Download Tech Report #13 Revised Fundamentals of an Environmental Monitoring Program PDF

TitleTech Report #13 Revised Fundamentals of an Environmental Monitoring Program
TagsDisinfectant Scientific Method Environmental Monitoring Mean
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Page 2

PDA Environmental Monitoring Task Force

Jeanne E. Moldenhauer, Chairperson, Vectech Pharmaceutical Consultants, Inc.
Aijaz Ahmad, Genentech, Inc.
Susan E. Arrigoni, Ortho-Clinical Diagnostics
Anthony M. Cundell, Ph.D., Wyeth-Ayerst Pharmaceuticals
Gary E. Strayer, Merck & Company, Inc.
John H. Ducote, Chiron Corporation
Susan F. Elder, Glaxo Wellcome, Inc.
Mary Beth Grace, Genentech, Inc.
David A. Ness, Abbott Laboratories, Inc.
Thaddeus G. Pullano, Ph.D., Wyeth-Lederle Vaccines and Pediatrics
James F. Quebbeman, Parke-Davis & Company
Berit ReinmŸller, Royal Institute of Technology
Miriam Rozo, Ortho-Clinical Diagnostics
Lydia Troutman, Schering-Plough Corporation

Technical Reviewers

Russell E. Madsen, PDA
Robert Mello, RJM Pharmaceutical Consultants
Kenneth H. Muhvich, Ph.D., The Validation Group
Glenn Wright, Eli Lilly & Company

Acknowledgements

Franco De Vecchi, VPCI, for providing information relating to HVAC systems and
environmental monitoring.

Anne Marie Dixon, Clean Room Management Associates, Inc., for providing the
ISO information required for this document.

Phyllis Karpiel, Fujisawa Healthcare, Inc., for providing the majority of the typ-
ing support.

Steve Yentes, Pfizer, Inc., for providing technical review of the document.

Elizabeth Joyce, Jordan Pharmaceuticals, Inc., for providing technical writing
review of the document.

Page 22

For most older-model samplers, the sampling volume
is less than one cubic meter. A sampling volume of ten
cubic feet is considered insufficient in Europe. Many
of the newer model samplers are also capable of sam-
pling one cubic meter.

4.4.1 Non-Viable Monitoring

Monitoring of non-viable airborne particulates is a nec-
essary component of an environmental monitoring pro-
gram. Such monitoring demonstrates control of poten-
tial contaminants in the environment to which the prod-
uct, during the manufacturing process, is exposed. Clas-
sification of production areas is generally made based
upon the level of non-viable particulates in the air.

Federal Standard 209E describes, in detail, classifica-
tion of air cleanliness for clean-rooms and clean zones
based on specified concentrations of airborne particu-
lates. It prescribes methods for verifying air cleanli-
ness in the traditional particulate size range(s) and also
with respect to ultra-fine particles. This document has
been commonly referenced with respect to non-viable
particulate monitoring in the pharmaceutical, biologi-
cal, biotechnology, and medical device industries as
well as the electronics industry. More recent publica-
tions on the classification of air cleanliness are the ISO
14644 series of standards on ÒCleanrooms and associ-
ated controlled environments,Ó and ISO 14698 series
of standards on ÒBiocontamination in a clean room en-
vironment.Ó Following the publication of the ISO
14644-1 and 14644-2 standards, Federal Standard 209E
is expected to be retired (as a standard for conducting
business with the US government) by the end of 2001.

The 1987 FDA aseptic processing guide recommends
daily monitoring for non-viables during operations, and
in the United States, monitoring non-viable particles
equal to or larger than 0.5 mm during routine manufac-
turing operations is common (exceptions include asep-
tic powder filling operations). Although monitoring
particles in different size ranges may seem prudent,
particles of 0.5 mm and larger are generally recog-
nized as indicators of environmental contamination.
Requirements outside of the United States may also
include monitoring 5.0 mm particles.

A commonly used monitoring method is optical par-
ticle counting. It is based on the principle of passing an

aerosol through a focused light source, which results in
light scattering from single particles by refraction, re-
flection, and diffraction. In this way, both the size, based
on the intensity of the scattered light, and the number
of particles can be measured simultaneously. This
method provides real-time data on the environment and
provides a useful tool to demonstrate that the environ-
ment remains in a state of control with respect to par-
ticulate contamination.

Selection of an optical particle counter for use in a clean
room or other controlled environment is typically based
on such factors as sensitivity, flow rate, particle size
range, portability, data storage capability, alarm capa-
bility, construction, and sanitization compatibilities.
Although there are technical differences between in-
struments from different manufacturers, it is generally
accepted that these instruments are interchangeable.
However, when switching from one manufacturerÕs in-
strument to anotherÕs, it may be prudent to assess
whether a change in alert or action levels is indicated,
due to differences in equipment sensitivity.

