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Sanitation of Pharmaceutical Facilities

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 Peer Reviewed: Facility Sanitation
Sanitation of Pharmaceutical Facilities
Tim Sandle
ABSTRACT
Maintaining environmental control
including microbiological contamina-
tion in a pharmaceutical manufacturing
environment is primarily dependent on
the facility sanitization program. Saniti-
zation considerations are specific for fa-
cility rooms, equipment, and personnel.
Sanitization comprises cleaning and dis-
infection. Cleaning is necessary prior to
the application of disinfectant to enable
sufficient contact time of the disinfecting
agent with the surface. Disinfectants vary
in their spectrum of activity, modes of ac-
tion, sites of action in microorganisms, and
efficacy. Disinfectants kill vegetative mi-
cro-organisms but do not necessarily kill
bacterial spores. There are many different
types and categorizations of disinfectants
such as non-oxidizing disinfectants and
oxydizing agents. Many pharmaceutical
manufacturers will have two “in-use” disin-
fectants and a third disinfectant for major
contamination incidents. Rotation of dis-
infectants is often implemented to satisfy
the requirements of regulators. Cleaning
and disinfection must be detailed in a Stan-
dard Operating Procedure (SOP) to ensure
consistency of practice. The effectiveness of
cleanroom sanitization is assessed through
the site environmental monitoring pro-
gram. Viable monitoring is undertaken us-
ing microbiological growth medium. Reg-
ulatory agencies expect the pharmaceutical
manufacturer to have evaluated the efficacy
of disinfectants. While suspension testing
is useful for initial screening, comparative
surface (or carrier) testing is more relevant.
USP <1072> lists common materials used
in clean rooms that should be considered
when developing disinfectant surface test-
ing. To demonstrate the effectiveness of a
disinfectant, it must be challenged using a
panel of organisms that is reflective of the
natural microflora of the facility. The bio-
cidal activity of the disinfectant should be
taken into account when selecting the panel
of organisms. The use of microbial isolates
from the manufacturing facility is increas-
ingly becoming a regulatory expectation.
Surface tests cannot demonstrate the effect
of a range of environmental factors in ac-
tual environmental conditions. Field tri-
als are an important part of the qualifica-
tion of a sanitizer to determine if cleaning
techniques are suitable and if the cleaning
frequencies of cleanrooms require modifi-
cation.
INTRODUCTION
This article provides an introduction to
the sanitization and bio-decontamination
of pharmaceutical manufacturing facilities.
This topic is especially relevant for manu-
facturing of sterile products.
Pharmaceutical facilities used for manu-
facturing of sterile products are comprised
of a series of rooms called cleanrooms.
Cleanrooms and zones are typically classi-
fied according to their use or main activity
within each room or zone. Cleanrooms are
confirmed by the cleanliness of the air by
the measurement of particles. Pharmaceu-
tical cleanrooms are classified by standards
in either EU and WHO GMP guidance
for aseptically filled products (alphabet-
ic notation) or by International Standard
ISO14644 (numeric classification). The
cleanliness of the air is controlled by the
HVAC system (Heating, Ventilation and
Air-Conditioning) in the facility.
Cleanrooms are designed to minimize
and to control contamination. There are
many sources of contamination. The at-
mosphere contains dust, microorganisms,
condensates, and gases. Manufacturing
processes will also produce a range of
contaminants. Wherever there is a pro-
cess which grinds, corrodes, fumes, heats,
sprays, turns, etc., particles and fumes
are emitted and will contaminate the sur-
roundings (1). The foremost concern in
pharmaceutical manufacturing of sterile
products is microbial contamination.
Maintaining environmental control in
a pharmaceutical manufacturing environ-
ment is primarily dependent on the facil-
ity’s cleaning and disinfection program.
The program requires the selection of the
appropriate disinfectants, their proper ap-
plication, and validation of their capability
to inactivate vegetative cells.
