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Usp Guidances On Environmental Control Including Related Usp FDA Emea Pda Activities
Usp Guidances On Environmental Control Including Related Usp FDA Emea Pda Activities
Environmental Control
including related USP, FDA,
EMEA & PDA Activities
James Agalloco
Agalloco & Associates
USP Activities
cfu/m3
04
USP
FDA 1116
<1
<3
n/s <20
<10 <100
<100 n/s
A New Reality?
It is not possible to maintain a manufacturing
environment that is sterile.
In any environment where human operators are
present microbial contamination is inevitable.
Best clean room environment design and
operating practices cannot prevent the shedding
of microorganisms into the environment by
human operators
Thus, an expectation of zero contamination at all
locations during every aseptic processing
operation is technically wrong and unrealistic.
Monitoring Frequencies
Table 2. Suggested Frequency of Sampling for Aseptic Processing Areas
-----------------------------------------------------------------------------------------Sampling Area
Frequency of Sampling
-----------------------------------------------------------------------------------------ISO Class 5 or better room
Each operating shift (if a Class 5
rated hood is used only for control
of non- viable particulate,
microbiological testing is not
required.
Isolator systems:
Active air sampling
Surface monitoring
Twice/week
Once/week
Settle Plate
(9cm) 4hr
exposure
Contact
Plate or
Swab
Glove or
Garment
Isolator
(ISO 5 or
better)
<0.1%
<0.1%
<0.1%
<0.1%
ISO 5
<1%
<1%
<1%
<1%
ISO 6
<3%
<3%
<3%
<3%
ISO 7
<5%
<5%
<5%
<5%
ISO 8
<10%
<10%
<10%
<10%
Grade
2.
3.
4.
Significant Excursions
Excursions beyond approximately 15 CFU
recovered from a single sample, whether
airborne, surface or personnel should
happen very infrequently in aseptic
processing environments. However, when
such occurrences do occur they may be
indicative of a significant loss of control,
particularly when they occur within the ISO
5 critical zone in close proximity to product
and components. Therefore, any excursion
>15 CFU should be the subject of a careful
and thorough investigation.
Disinfection Targets
Type of Microorganisms
Examples
Bacterial spores
Bacillus subtilis and Clostridium
Mycobacteria
Nonlipid-coated viruses
Fungal spores and
vegetative molds and
yeast
Vegetative bacteria
Lipid-coated viruses
sporogenes
Mycobacterium tuberculosis
Classifying Disinfectants
Aldehydes
Sporicidal agent
2% Glutaraldehyde
Alcohols
General purpose
disinfectant,
antiseptic, antiviral agent
Sporicidal agent
Phenolics
General purpose
disinfectant
Ozone
Sporicidal agent
8% Gas by weight
Hydrogen peroxide
Substituted
diguanides
Antiseptic agent
0.5% Chlorhexidine
gluconate
Peracetic acid
Ethylene oxide
Vapor-phase sterilant
Quaternary
ammonium
compounds
General purpose
disinfectant,
antiseptic
Dependent on Application
Benzalkonium chloride
-Propiolactone
Sporicidal agent
-Propiolactone
Disinfectant Effectiveness
The effectiveness of a disinfectant
depends on its intrinsic biocidal activity, the
concentration of the disinfectant, the
contact time, the nature of the surface
disinfected, the hardness of water used to
dilute the disinfectant, the amount of
organic materials present on the surface,
and the type and the number of
microorganisms present.
Resistance to Disinfectants?
The development of microbial resistance
to disinfectants is less likely to occur at
relevant levels, as disinfectants are more
powerful biocidal agents than antibiotics.
In addition, they are normally applied in
high concentrations against low populations
of microorganisms usually not growing
actively, so the selective pressure for the
development of resistance is less
profound.
Disinfectant Rotation
The rotation of an effective disinfectant
with a sporicide is encouraged. It is
prudent to augment the daily use of a
bactericidal disinfectant with weekly (or
monthly) use of a sporicidal agent. The
daily application of sporicidal agents is not
generally favored because of their tendency
to corrode equipment and because of the
potential safety issues with chronic
operator exposure.
Control of Environments - 1
Development of a chapter on Microbiological
Control & Monitoring of Non-Aseptic Processing
Environments <1111> has been discussed by
USP MSA.
There were significant problems right from the
onset.
Control of Environments - 2
We think we know what we dont want:
TAMC
cfu/g or
mL
TCYMC
cfu/g or
mL
Absence of Specified
Organism Requirement (1
g or mL)
Tablets and
capsules
1000
100
Oral liquids
100
10
Rectal products
1000
100
Topical and
nasal products
100
10
S. aureus; P. aeruginosa
Vaginal
products
100
10
Inhalants
100
10
S. aureus; P. aeruginosa; C.
albicans
S. aureus; P. aeruginosa
Bile-tolerant Gramnegative bacteria
(Containing unprocessed
animal, plant or mineral
ingredients)
E. coli
-
Tools &
Utensils
Personnel Traffic
Flow
Effects from
adjacent
areas
Seasonal
Effects
Disinfection
Non-Product Contact
Equipment
HVAC
Environment
Storage
Conditions
Validation
Personnel
Practices &
Training
Product &
Material Flow
Process
Equipment
Cleaning &
Maintenance
Personnel Garb
& Hygiene
Manufacturing
Process
Product filling
Raw materials
Components
<1211> Sterilization
Broader definition for overkill sterilization
method.
