environmental monitoring webinar

Rapid/Automated Environmental

Monitoring on the Manufacturing Floor

Amy McDaniel, Ph.D.

Pfizer Biotech, Sanford, NC, USA

Outline

• Introduction to Pfizer Biotech, Sanford

• Introduction to Rapid Microbial Methods

(RMM) for Environmental Monitoring (EM)

• Implementation of the Growth Direct II in a

manufacturing facility–Evaluation of Consumables

–Beta Instrument Evaluation

–Commercial instrument installation

• Conclusions

Introduction to Pfizer Biotech,

Sanford, NC

Sanford’s Role:• Commercial manufacturing for Prev(e)nar and Prev(e)nar13 conjugate

• Commercial manufacturing for CRM197 carrier protein

• Supply clinical trial materials for microbial / conjugate products

• Commercial launch and production site for microbial / conjugate products within the PGS

network

• Contract manufacturing for microbial vaccines

Disclaimer:This presentation is a case study of a system evaluation and implementation, it is not intended

to advertise or endorse any vendor’s technology.

Why RMM for EM?

4

Get materials

Sample in

Manufacturing

Wait for

settle plates

Wait for

incubation

Return to lab

Read

Results

Identify samples

Get materials

Prepare on

mfg floor Collect samples

according to role

Pre

sent

Futu

re?

Prepare in lab

Clean carts

Gown

Travel to manufacturing

Incubate plates

Clean up

Data entry

De Gown

QC Identifies samples

BioProcess Technicians

QC reviews results

Growth Direct communicates

with LIMS to download results,

sends alerts electronically as

programmed

Growth Direct

segregates

positive plates for

identification (in

QC lab), discards

negative plates

QC micro analysts

Reduced Time

to Results

Load samples into automated

technology

Why RMM for EM?

5

Get materials

Sample in

Manufacturing

According to

worklist

Wait for settle plates

(may exit the suite

and then return)

Wait for

incubation/transfer

plates to second inubator

Return to lab

Read

Results

Identify samples

Prepare

materials

Collect samples

according to role,

with reduced risk

of missed samples

due to automated

feedback loop

Pre

sent

Futu

re

Prepare in lab

Clean carts

Gown

Incubate plates

Clean up

Data entry

Into LIMS

De Gown

QC Identifies samples

QC reviews results

Growth Direct communicates

with LIMS to download results,

sends alerts electronically as

programmed

Growth Direct

segregates

positive plates for

identification (in

QC lab), discards

negative plates

QC micro analysts

Potential impact to controlled environment =

Potential for human error due to manual steps=

Potential for

Reduced Time

to Results

Load samples into automated

technology

Travel to manufacturing

6

Shift huddles utilize a short, routine meeting & white board to monitor/manage Micro lab operations

How are current EM sampling issues identified?

Relies on analyst knowledge and

memory to communicate any

missed samples.

The ideal technology should be programmed to

automatically read bar-coded labels, “know” what samples

to expect, and send email alerts if a sample is missing.

Error proof and time saving!

RMM for EM: Standard Work Confirms

Advantage

Break

Equipment / Process Controlled Analyst Controlled

Collecting Supplies

Travel to Area

Gowning

Cart Cleaning

Prep Equip and Materials in Manuf.

European Grade (4 carts) (20 Air sites)

Prepping Cart/Clean Up/Data Entry

Degowning/Travel to Lab

Data Download/Incubation

Collecting Supplies

Travel to Area

Gowning

Cart Cleaning


US Classification (2 carts) (8 Air sites)





Collecting Supplies

Break

Travel to Area

Gowning

Cart Cleaning


Hood Monitoring

Settle Plates (Room)

B Room

C Rooms (27 VA)

Clean Up/Data Entry/Data Download

Degown/Travel to Lab/Clean Up/Incubate

Lunch

EM

0# # # # # #12 13 14 15 16 17

Hours Evening Night

Weekly Requ

Samples /Tests

TestTask

TypeTask

Day 1

8 9 10 11

Po

ten

tia

l E

M R

ole

(3

) H

oo

ds

Why GDII? What technologies are

available for Rapid/Automated EM?

Air Sampling• Active Air Sampling:

– IMD (Instant Microbial

Detection, Biovigilant)

– BioLaz (Particle Measuring

Systems)

– BioTrak (TSI)

– Growth Direct II (Rapid Micro

Biosystems)

• Passive Air:– Growth Direct II

Surface Sampling• Swabbing & preparation

with:– ScanRDI (BioMerieux)

– ATP systems (e.g., Celsis,

PallCheck, MilliFlex Rapid)

– Growth Direct II

• RODACS:– Growth Direct II

Growth Direct II: What is it?

9

User Interface Touch Screen

Interface to

Network or LIMS

Incubators1 or 2 temperatures

300+

capacity/incubator

Interior

View

Input Queue

Cassette

Elevator

Slide graphics courtesy of Rapid Micro Biosystems

GDII: How does it work?

