MICRO BIO LO GY TO PIC S

The Environmental
Monitoring Program in a
GMP Environment

IMAGE SOURCE, MEDICALRF.COM/GETTY IMAGES

Scott Sutton

22 Journal of GXP Compliance

Microbiology Topics discusses various topics in microbiology of practical use

in validation and compliance. We intend this column to be a useful resource
for daily work applications.
Reader comments, questions, and suggestions are needed to help us fulfill
our objective for this column. Please send your comments and suggestions
to column coordinator Scott Sutton at scott.sutton@microbiol.org or journal
coordinating editor Susan Haigney at shaigney@advanstar.com.

KEY POINTS
The following key points are discussed in this article:
The routine environmental monitoring program is a critical aspect
of documenting the state of control of the facility
Recommendations for the selection of sample sites to be used in the
qualification program are provided. These recommendations are
directed at providing data to allow creation of a program useful in
determination of the state of control of the facility
The qualification study should provide data to allow determination of
meaningful alert and action levels for that facility. It must be noted
that there are significant technical and scientific issues with the regulatory guidelines for the areas of an aseptic core regiona suggestion consistent with proposed revisions to United States Pharmacopeia
chapter <1116> Microbiological Control and Monitoring Environments Used for the Manufacture of Healthcare Products is provided
Explicit examples are provided from publically-available sources
(FDA-483 observations and warning letters) of enforcement activities based on good manufacturing practice failures in the environmental monitoring program
A discussion is provided on the relative values of 483 observations and warning letters as useful indicators of US Food and Drug
Administration policy.

Scott Sutton, Coordinator

INTRODUCTION
The qualification, or requalification, of an aseptic
manufacturing facility depends in large part on the
demonstration of controlled microbial conditions. The
following are several areas where this is especially true:
Cleaning studies
Contamination control planning (1)
Equipment hold time studies (establishment of
clean and dirty hold timesprocess hold times
are process-specific)
Selection of sample sites for environmental
monitoring
Establishment of facility-relevant alert and action
levels for controlled environments.
This article examines the environmental monitoring
(EM) program, its sample sites, frequency of testing,
and establishment of alert and action levels. A method
to qualify and justify the selection of the sample
sites within a facility used for routine environmental
monitoring is presented. This discussion is not meant
to describe the only possible approach to this selection
but rather one that the author has used in the past with
success. Due to the limitations of space, this discussion
does not include sampling of the water system, gasses,
or personnel which have distinct considerations.
WHAT IS THE POINT OF THE EM PROGRAM?
In trying to determine the appropriate parameters of
a complex program such as environmental monitoring, we first have to agree upon the scope and
purpose of the program. The purpose of the EM
program is to document the state of control of the
facility, not to determine the quality of the finished
product. The US Food and Drug Administration
guidance document (2) is very clear on this point in
section X.A.1 and states:
In aseptic processing, one of the most important
laboratory controls is the environmental monitoring program. This program provides meaningful
information on the quality of the aseptic processing environment (e.g., when a given batch is being
manufactured) as well as environmental trends of
ancillary clean areas. Environmental monitoring
should promptly identify potential routes of con-

tamination, allowing for implementation of corrections before product contamination occurs (211.42
and 211.113).
Section X.A.2 of the guidance states, Environmental monitoring data will provide information on the
quality of the manufacturing environment.
Recent publications have reinforced the position that
the EM program looks to document the state of control
of the facility. Hussong and Madsen (3) point out that
the microbiological assays used have limits of quantification higher than the customary control levels and so
are subject to a great deal of variability. This consideration, by their argument, reduces the precision and
predictive ability of the data. Therefore, the trend of
the data is the critical aspect, and this information cannot be used in finished product quality decisions. In
other words, pristine EM data for an aseptic processing
facility speaks to the state of control of that facility, not
to the sterility of products produced there.
Farrington expanded this thesis in a subsequent
article (4). He observed that the relationship of EM
data to finished product quality was an unproven,
but commonly held belief. In the absence of data, we
cannot assume it is true, but that it is undeniable that
these data (and particulary the trending of these data)
show the state of control of the facility. He argues
that the regulatory concern over contamination from
environment makes sense, but must be applied with
judgment and scientific rigor. The major problem with
EM data, of course, is the fundamental imprecision
and variability of these data. This imprecision renders
the data all but useless as quantitative predictors of the
system, but valuable as raw data for the determination
of trends in the facility as a whole. Farrington makes
the interesting observation here that these concerns
about traditional EM methods are also a concern for
rapid methods.
Farrington is not the only worker to point out the
fundamental problem using rapid methods to generate inherently imprecise and variable data. Sutton (5)
has more than once pointed out the questionable value
of generating bad data quickly over generating bad
data slowly. The data are not inherently better for
being read off an extremely expensive machine. This
is not to say that the rapid methods are not needed or
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MICROBIOLO GY TO PIC S