TYPES OF SANITIZATION
Sanitization differs depending on the
specific area of concern. Three areas are
discussed: Rooms, equipment, and person-
nel.
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Tim Sandle
Room Sanitization
Cleanrooms and clean areas must be
regularly cleaned and disinfected. This is
normally undertaken by cleaning with de-
tergent followed by the application of a dis-
infectant. Sometimes more than one dis-
infectant application is necessary such as
following a production shutdown. It may
be necessary to remove the residue of the
disinfectant using water.
Arguably the most effective cleaning and
disinfection process is undertaken manual-
ly by use of wiping techniques. Some facil-
ities utilize fumigation or fogging methods.
These methods are effective when surfaces
are clean and the sanitizing agent can reach
all of the cleanroom surfaces.
When cleaning rooms manually, the
equipment used (mops and buckets)
should be of an appropriate design for the
grade of cleanroom. Cleaning procedures
require a strict cleaning regime. Clean-
ing and disinfection using cloths and mop
heads is ideally performed by saturating the
cleaning item and wiping the area using a
series of parallel overlapping strokes with
an approximate one quarter overlap. Cir-
cular motion should never be used. The
direction of the cleaning should be towards
the operator (from top to bottom, from
back to front). Only one application of the
disinfectant or detergent should be applied
to avoid over-concentration. Cleaning and
disinfection should begin with the visually
cleanest area first and towards the dirtiest
area last.
Cleaning is normally undertaken in
each process area before use. In general,
the frequency of cleaning should be estab-
lished through risk assessment based on a
review of environmental monitoring data
before and after the disinfection process.
The review should consider the numbers
of microorganisms recovered and the types
of species. With species, a check should
be made on the frequency of recovery of
spore-forming microorganisms. A high
recovery of microbial contamination could
signal a concern with the disinfectants used
or with their frequency of rotation.
Journal of GXP Compliance Volume 18 Number 3
Equipment Sanitization
Effective cleaning and sanitization of
equipment is important because equipment
may not be amenable to visual inspection.
Also, equipment may be prone to biofilm
formation.
The main method for cleaning industri-
al equipment is by making the mechanism
for cleaning integral to the equipment itself.
This can be achieved by use of pressure,
heat, steam sterilization, mechanical re-
moval, or chemical cleaning agents. Auto-
mated methods are termed “Clean-in-Place
(CIP)” or “Steam-in-Place (SIP).” Prior to
chemical or heat treatment, attempts must
be made to remove process residues and
particles using steam or high pressure wa-
ter cleaning. Alkali-based disinfectants
and detergents are commonly used for CIP
systems; sodium hydroxide is among the
most widely used. Such caustic alkalis can
readily remove organic deposits without af-
fecting the equipment. It is important that
the equipment cleaning process is validat-
ed.
Glove Sanitization
The gloved hands of staff undertaking
critical activities should be sanitized on a
frequent basis using an effective hand san-
itizer. Aseptic techniques performed by
trained personnel are most important. The
sanitizing agent itself is not a replacement
for poor aseptic techniques.
There are many commercially avail-
able hand sanitizers. Most commonly
used types are alcohol-based gels contain-
ing either ethanol or isopropanol. An EU
standard (EN 1499 (2) and EN 150025A
(3) provides test methodology to validate
the efficacy of the hand sanitizer. Testing
determines if a hand sanitizer can reduce
the number of transient microflora under
simulated practical conditions. There are
three key variables which affect the use of
hand sanitizers. These are the agitation and
rubbing the hand sanitizer into the glove,
the frequency of application, and the quan-
tity applied (5). Of these, consistency of
the rubbing technique in ensuring that all
surfaces of the hand come into contact with
the sanitizer is most important.
TYPES OF DISINFECTION
AGENTS
A disinfectant is one of a diverse group
of chemicals which reduces the number of
micro-organisms present on an inanimate
object. Disinfectants kill vegetative mi-
cro-organisms but do not necessarily kill
bacterial spores. To be effective, disinfec-
tants must meet either European standards
(the CEN series) or US standards (the
AOAC standards) for disinfectant efficacy.