Patented technology uses a blue light causing the micro-colonies to autofluoresce: this is captured on a CCD chip

Growth Direct™ Imaging Visual Plate Counting

Day 5Day 4Day 3Day 2Day 1

The Growth Direct™ counts the same colonies in half the time of the traditional method.

0.5µ

Powerful software starts to detect colonies within hours, enabling real-time enumeration of organisms

12 hrs 16 hrs 20 hrs 24 hrs 28 hrs 32 hrs

An A. brasiliensis Microcolony in CHO cells

Technology overview: Growth Direct II

Traditional EM Growth Direct II

Media: TSA w/PS80 & lecithin (surface)

TSA (air)

TSA w/PS80 & lecithin with membrane overlay (based

on technology requirements)

Manual sampling by qualified personnel Manual sampling by qualified personnel

Automatic confirmation of required samples

Load plates into incubator at 1st temperature

Transfer plates to 2nd temperature

Automatic incubation at 1st temperature

Automatic transfer to second temperature at specified

time

Manual reading of plates Automatic reading of plates based on natural

fluorescence

Manual entry of data into LIMS Automatic download of results to LIMS

Discard plates or save for microbial ID Automatic handling rules to allow retrieval of plates for

ID based on program, or automatic disposal followed

by manual waste removal

Evaluating the Growth Direct II (GDII)

• Phase I: Evaluation of Consumables

• Phase II: Evaluation of Beta Unit

GDII: Evaluation of Consumables

• Why?– The intention was to train manufacturing

technicians to take EM samples

– Designed the study to compare an

experienced analyst (QC Micro) with a

new technician

– Assess handling of plates, switching

lids, general equivalence of results with

offline incubation


Active air sampling

• Same sampling

apparatus able to be

used for GDII and

traditional testing

• Media accommodated

within the sampler with

an adaptor (made by

manufacturer of the

sampling device)

Passive Air sampling:

• No difference in testing set

up for GDII and traditional

• Traditional plates are

slightly larger diameter than

GDII


Surface Sampling with RODACs:

• Currently the only technology capable of automating this

element of EM

• Same convex surface of the plate with black membrane

overlayed on agar

• Diameter of the test surface is the same, GDII plates

have a wider base


17

Grade Sample TypeResults (Avg CFU/plate)

Growth Direct TraditionalA Active Air 0 0

Settle Plates 0 0Surface #1 0 0Surface #2 0 0

B Active Air 3 3Settle Plates 1 1Surface #1 0 0Surface #2 1 1

C Active Air Site #1 9 11Active Air Site #2 7 8Settle Plates 3 1Surface #1 0 0Surface #2 5 1Surface #3 0 0Surface #4 2 1Surface #5 0 0

D Active Air Site #1 23 24Active Air Site #2 13 14Settle Plates 1 2Surface #1 5 5Surface #2 0 0Surface #3 1 1Surface #4 0 0Surface #5 0 0

Grade A: 1 active air site, 1 settling plate, 2 analysts, two reps each2 surface sites, 2 analysts, 2 reps each

Grade B: 2 active air locations, 1 settling plate, 2 analysts, 2 reps each 3 surface sites, 3 analysts, 2 reps each

Grade C/D 2 active air sites, 1 settling plate, 2 analysts, 2 reps each5 surface sites, 3 analysts, 2 reps each

GDII: Evaluation of Consumables: Data

• Preparation for onsite evaluation in a GMP manufacturing

facility:– Project plan

– Change control

– Impact assessment

– Evaluation Protocol

• Install the unit

• Execute evaluation protocol

GDII: Beta Evaluation

GDII: Beta Evaluation - Planning

• Proposal was to locate it within the classified area in manufacturing

– To gain the full benefit of efficiency, plates not moving out of the area, carts

not moving in

• Equipment pass through (Grade D)

– Evaluated options with project manager

– System requires water (to humidify incubators), air (to power the robotics),

230V power, gives off 4200BTU/hr of heat (all assessed for impact and

accommodated)

• Evaluated Risk of microbial growth in controlled area

– Closed incubators

– Plates are individually closed (lids lock to the base)

– Disposal chamber is contained within the instrument

– Increased monitoring around the instrument performed during evaluation

19

GDII: Beta Evaluation – Site Installation

Equipment pass through to

manufacturing. Uncontrolled

corridor looking into the pass

through.

Modular installation of unit

was preceded by vendor

assessment of area.

GDII: Beta Evaluation – Site Installation

Stacked incubators showing location of plates (the

parking deck), touch screen and keyboard interface.