desirable, only that they are not a panacea and must be

applied with forethought.
SHOULD THE SAMPLE SITES BE IDENTIFIED?
There is a school of thought that believes that
sample sites for the EM program should not be
defined, that sampling from a defined location will
encourage the cleaners to pay particular attention to
those sites and skew the data. This is incorrect and
contrary to good manufacturing practice (GMP). For
example, the FDA aseptic processing guideline (2,
Section X.A.1) states:
It is important that locations posing the most
microbiological risk to the product be a key part
of the program. It is especially important to monitor the microbiological quality of the critical area
to determine whether or not aseptic conditions are
maintained during filling and closing activities. Air
and surface samples should be taken at the locations
where significant activity or product exposure occurs
during production. Critical surfaces that come in
contact with the sterile product should remain sterile
throughout an operation. When identifying critical
sites to be sampled, consideration should be given
to the points of contamination risk in a process,
including factors such as difficulty of setup, length of
processing time, and impact of interventions. . .
All environmental monitoring locations should be
described in SOPs with sufficient detail to allow for
reproducible sampling of a given location surveyed.
Written SOPs should also address elements such as
1. frequency of sampling, 2. when the samples are
taken (i.e., during or at the conclusion of operations),
3. duration of sampling, 4. sample size (e.g., surface
area, air volume), 5. specific sampling equipment
and techniques, 6. alert and action levels, and 7. appropriate response to deviations from alert or action
levels.
In other words, the sites used in the routine EM
program must be justified and identified. Section
X.A.2 states, Microbiological monitoring levels
should be established based on the relationship of
the sampled location to the operation. The levels
should be based on the need to maintain adequate
microbiological control throughout the entire sterile
24 Journal of GXP Compliance

manufacturing facility. . . Environmental monitoring

data will provide information on the quality of the
manufacturing environment.
This concern also appears in 483 observations
and warning letters. Warning letters and many 483
observations are posted on FDAs website (6). The
following 483 observation dealt with significant issues in justification of the EM sample sites (7):
Regarding the increased non-routine surveillance monitoring performed to further evaluate the
Building 37 Flu manufacturing facility, there was no
plan in place specifying the locations to be tested,
method of sampling, and actions to be taken when
microbial contamination was noted. Samples containing colony forming units (CFU) were evaluated
for morphological characteristics, and only colonies
exhibiting Gram-negative characteristics were Gram
stained and identified.
The [redacted] method used for increased surveillance monitoring of the environment has
not been qualified.
So, clearly it is important to have a rationale for
the location, frequency and number of sample sites.
This can be done by a qualification study that will
utilize many more sample sites than will be present
in the routine program, but will serve to identify
those sites most useful to routine monitoring.
NUMBER OF SITES FOR QUALIFICATION STUDIES
International Organization for Standardization
(ISO) 14644-1 (8) describes a method to determine
the number of sampling sites for site qualification. Annex B states that we should determine the
minimum number of sample sites by the following
equation:
NL = A
where
NL is the minimum number of sampling
locations (rounded up to a whole number)

A is the area of the clean room or zone
in meters2 .
This might work well enough for non-viable
particulate measures (which is the intent and scope

