produce their flagship product

• As happens with virtually all large capitalprojects, delays happened and budgets weregetting depleted

• The CEO finally declared that the facility wouldbe operational by a specific date, or SeniorManagement heads would roll

• Investor credibility was at stake

More Background

• Environmental control in the Clean Areas was amajor issue

• HVAC PQ measurements:

• Temp/RH control

• Total particulates

• Viable particles (air and surface)

• HVAC PQ Acceptance Criteria had to be met for7 consecutive days to be able to say the facilitywas operational

Environmental Control Components

• Functional HVAC equipment

• Air balancing – Room ΔP’s and Airflows

• Approved Procedures

• Access

• Gowning

• Cleaning

• Trained personnel

Environmental Control Issue

• Sporadic Viable hits

• Hits were speciated – a very tenacious mold

• Could not get 7 consecutive “good” days ofmonitoring data

• Time was running out

Final Solution

• Brute force

• Used full strength SporKlenz as the cleaningagent

• SporKlenz is usually diluted 10:1

• It worked

• 7 consecutive days data below Viable AcceptanceCriteria

Unintended Consequences

• They were now committed to using full strengthSporKlenz

• Management was reluctant to spend theresources to justify changing the Cleaningprocedure

• In hindsight, this was a mistake

• Facility smelled like a spoiled salad

More Unintended Consequences

• SporKlenz is corrosive

• Walls, floors and ceilings looked 10 years oldafter 8 months

• SporKlenz interfered with caulk adhesion toceiling ties

• Random ΔP loss in Clean Rooms

• Occurrences caused a CAPA

Even MoreUnintended Consequences

• Approximately 14 months after official startup,we HAD to have a 2 week facility shutdown

• Walls, floors and ceilings were refinished

• Ceiling tiles and grids were replaced

Even MoreUnintended Consequences

• “Fairy dust” – corrosive fumes attackedaluminum evaporator coils of product storagerefrigerators

• Refrigerator manufacturer would not guaranteeequipment operation

• We had to replace evaporator coils with aphenolic coated version

• Required requalification (on very short notice)

• We met our timelines anyway

Key Learnings

• Construction people need to be trained in GMPoperations

• Early facility cleaning and monitoring is worthdoing

• Access control, including “going clean” to someextent is important even in the early stages ofconstruction

• Start monitoring early

Questions?

52

Feel free to contactKelly Thomas or Rich Yeaton

at 603 421 2748 or

Thomas@atlanticvalidation.com

Yeaton@atlanticvalidation.comwith any followup questions