Definitions for BB/BI and bioburden
sterilization methods
Clarification of the role of the biological
indicator in sterilization validation.
Clarify understanding of PNSU, SAL and
risk to patient.
<1211> Sterilization
Introduction to Sterilization
Sterilization Validation Approaches
Overkill
Bioburden / Biological Indicator (terminal / lab media)
Bioburden (primarily for radiation)
Sterility Assurance
Validation
Routine Operation
Physical & Microbiological Data
Chemical Indicators & Integrators
BI <55>,
<1035>
Parametric
<1222>
N/A
X-ray Sterilization
Gas Sterilization
Vapor Sterilization
Chemical Sterilization
N/A
Filtration
N/A
Process
Steam Porous loads
Steam Non-Porous loads
(Terminal/Lab)
FDA Activities
Facility &
Room
D/M
Personnel
Daily
Sterility
Assurance
QA/QC
Media Fills
D = Design
M = Maintenance
Aseptic
Processing
Line
D/M
Rick Friedman
Disinfection
Regimen &
Actual
Practices
Process
-personnel flow
-material flow
-layout
HVAC/
Utilities
Response to
Deviations &
Environmental
Control Trends
Number of CFU
FDA Belief
Start Shift
Industry Experience
Time
microbiological contamination -
Container-Closure Integrity
New FDA guidance issued February 2008 states that the
advantages of using container and closure system
integrity tests in lieu of sterility tests include:
EMEA Activities
EN / ISO 14644-1
An Overview of Revisions to
PDAs TR #22 --PROCESS SIMULATION FOR
ASEPTICALLY FILLED PRODUCTS
Solutions
Suspensions
Creams, Ointments, & Emulsions
Lyophilized Products
Powder Formulations
Aseptic Compounding
Solution formulations aseptic steps may be
limited to set-up, sampling, and in-situ filter
integrity testing.
Suspensions, ointments and other non-filterable
formulations may require a substantial number
of aseptic steps.
Processes requiring the addition of sterile
powders should employ an acceptable placebo
material in containers identical to those utilized
in the process being evaluated.
Blending, milling and subdivision process
performed at sterile powder fill sites require
similar attention.
Interventions
The human operator is by far the greatest
source of microbial contamination during
an aseptic process.
To demonstrate aseptic processing
capability, process simulations should
include all the inherent (part of the
process) and corrective (problem
resolution) activities that occur during an
aseptic filling process.
An entire section devoted to intervention
related issues was added.
Types of Interventions
Inherent
Line set-up
Replenishment of
components
Weight / volume
checks / adjustments
Environmental
monitoring
Breaks, lunch
Corrective
Stopper jams
Broken / fallen glass
Defective seals on
containers
Liquid leaks
Other mechanical
failures requiring
manual correction
Inherent Interventions
An intervention that is an integral part of
the aseptic process required for either setup, routine operation and/or monitoring,
e.g., aseptic assembly, container
replenishment, environmental sampling, etc.
Inherent interventions are required by
batch record, procedure, or work
instruction for the execution of the aseptic
process.
Corrective Interventions
An intervention that is performed to correct
or adjust an aseptic process during its
execution. These may not occur with the
same frequency (or at all) in the aseptic
process. Examples include such activities
as: clearing component miss-feed, stopping
leaks, adjusting sensors, and replacing
equipment components. Corrective
measures should be taken to reduce their
extent and frequency.
Interventions - 2
Identifying interventions
Inherent
Corrective
Personnel Qualification - 1
Personnel successfully meet the firms
gowning certification requirements.
They should have completed all relevant
training, including but not limited to GMP
training, procedure training, gowning
training, clean room practices training, and
specific clean room operation, function and
relevant intervention procedure training.
New section in this draft addresses
personnel in greater detail.
Personnel Qualification - 2
They should demonstrate their proficiency in
aseptic technique by successfully performing a
qualification test entailing manual media
manipulation.
or
They should participate in a successful aseptic
process simulation run in which they perform the
same function(s) to the extent that they will
perform it during actual production.
Set-up and other complex interventions are
excluded from this qualification.
Acceptance Criteria
Simulate the process as closely as possible.
Methodology and limits must be justifiable and
documented.
The methodology should confirm a low process simulation
contamination rate, and the selected limit must be
routinely achievable.
Any positive unit is significant, regardless of run size, and
should result in a thorough, documented investigation.
Process simulation contamination rates approaching zero
should be achievable using automated production lines in
well designed aseptic processing facilities, blow-fill-seal
and form-fill-seal and in isolator-based systems.
Recurring positive units in successive process simulations
indicate a problem and should be investigated and
resolved even when the acceptance criteria are met for
each individual simulation.
New Appendixes
Appendix 2 Media Preparation and
Sterilization
HVAC
Effects from
adjacent
areas
Seasonal
Effects
Equipment Design
Disinfection
Area
Equipment
Environment
Equipment
Storage
Conditions
Validation
Product
Personnel
Practices &
Training
Product &
Material Flow
Personnel
Hygiene
Cleaning &
Maintenance
Procedures
Qualification
Sterilization
Lilly / Ed Tidswell
Conclusion
Technology Focus
Recognition that personnel are the contamination
source of concern has led to designs that exclude
them
The approaches usually rely on means to:
Blow-fill-seal
Robotics
Advanced machine designs
Closed Isolators
Open Isolators
PostScript
The challenge in
aseptic processing is
always personnel:
As a source of
microbial and
particle
contamination.
As a brake on the
implementation of
improved
technology.