Scott Sutton, Coordinator

of 14644-1), but we also wish to consider viable

air sampling (both passive and active) and viable
surface monitoring. Frequently, the sample site
study is worked into the facility HVAC performance
qualification study for ease of documentation and
logistic considerations. For the initial facility HVAC
qualification protocol, both viable and non-viable
active air sampling sites should be done at the same
locations (or as close as practical to avoid compromising the other measure or the product integrity).
This leaves determination of the number of sites for
passive air sampling and surface sampling.
PASSIVE AIR SAMPLING
Passive air sampling (i.e., settle plates) is a frequentlyused measure of clean room (or controlled zone)
monitoring. Settle plates have several advantages in
this regard, chief among them the ability to remain
in continuous exposure for up to four hours (four
hours is cited in European Union [EU] 2008 guidance
[9]extended exposure times must be demonstrated
via demonstration of the growth promoting capabilities
of the aged and exposed media). In addition, passive
viable monitoring (settle plates) is not disruptive to the
immediate environment and so may possibly sample
sites very near product exposure points (see reference
10 for a discussion of these, and other, advantages).
In addition, settle plates are not as prone to variation
among different vendors as are active samplers (11).
However, it is not clear whether all the advantages cited
for passive sampling apply in areas of laminar air flow
at the rates used for modern clean rooms. In addition,
settle plates may be particularly susceptible to handling, transport, and lab contamination. However you
view their usefulness, current regulatory expectation
for air monitoring includes their use and the justification of sampling sites. A prudent measure is to use
the same number of sampling sites for settle plates
as used for the active viable and non-viable sampling
programs. These will not be the same sites but will be
similar in number.
SURFACE SAMPLING
This leaves us with determination of the number of surface sampling sites for the qualification

study. There is no regulatory guidance directed

to this point for the international pharmaceutical industry. Even the Pharmaceutical Inspection
Convention and Pharmaceutical Inspection Cooperation Scheme (PIC/S), which generally can be
counted on to provide details on almost everything
microbiological, is silent on this point (12). Oddly
enough, even the Parenteral Drug Association
(PDA)s Technical Report #13 (13) offers no help
here. We are left to our own devices. One approach
to determination of the number of sites would be
to address it in a manner similar to that of ISO
14644-1 for the walls and floors (as relevant). Each
surface would then be treated as a separate item
and the minimum number of sites determined for
each. While this might work for walls and floors,
the number of surface sampling sites for equipment
remains unanswered and is not noticeably amenable to this approach. This, quite frankly, may well
be something that must be left to determination at
each individual sitethe numbers could be driven
by the nature of the equipment and the associated
manufacturing process.
SELECTION OF SAMPLE SITES FOR THE
QUALIFICATION STUDY
Having determined the number of sites for each
room, we now need to determine their location for
this qualification study. One of the goals of this
study is to provide data to assist in the determination of appropriate sample sites. This method of
determining sample site number will provide an
unreasonably large number of sample sites for routine surface sampling. It is from the data collected
that the determination of the routine surface and air
sample sites will be decided.
The selection of sample sites should be designed
to provide useful information for eventual selection of routine sample sites. Several technical and
guidance documents from PDA, FDA, EU, and the
United States Pharmacopeia (USP) are relevant.
Parenteral Drug Association
PDA Technical Report #13 provides the following
guidance in this regard:
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Factors to consider in selecting sites for routine

surveillance are:
1. At which sites would microbial contamination most likely have an adverse effect on product
quality?
2. What sites would most likely demonstrate
heaviest microbial proliferation during actual
production?
3. Should site selection involve a statistical design
(e.g., following the calculations in Federal Standard 209E) or should site selection be made on
the basis of grid profiling? Should some sites for
routine monitoring be rotated? [Note from author:
As 209e has been withdrawn in favor of ISO 14644, the
answer is No]
4. What sites would represent the most inaccessible or difficult areas to clean, sanitize, or disinfect?
5. What activities in the area contribute to the
spread of contamination?
6. Would the act of sampling at a given site disturb
the environment sufficiently to cause erroneous
data to be collected or contaminate product? (13).
The US Food and Drug Administration
The FDA aseptic processing guidance document (2)
states in section IVA:
Air in the immediate proximity of exposed sterilized containers/closures and filling/closing operations
would be of appropriate particle quality when it has a
per-cubic-meter particle count of no more than 3520
in a size range of 0.5 m and larger when counted
at representative locations normally not more than
one foot away from the work site, within the airflow,
and during filling/closing operations. This level of air
cleanliness is also known as Class 100 (ISO 5). We
recommend that measurements to confirm air cleanliness in critical areas be taken at sites where there is
most potential risk to the exposed sterilized product,
containers, and closures. The particle counting probe
should be placed in an orientation demonstrated to
obtain a meaningful sample. Regular monitoring
should be performed during each production shift. We
recommend conducting nonviable particle monitoring with a remote counting system. These systems are
capable of collecting more comprehensive data and are
26 Journal of GXP Compliance