These standards involve challenging disin-
fectants with high populations of a range of
different microorganisms and noting the
log reduction after a period of time. Such
studies are undertaken for the disinfectant
solution (the suspension test), on surfaces,
and in “the field” to develop appropriate
cleaning frequencies.
Disinfectants vary in their spectrum
of activity, modes of action, and efficacy.
Some are bacteriostatic in which the ability
of the bacterial population to grow is halt-
ed. Here the disinfectant can cause selective
and reversible changes to cells by interact-
ing with nucleic acids, inhibiting enzymes,
or permeating into the cell wall. Once the
disinfectant is removed from contact with
bacteria cells, the surviving bacterial pop-
ulation could potentially resume growth.
Other disinfectants are bactericidal in that
they destroy bacterial cells through differ-
ent mechanisms including causing struc-
tural damage to the cell, lysis, and leakage
or coagulation of cytoplasm (6). The mech-
anisms of action are not always completely
known and continue to be investigated.
Surface disinfectants have varying
modes of action against microbial cells due
to their chemical diversity. Different dis-
infectants target different sites within the
microbial cell. These include the cell wall,
the cytoplasmic membrane (where the ma-
trix of phospholipids and enzymes provide
various targets) and the cytoplasm. Some
disinfectants, on entering the cell either by
disruption of the membrane or through
diffusion, proceed to act on intracellular
components.
 Peer Reviewed: Facility Sanitation
There are different approaches to the
categorization and sub-division of disin-
fectants, including grouping by chemical
nature, mode of activity, or by bacteristatic
and bactericidal effects on micro-organ-
isms (7). These and other factors such as
efficacy, compatibility, cost, and current
health and safety standards (8) must be
considered when selecting disinfectants for
use in the facility. The following describes
the primary types of disinfectants currently
in use categorized as non-oxidizing and ox-
idizing agents.
Non-Oxidizing Disinfectants
The non-oxidizing disinfectants include
alcohols, aldehydes, amphoterics, phe-
nolics, and quaternary ammonium com-
pounds (QACs or “quats”).
Alcohols. The effectiveness of alcohols
against vegetative bacteria and fungi in-
creases with their molecular weight (eth-
anol is more effective than methanol and
isopropyl alcohols are more effective than
ethanol). Alcohols act on the bacterial cell
membrane by making it permeable. Effica-
cy is increased with the presence of water
leading to cytoplasm leakage, denaturation
of protein, and eventual cell lysis. The ad-
vantages of employing alcohols include
a relatively low cost, little odor, and rapid
evaporation (9).
Aldehydes. Aldehydes include form-
aldehyde and glutaraldehyde. Aldehydes
have a non-specific effect in the denatur-
ing of bacterial cell proteins and can cause
coagulation of cellular protein. There are
safety concerns about the use of some alde-
hydes (10).
Amphoterics. Amphoterics have both
anionic and cationic character and pos-
sess a relative wide spectrum of activity.
Amphoterics are limited by their inability
to damage endospores. Amphoterics are
frequently used as surface disinfectants.
Examples include the alkyl di(aminoethyl)
glycine group of compounds.
Phenolics. Synthetic phenols are widely
available such as the bis-phenols (triclosan)
and halophenols (chloroxylenol). Phenols
are bactericidal and antifungal, but are not
effective against spores. Some phenols
cause bacterial cell damage through disrup-
tion of proton motive force, while others at-
tack the cell wall and cause leakage of cellu-
lar components and protein denaturation.
Quaternary ammonium compounds.
QACs or “quats” are cationic salts of organ-
ically substituted ammonium compounds
that have a fairly broad range of microbial
activity. They are ineffective against bac-
terial spores. QACs are possibly the most
widely used of the non-oxidizing disinfec-
tants. Example QACs include cetrimide
and benzalkonium chloride. Their mode
of action is on the cell membrane leading
to cytoplasm leakage and cytoplasm coag-
ulation through interaction with phospho-
lipids (11).
