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Designing and Implementing an

Environmental Monitoring Program

to Satisfy EU and US Requirements
Dan Larrimore
QC Microbiology Supervisor
Baxter Healthcare Corporation
Medication Delivery
Bloomington, IN

Where will the product be marketed? Who will
regulate the program?




How do I satisfy everyone???? 2

3.5 100 A
4.5 1,000 B
5.5 10,000 C
6.5 100,000 D

Environmental Monitoring

Performance Qualification (PQ)

Non-viable Monitoring
-US Federal Standard 209 E (soon to be replaced
by ISO 209)
Viable air monitoring
-Quantitative air sampling and passive or
qualitative air sampling
-Surface monitoring
Environmental Monitoring PQ

Non-Viable particulate Monitoring

-Determine the number of sites to be monitored.
Using: A/(Nc)0.5 or A/25 (whichever is less)

where A=the area of the classified room

N=the air classification (U.S.Customary)

Environmental Monitoring PQ
Quantitative Viable Air Alternatively, the
Monitoring following strategy can be
used to determine worst
-No regulatory guidance case locations.

Perform at locations that are Class 100 Class Class

10,000 100,000
worst case or at
locations that are high risk 1 sample 1 sample 1 sample
in the case of aseptic every 4 every 6 every 8
processing (e.g. near open feet feet feet
Environmental Monitoring PQ
Qualitative Air Monitoring
-Fallout or Settle Plates
-Usually only in class 100 and class 10,000 areas.

Placed at high risk locations (near open

containers) during filling.
Stagger locations until worst case locations are
Environmental Monitoring PQ
-Perform static monitoring of all types in all areas
for at least 5 working days to establish baseline
particulate and microbial levels after initial
sanitization (usually at least 3).
-For non-viable particulate monitoring, it is
important to to vacate the area for ~ 20 minutes
before monitoring.
-After passing results are obtained, then proceed
with dynamic monitoring.
Environmental Monitoring PQ
Perform dynamic monitoring of all types for 10-30
working days.

Activities should mimic routine production during


Sanitization routines should match proposed

production sanitization schemes.
Environmental Monitoring PQ

Establish limits after the PQ. Certain rooms
may not conform to established criteria under
dynamic conditions.

Gowning rooms
Environmental Monitoring
Class 100
Each operating shift
Supporting Class 10,000 areas
Each operating shift
Other class 10,000 areas and 100,000 areas
Twice per week.
Frequencies may be reduced after sufficient
history has been established.
Environmental Monitoring
Viable Air monitoring
Class 100 Class Class
Limits: CFU/Ft3 10,000 100,000
NMT 0.1 < 0.28 < 2.5
Average <
Special considerations:
The MCA limit for the class 100 area is
considerably lower than the FDA limit.
Environmental Monitoring
Passive or Settle plate monitoring for a 4
hour exposure
Class 100 Class 10,000

Limit < 1 CFU/plate NMT 5 CFU/plate

Environmental Monitoring
Non-viable Air monitoring

Special Considerations:
-Continuous monitoring is the industry standard.
-MCA expects to see static monitoring with some
-5 micron limits

Environmental Monitoring
Limits: Particles/Ft3
Class 100 Class 1000 Class Class
10,000 100,000
> 0.5 < 100 (static < 1000 < 10,000 < 100,000
and dynamic) (static) (static and (static and
< 10,000 dynamic) dynamic)
> 5.0 0 (static and 0 (static) < 57 (static) < 570 (static)
dynamic) < 57 < 570 Monitor only
(dynamic) (dynamic) (dynamic)
Environmental Monitoring
Surface Monitoring
Contact Plates and swabs CFU/plate or 25 cm 2
Class 100 Class 10,000 Class 100,000

NMT 2 NMT 5 (walls, ceiling, NMT 50

Average < 1 and equipment)
NMT 10 (floor)

Special considerations:
MCA expects to see the use of swabs for
inaccessible parts. 16
Personnel Monitoring
Personnel Limits:

Class 100 Class 10,000

Gloves NMT 3/ hand NMT 5 cfu/hand
Average < 1
Gown NMT 5/plate Not Defined

Frequency: Glove Monitoring: Daily

Gown Monitoring: At least weekly
Special considerations:
-MCA will expect to enter, random, and exit glove
monitoring. 17
Water Systems PQ
Municipal Water and Softener/RO system
-Test Daily for CaCO3 (hardness), chlorine,
aerobic heterotrophic microbial content, and

-City water testing results should be available

through FOI at the local utility authority.