generally less invasive than portable particle counters.

See Section X.E. for additional guidance on particle
monitoring.
Some operations can generate high levels of product
(e.g., powder) particles that, by their nature, do not
pose a risk of product contamination. It may not, in
these cases, be feasible to measure air quality within
the one-foot distance and still differentiate background
levels of particles from air contaminants. In these
instances, air can be sampled in a manner that, to the
extent possible, characterizes the true level of extrinsic
particle contamination to which the product is exposed. Initial qualification of the area under dynamic
conditions without the actual filling function provides
some baseline information on the non-product particle
generation of the operation.
Further, Section X.A. states:
Sample timing, frequency, and location should be
carefully selected based upon their relationship to the
operation performed.
It is important that locations posing the most
microbiological risk to the product be a key part of
the program. It is especially important to monitor the
microbiological quality of the critical area to determine
whether or not aseptic conditions are maintained
during filling and closing activities. Air and surface samples should be taken at the locations where
significant activity or product exposure occurs during
production. Critical surfaces that come in contact with
the sterile product should remain sterile throughout
an operation. When identifying critical sites to be
sampled, consideration should be given to the points of
contamination risk in a process, including factors such
as difficulty of setup, length of processing time, and
impact of interventions.
European Union
The EU guidance document Manufacture of Sterile
Medicinal Products (9) provides some site selection guidance:
18. Where aseptic operations are performed monitoring should be frequent using methods such as settle
plates, volumetric air, and surface sampling (e.g., swabs
and contact plates). Sampling methods used in operation should not interfere with zone protection.

Scott Sutton, Coordinator

United States Pharmacopeia

Similarly, the following guidance in the proposed revision to USP chapter <1116> (14) is of general interest:
Microbiological sampling sites are best selected
when human activity during manufacturing operations are considered. Careful observation and mapping of a clean room during the qualification phase
can provide information concerning the movement
and positioning of personnel within these rooms.
Such observation can also yield important information about the most frequently conducted manipulations and interventions.
Other areas of concern relative to introduction of
contamination into clean rooms are at entry points
where equipment and materials move from areas of
lower classification to those of higher classification.
Therefore, areas within and around doors and airlocks should be included in the monitoring scheme.
Specific considerations for sample site selection
in the qualification study can be distilled from
these different sources. After the minimal number
of sites in a room is determined, their most useful
location must be determined. This determination
should be documented in a written justification and
should consider the following:
Contamination vectors (e.g., handles, control
panels, doors, etc.)
High traffic areas
Personnel flow
Material flow
Waste flow
Surfaces that are difficult to disinfect
HVAC returns
Product risk
Extent of product exposure
The type of activity performed near that site
Interventions and manipulations
Surfaces that are difficult to disinfect.
SAMPLING FREQUENCY FOR THE
QUALIFICATION STUDY
The sampling frequency for the qualification of a
specific controlled environment should, in general,
follow that of the regulatory recommendations
for that level of control. This is a matter of some