GDII: Beta Evaluation - Project Plan

• Month 1: – System install

– Train technicians on EM

– Program the test methods (two tiered incubation, load sampling sites,

load trend rules, load response to growth – output queue)

– Evaluate LIMS interface capability, network interface capability

• Success criteria– Successful install (operational without rework) – June 26-28 (sample

ran successfully)

– Successful test method input (methods are accepted without rework

or computer issues, or with successful & timely resolution)

– Integration with LIMS is assessed as feasible

– Integration with network is assessed as feasible (“Pfizerized” PC on

7/2, connected to network)

22

√

√

√

√

• Months 2/3:

– 156 samples completed

– Inconsistencies evaluated (no discrepancies in action limits reached

by one system and not the other)

– Results indicated acceptability of the technology

GDII: Beta Evaluation - Project Plan

1133 C Air Site 2 3 6

1133 C Tank 120185 Top 0 0

1133 C Tank 120180 Top 2 0

1134 C Air Site 1 2 0

1134 C Air Site 2 2 2

1134 C Air Site 3 7 2

1134 C Tank 120110 Bottom 0 0

1134 C Wall 0 0

1134 C Counter 1 0

1134 C UP-1134 0 0

1135 C Air Site 1 4 1

1135 C Air Site 2 2 3

1135 C Air Site 3 8 1

1135 C Door to Rm 1131 0 0

1135 C Door to Rm 1145 11 0

1135 C Door to Rm 1153 0 0

1135 C Wall 0 0

1137 C Air Site 1 0 0

1137 C Air Site 2 0 1

Room Grade Sample Location

Growth

Dire/methodct

Result #CFU

Traditional EM

Result #CFU

GDII Beta Evaluation:

Potential Standard Work Efficiencies

Break

Equipment / Process Controlled Analyst Controlled

Collecting Supplies

Travel to Area

Gowning

Cart Cleaning






Collecting Supplies

Travel to Area

Gowning

Cart Cleaning


US Classification (2 carts) (8 Air sites)





Collecting Supplies

Break

Travel to Area

Gowning

Cart Cleaning


Hood Monitoring

Settle Plates (Room)

B Room

C Rooms (27 VA)

Clean Up/Data Entry/Data Download

Degown/Travel to Lab/Clean Up/Incubate

Lunch

EM

0# # # # # #12 13 14 15 16 17

Hours Evening Night

Weekly Requ

Samples /Tests

TestTask

TypeTask

Day 1

8 9 10 11

Po

ten

tia

l E

M R

ole

(3

) H

oo

ds

XX

X

XX

XX

X

XX

*

*

*

*

*

*

* Timing/collection supplies (carts)

could be reduced

X Step could be eliminated

GDII: Commercial Unit installation

Successful Beta Evaluation led to purchase of a commercial unit – Installed April 2014

Validation work slowed through the summer months due to resources

Growth Direct II:

Overall Validation Strategy

Instrument Qualification• Per USP <1058>

• IQ by vendor/Pfizer– Software/hardware components

– Utilities verified

– System set up/documentation

• OQ by vendor/verified by Pfizer– Sequence of operations

• PQ by Pfizer– E. coli, S. aureus, A. brasiliensis spike

study verifying method successfully stored

– Handling rules verified

– Response to growth verified (alert/action

notifications sent)

Method Validation• Post-exposure recovery

• Accuracy / precision

• Concurrent testing (traditional/GDII)

• Strategy for settling plates

• Incubation parameters

– 2-tiered temp, 3 day/2 day

(current traditional method)

– 2-tiered 2 day/1 day*

– Single temp (32°C)**

– Single temp (22.5°C)**

*Potential to reduce incubation time

and receive more real-time results

**Potential to increase incubator

capacity with a single temp.

incubation (both incubators at one

temp.)

Why Transfer Sampling to Manufacturing?

• Aligns with current sampling responsibilities– Manufacturing technicians currently take in process & release

samples from the process

• Minimizes flow of materials and personnel– Reduces risk of contamination in controlled areas

• Increased awareness & ownership of EM– Visual status of results and automated tracking of samples provides

real time feedback

• Better root cause analysis for events due to depth of

knowledge of manufacturing processes ongoing during

sampling

Category Action

Training QC oversight & periodic audits

LIMS Limited access role for technicians

Procedures

• Specify process flow & roles/responsibilities

• Impact evaluation for any program changes

• Material handling

• Continuity plan

Processes

Standard work

Evaluation of EM data trends

QC Oversight

QC release of EM media

QC authorization of data

QC review and reporting of trend analysis

Periodic Review Periodic review of program & controls

Implementation Controls for Transfer of

Sampling Responsibilities

Documented in an approved risk assessment

Summary

Changes & Benefits: No Changes:

• Automation/incubation •Reduce human error

•Earlier detection & response

• Sampling by manufacturing•Minimize flow of personnel & materials

•Increased awareness of EM

• Consumables•Membrane overlay – supports technology

•Base easier to manipulate

•Fundamental methodology is same•Media type

•All positive plates evaluated by QC

•Release of consumables by QC

•Program oversight by QC

•Environment•Air classification

•Clean utilities

•Personnel/material flow

•Acceptance criteria for action levels

Conclusions

• Rapid/Automated methods for EM can add value:– Standard work efficiencies

– Environmental control (with faster results and notifications of trends

or events)

– Right First time (by automating receipt of expected samples and

counting errors)

• Moving EM technology and sampling to the

manufacturing area:– Increases efficiencies mentioned above

– Decreases movement of materials in and out of controlled area

– Improves awareness of technicians to EM

– Ownership of the EM program resides with QC, Manufacturing is a

sampling resource

• The Growth Direct II is a significant benefit for an

environmental monitoring program

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