Water Systems PQ
Feed water
Usually RO or SFS

Test Daily for CaCO3 (hardness), chlorine,

conductivity, aerobic heterotrophic microbial
content, and coliforms.

Water Systems PQ
Water for Injection (WFI)

Test all ports daily for conductivity, TOC,

microbial count, and endotoxin.

Test the WFI storage tank daily for heavy

metals and nitrates.

All testing should occur for at least 30 working

days. 20
Water System Monitoring
Feed water
Microbial testing
Use R2A for microbial monitoring and M-Endo LES
for coliform monitoring
1 ml to 100 ml for heterotrophic microbial monitoring
100 ml for coliform monitoring
Daily for distillation unit feed water and city water

Water System Monitoring
Water for Injection (WFI)
Microbial testing
Use R2A for microbial monitoring
At least 200 ml
Daily for formulation ports and weekly for
other ports
< 10 CFU/100 ml
Do not set a specification of No Pseudomonas
species 22
Water Systems
Water for Injection (WFI)
Chemical testing
TOC, Conductivity, Heavy Metals, and Nitrates
Daily for formulation ports (TOC and conductivity)
Weekly for other ports (TOC and conductivity)
Weekly or Monthly for the WFI storage Tank
(Heavy metals and Nitrates)
TOC: < 500 ppb
Conductivity: Temperature dependant
Heavy Metals: < 0.1 ppm -Nitrates: < 0.2 ppm
Steam System PQ
Frequencies and Tests:

Test all ports daily for conductivity, TOC,

microbial count, and endotoxin.

Test the last point of use for dryness fraction and

non-condensable gasses.

All testing should occur for at least 30 working

Steam System
Routine Monitoring
-Test all ports monthly for conductivity, TOC,
microbial count and endotoxin.

-Test the last point of use for dryness fraction and

non-condensable gasses semi-annually or

FDA Observations
Environmental Monitoring
Surface monitoring for class 100,000 compounding
and support areas is not conducted periodically.
Failure to investigate exceeded environmental
monitoring action levels in the sterile filling room
No justification for sampling locations in the
classified areas.
Testing is not routinely performed to determine that
classified areas meet the air classification standards as
established in Federal Standard 209E.
No microbial monitoring of air is performed in the
class 100 unloading rooms. 26
FDA Observations
Environmental Monitoring
Areas in which aseptic assembly is conducted is not
classified or monitored under dynamic conditions.
Gowning rooms are not classified.
Environmental monitoring results are not formally
trended and reported.
Areas in which aseptic filling operations are located
have not been validated. Levels of viable and non-
viable particles cannot be related to media fills.
FDA Observations
A leaking valve was observed on the WFI system, and
this leak was not repaired for six days.
WFI is not sampled through hoses, though hoses are
routinely used in the production areas.
Water with high levels of gram negative organisms
was used for formulation, but the lot was released
No written procedures for changing hoses for use with
the WFI system in the compounding area exist.
Frequent endotoxin failures at WFI compounding
points of use occurred. Actions to determine the root
cause were not implemented.
-Guideline on Sterile Drug Products Produced by Aseptic
Processing. Center for Drugs and Biologics and
Office of Regulatory Affairs, FDA. 1987
-General Information Chapter <1116 > Microbiological
Evaluation of Clean Rooms and Other Controlled
Environments, USP-NF 24, USPC, Inc., Rockville,
MD, 2000 p. 2099.
-Medicines Control Agency Rules and Guidance for
Pharmaceutical Manufacturers and Distributors 1997.
-Parenteral Drug Association Technical Report No. 13,
Vol. 55
Contact Information
Dan Larrimore
E-mail: dan_larrimore@baxter.com