discussion as the recommendations in Europe (EU

Annex 1), ISO, and the US (USP) are not in complete agreement. The qualification study may benefit from more frequent sampling and under more
conditions (e.g., sampling under both dynamic and
at-rest conditions) than are planned for the routine
monitoring program.
The EM qualification protocol should allow for
the sampling frequency to be described in detail and
justified. As this justification will rely on the selection
of sites that show consistently higher colony forming
unit (CFU) recovered, there will need to be enough
sampling to allow the sites to be identified. It is recommended that the frequency of sampling be accelerated
(particularly in lower class-controlled environments)
during the qualification study to allow collection of
sufficient data from each site to all this determination
of meaningful routine sample sites.
DURATION OF QUALIFICATION STUDY
The duration of the qualification study should be
determined by the need to acquire sufficient data
and the frequency of testing for that sample site.
A site tested on a weekly basis may require three
months of data (at least 12-14 data points) before
enough data are available. The qualification protocol should justify the duration of the study on this
basis (and not what best fits the mandated timeline
for facility qualification).
SELECTION OF ROUTINE SITES
The qualification study should include sufficient replicates under conditions both at rest and dynamic
to allow identification of sites that provide useful
information. It should be clarified that the term useful
information is not meant to describe those sites that
give the most desireable counts but rather those sites
that either give the highest counts (i.e., serve as the
most sensitive measure of the state of control of the
room) or were shown to be appropriately placed to
herald a problem in the room. The number of sites in a
room or zone should similarly be driven by data generated during this study. Both the number and location
of sites or each clean room or zone should be justified
in the report from this qualification study.
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The following section (X.A.1) from the FDA guidance (2) is relevant for consideration:
All environmental monitoring locations should be
described in SOPs with sufficient detail to allow for
reproducible sampling of a given location surveyed.
Written SOPs should also address elements such as
1. frequency of sampling, 2. when the samples are
taken (i.e., during or at the conclusion of operations),
3. duration of sampling, 4. sample size (e.g., surface
area, air volume), 5. specific sampling equipment and
techniques, 6. alert and action levels, and 7. appropriate response to deviations from alert or action levels.
The generation of relevant data to justify sample sites
is taken seriously by FDA. An example of this can be
found in an FDA-issued warning letter (15):
For environmental and personnel monitoring:
Your active air-sampling unit in one aseptic filling
room is not located in a critical area representative
of exposure of open containers on the aseptic line.
The active air sampling unit was observed positioned behind stoppered vials. . .
You have not evaluated the microbiological burden
generated from the manual aseptic connection from
the source vessel to the XXX filling vessel.
It is not sufficient to pick a few sites around the
room and then apply alert and action levels as recommended by some guidance document. The location,
control levels, and frequency of sampling must be justified by data and a rational analysis.
ESTABLISHMENT OF ALERT AND ACTION LEVELS
Data from the qualification study should be used to
set the initial operating alert and action levels for the
routine environmental monitoring program. A good
rule of thumb is that the alert level should be at the
95th percentile of observed readings for a given period
of time, the action level at the 99th percentile (see the
PDA Technical Report #13 for an excellent discussion of
setting alert and action levels). While common industry practice is to uncritically accept regulatory recommendations for predefined clean zones, this practice
is discouraged in the US (see reference 2, especially
section X.A.2 Establishing Levels and a Trending Program). There is controversy over the regulatory guidance for highly controlled areas as well with concern
28 Journal of GXP Compliance

that control levels set so far below the level of quantification for plate count assays (generally 25-30 CFU per
plate, compared with regulatory guidance setting alert
and action levels as low as single digits). This concern
led USP to suggest a frequency distribution approach
for these areas (14). An interesting discussion of this
approach can be found in Caputo and Huffman (16).
Whichever approach is chosen to the determination
of the inital alert and action levels, they should be one
of the deliverables from the EM qualification program.
Once these are established there must be a mechanism in place to track and trend them in real time
and to investigate excursions. The recent upset over
vaccine production featured a failure to investigate
repeated excursions that figured prominently in 483
observations (17) and in the associated warning letter
(18). A second example of this enforcement stance
can be seen in the warning letter from 2009 regarding
manufacture control of a parenteral medication (19).
Collection of data and then failure to use the data to
determine the state of control for the facility is clearly
at odds with GMP and will be cited.
We would be remiss if the role of the historical database was not discussed in the setting of alert and action
levels. This expectation is described in the FDA aseptic
processing guidance document (section X.A.2) as:
Microbiological monitoring levels should be established based on the relationship of the sampled location to the operation. The levels should be based on
the need to maintain adequate microbiological control
throughout the entire sterile manufacturing facility.
One should also consider environmental monitoring
data from historical databases, media fills, cleanroom
qualification, and sanitization studies, in developing
monitoring levels (2).
That this is a long-standing expectation of FDA is
evidenced by an FDA-483 observation from 2001 that
reads (in part), 44. The firms microbial alert and action limits established for the XX to XXX manufacturing areas are not based on historical data taken from
the EM Program (20).
THE MICROORGANISM CATALOG
FDA has clearly recommended establishment of a
listing of common microorganisms found in the