In addition to portable particle counters, systems have
been developed for permanent installation in manufac-
turing areas to allow continuous monitoring of the
manufacturing process with centralized data storage and
alarm capabilities.

4.4.2 Viable Monitoring

Microbes in air are generally associated with solid or
liquid particles. These particles may consist of a single
unattached cell or more commonly as clumps of organ-
isms. Organisms may adhere to a dust particle or other
Òraft,Ó or, if unattached, exist as a free-floating particle
suspended in the air. These particles may remain sus-
pended in the air for extended periods of time due to
the local air currents. HVAC systems in controlled en-
vironments are designed to remove these particles
through frequent air changes or with unidirectional air-
flow in critical areas.

Although total particulate determinations can be use-
ful in monitoring air quality in a pharmaceutical,
biotech, biological, or medical device facility, viable
airborne contamination is of primary importance in
manufacturing environments that require control of
bioburden in the final product. This is particularly true

16 PDA Journal of Pharmaceutical Science and Technology

Page 23

Vol. 55, No. 5, September/October 2001, Supplement TR13, Revised 17

for aseptic production processes, although it applies to
all production processes requiring control of viable
contaminants in the final product (including those used
to manufacture terminally sterilized products).

4.4.2.1 Sites

The principles previously mentioned for site selection
in Section 3.2 are applicable. However, in addition to
these general considerations for sampling site selection,
there are considerations more specifically aimed at air-
borne monitoring. A monitoring location specified for
critical areas (i.e., Class 100, laminar flow) by the 1987
FDA Guideline on Sterile Drug Products Produced by
Aseptic Processing is not more than one foot away from
the work site, and upstream of the air flow, during fill-
ing/closing operations. It is important to consider air
flow patterns in choosing these critical sampling loca-
tions, as well as the introduction of potential contami-
nants by environmental monitoring personnel, equip-
ment, and practices. The potential for contamination of
the product due to the necessity of monitoring must be
considered and avoided.

Additional monitoring locations should be chosen based
upon a defined rationale for the remainder of the room
in which the process is occurring. This can be based
upon initial validation/qualification sampling of the
environment, personnel flow, and processing activity
levels.

4.4.2.2 Methods

The FDA currently expects active air sampling of envi-
ronments on a routine basis to demonstrate control of
possible viable airborne particulates (see reference, Sec-
tion 4.4). Therefore, although useful in some circum-
stances, passive methods such as settling plates are not
generally recommended for such monitoring programs
in the United States. Generally, quantitative sampling
methods are required, with operating levels being de-
fined per unit volume of air.

Presently, several countries outside the United States
require the use of settling plates as well as active air
sampling. Thus, an airborne monitoring program may
require the use of both active and passive air sampling

methods to satisfy the requirements of the countries in
which the final product will be sold. Settling plates may
also be useful for monitoring isolators or laminar air-
flow cabinets.

4.4.2.3 Equipment

A number of types of viable airborne sampling devices
are currently used routinely in the industry, and others
are available for particular uses such as viable particle
size distribution. The most commonly used types of
equipment will be presented here to attempt to provide
an overview of the advantages and disadvantages asso-
ciated with each instrument. These considerations are,
of course, subject to individual interpretation, special-
ized uses, and application to traditional clean rooms or
to barrier/isolation systems.

Generally, active air samplers are used for monitoring
viable airborne contamination levels in production fa-
cilities. These instruments allow the measurement of
known volumes of air, allowing quantification of air-
borne viable contaminants by unit volume of air.

The most widely used instruments are of the solid cul-
ture medium impaction type. These include the follow-
ing categories and representative instruments:

1) Slit Impactors

Slit-to-Agar (STA) Air Sampler

The slit-to-agar air sampler utilizes a revolving agar
plate at a precise distance from a slit-type orifice to
impinge the air sample (and particles) directly onto
the surface of a solid nutrient collection medium.

Advantages:

¥ Measures a large volume of air

¥ Time-concentration relationship is available

¥ Remote sampling probe can be used

¥ Can be used for sampling compressed gases

Disadvantages:

¥ Equipment is large and cumbersome

¥ Some equipment cannot be steam sterilized

¥ Some systems require 150 mm agar plates

Page 43

PDA Journal of
Pharmaceutical Science and Technology

Supplement TR13, Revised Volume 55

September/October 2001 EDITOR: Lee Kirsch No. 5

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2001 OFFICERS AND DIRECTORS
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President: Edmund M. Fry

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