Scott Sutton, Coordinator

aseptic manufacturing environment. This expectation is laid out in section X.B. (2), as follows:
Characterization of recovered microorganisms
provides vital information for the environmental monitoring program. Environmental isolates
often correlate with the contaminants found in a
media fill or product sterility testing failure, and
the overall environmental picture provides valuable information for an investigation. Monitoring
critical and immediately surrounding clean areas
as well as personnel should include routine identification of microorganisms to the species (or,
where appropriate, genus) level. In some cases,
environmental trending data have revealed migration of microorganisms into the aseptic processing
room from either uncontrolled or lesser controlled
areas. Establishing an adequate program for differentiating microorganisms in the lesser-controlled
environments, such as Class 100,000 (ISO 8), can
often be instrumental in detecting such trends. At
minimum, the program should require species (or,
where appropriate, genus) identification of microorganisms in these ancillary environments at frequent
intervals to establish a valid, current database of
contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective).
The EM qualification study is an excellent opportunity to start this catalog, and to generate
information on the effectiveness of the cleaning
and sanitization program from a microbiological
perspective. Make sure that the EM qualification
program includes relevant evaluations.
A NOTE OF CAUTION ON 483S
There is a great deal of interest currently in the topic
of objectionable organisms. And in fact you might
even find 483 observations that relate to objectionable organisms in an aseptic manufacturing arena
(21). A quck check of the current good manufacturing practice (CGMP) guidance (22) shows the following three references to objectionables:
21 CFR 211.84(d)(6). Each lot of a component,
drug product container, or closure that is liable
to microbiological contamination that is objec-

tionable in view of its intended use shall be subjected to microbiological tests before use.
21 CFR 211.113(a). Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be
sterile, shall be established and followed.
21 CFR 211.165(b). There shall be appropriate
laboratory testing, as necessary, of each batch
of drug product required to be free of objectionable microorganisms.
There are two problems with referencing objectionables with aseptic manufacture: the first is
that it begs the question of what permissible microorganisms might be in the aseptic environment,
and secondly that it misrepresents the requirements
in 21 CFR 211 which relate to non-sterile finished
dosage forms. The point here is that we must be
careful of over-interpreting 483 observations as
teaching tools. While they can be enlightening, in
the end they are only one inspectors opinion on
that particular day and faced with a particular set
of conditions. Everyone has an off day, and we may
never know all the background that went into the
483 observation.
Having said that, the availability of warning
letters provides a window into CGMP that can be
very useful. Warning letters have been reviewed at
the district, frequently have been reviewed at the
national level, and can be considered to represent
FDA policy.
REFERENCES
1. PMF Newsletter, Volume 13, Number 6, Pharmaceutical
Microbiology Forum, June 2007, http://microbiologyforum.
org/PMFNews/PMFNews.13.06.0706.pdf
2. FDA, Guidance for Industry: Sterile Drug Products Produced by
Aseptic ProcessingCurrent Good Manufacturing Practice, 2004.
3. Hussong, D and RE Madsen, Analysis of Environmental
Microbiology Data From Cleanroom Samples, Pharm Technol. Aseptic Proc:10-15, 2004.
4. Farrington, JK., Environmental Monitoring in Pharmaceutical
ManufacturingA Product Risk Issue, Amer Pharm Rev.
8(4):26-30, 2005.
5. Sutton, S., Is Real-Time Release Through PAT CompatSummer 2010 Volume 14 Number 3

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ible with the Ideal of Science-Based Regulation? Pharm

Technol. 31(2):97-98, 2007.
6. FDA warning letters are posted at http://www.fda.gov/foi/
warning.htm and some 483 observations may be found at
http://www.fda.gov/ora/frequent/default.htm
7. FDA, Warning Letter to Sanofi Pasteur, Inc., 483 Inspectional Observations, Swiftwater, PA, April 18, 2006,
http://www.fda.gov/AboutFDA/CentersOffices/ORA/ORAElectronicReadingRoom/ucm056529.htm
8. ISO, ISO 14644-1 Cleanrooms and Associated Controlled
Environments - Part 1: Classification of Air Cleanliness, 1999.
9. EU, EudraLex: The Rules Governing Medicinal Products in the
European Union Volume 4: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use:
Annex 1 Manufacture of Sterile Medicinal Products, 2008.
10. Whyte, W., In Support of Settle Plates, PDA J Pharm Sci
Tech. 50(4):201-204, 1996.
11. Yao, M. and Mainelis, G., Investigation of Cut-Off Sizes
and Collection Efficiencies of Portable Microbial Samplers,
Aerosol Sci Technol. 40:595 606, 2006.
12. PIC/S, PI-006-2 Recommendations on Validation Master Plan,
Installation and Operational Qualification, Non-sterile Process
Validation, Cleaning Validation, 2004.
13. PDA, PDA Tech Report #13 (Revised), Fundamentals of an
Environmental Monitoring Program, 2001.
14. USP, Chapter <1116> Microbiological Control and Monitoring Environments Used for the Manufacture of Healthcare Products, Pharm Forum. 33(3), 2007.
15. FDA, Warning Letter to Pharmalucence, Inc., Sep. 23,
2008, http://www.fda.gov/ICECI/EnforcementActions/
WarningLetters/2008/ucm1048128.htm
16. Caputo, RA and A Huffman, Environmental Monitoring:
Data Trending Using a Frequency Model, PDA J Pharm Sci
Tech. 58(5):254-260, 2004.
17. FDA, FDA-483 Observation for Evans Vaccines, 2004.
http://www.fda.gov/downloads/AboutFDA/CentersOffices/
ORA/ORAElectronicReadingRoom/UCM062048.pdf
18. FDA, Warning Letter to Chiron Corporation December

30 Journal of GXP Compliance

9, 2004. http://www.fda.gov/ICECI/EnforcementActions/
WarningLetters/2004/ucm146700.htm
19. FDA, Warning Letter to Dabur Oncology PLC, April 22,
2009. http://www.fda.gov/ICECI/EnforcementActions/
WarningLetters/ucm164142.htm
20. FDA, FDA-483 Observation to Eli Lilly & Company, 2001.
http://www.fda.gov/downloads/AboutFDA/CentersOffices/
ORA/ORAElectronicReadingRoom/UCM064113.pdf
21. FDA, FDA-483 Observation for Genzyme Corporation,
2009, http://www.fda.gov/downloads/AboutFDA/CentersOffices/ORA/ORAElectronicReadingRoom/UCM191991.
pdf observations #13, 24, 25, 30, 31, 34
22. FDA, Code of Federal Regulations, 21 CFR 211, CGMP in
Manufacturing, Processing, Packaging, or Holding of Drugs and
Finished Pharmaceuticals. GXP

ARTICLE ACRONYM LISTING

CFR Code of Federal Regulations
CFU Colony Forming Unit
CGMP Current Good Manufacturing Practice
USP United States Pharmacopeia
EM Environmental Monitoring
EU European Union
FDA US Food and Drug Administration
GMP Good Manufacturing Practice
ISO International Organization for Standardization
PDA Parenteral Drug Association
PIC/S Pharmaceutical Inspection Convention
and Pharmaceutical Inspection
Co-operation Scheme

ABOUT THE AUTHOR

Scott Sutton, Ph.D., is owner and operator of The Microbiology Network (www.microbiol.org), which provides services to
microbiology-related users groups. Dr. Sutton may be reached
by e-mail at scott.sutton@microbiol.org.