Oxidizing disinfectants
This group includes oxygen-releasing
compounds (peroxygens) like peracetic
acid and hydrogen peroxide. They func-
tion by disrupting the cell wall, causing
cytoplasm leakage, and denature bacterial
cell enzymes through oxidation. Oxidiz-
ing agents have advantages in that they are
clear and colorless, thereby avoiding sur-
face staining.
SANITIZATION REGIME
There are several important process
considerations involved with sanitization.
These include cleaning, disinfection, selec-
tion and rotation disinfecting agents, and
the specific procedures utilized.
Cleaning
Cleaning, in the context of pharmaceuti-
cal manufacturing, is the process of remov-
ing residues and soil (dirt, grease, protein
etc.) from surfaces to the extent that they
are visually clean. This involves clearly de-
fined procedures that often require use of a
detergent or other cleaning agent. Deter-
gents generally work by penetrating the soil
and reducing the surface tension (which
fixes the soil to the surface) to allow its
removal. Hence many of the products are
surfactants (surface active agents).
Cleaning as described above is necessary
for cleanrooms prior to the application of
disinfectant. It is essential that a surface
or item of equipment has been properly
cleaned before disinfectant application in
order for the disinfectant to work efficient-
ly. This is particularly important for spori-
cidal disinfectants, many of which have
limited ability to effectively penetrate soil.
Disinfection
The critical aspect for disinfectant effi-
cacy is the contact time. The disinfectant
is only effective when left in contact with
the surface for the validated time. This
can be achieved more easily when the dis-
infectant is applied in overlapping strokes.
When rotation of disinfectants is required,
a water rinse normally employing Water for
Injection (WFI) is employed between the
change-over of disinfectants. This rinse re-
moves traces of disinfectant and detergent
residue such as anions which may reduce
the efficacy of the subsequent disinfectant.
A disinfectant will achieve the desired
effectiveness if it remains on the targeted
surface for an appropriate length of time.
Determining the optimal contact time of-
ten means striking a balance between what
is necessary to achieve the desired micro-
bial reduction and what is practical for re-
al-time use in the facility. At minimum, the
manufacturer’s recommended contact time
should be tested. Additional contact times
may also be evaluated if the manufacturer’s
recommended time is demonstrated to be
ineffective or if a shorter contact time is de-
sired (12).
Rotation of Disinfectants
Many pharmaceutical manufacturers
will routinely use two “in-use” disinfec-
tants in a specified rotational sequence
for the site disinfection program. A third
disinfectant will be available in reserve in
case a major contamination incident arises.
For example, a bioburden contamination
increase which appears resistant or diffi-
cult to eliminate using the routinely used
disinfectants may necessitate use of an ad-
ditional disinfectant. The reserve disinfec-
tant such as an oxidizing agent will often be
more powerful and sporicidal, the routine
use of which is restricted because of like-
ly damage to the equipment and premises.
The rotation of two primary disinfectants
is a requirement of regulatory bodies. The
www.ivtnetwork.com
Tim Sandle
EU GMP Guide states that “where disinfec-
tants are used, more than one type should
be employed” (Annex 1). Nevertheless, the
case for rotation has not been scientifical-
ly proven in that there are very few studies
providing empirical evidence. However, it
remains that rotation is often implemented
to satisfy the requirements of regulators.
Cleaning and disinfection procedures
Cleaning and disinfection must be de-
tailed in a Standard Operating Procedure
(SOP) to ensure consistency of practice.
Furthermore, sufficient detail in SOPs is
important because detergents and disin-
fectants are only partially effective if they
are not applied correctly. An SOP should
describe:
• The type of detergents and disinfec-
tants to be used. These agents must be
compatible
• The frequency of rotation of disinfec-
tants
• A list of suitable cleaning materials
• Cleaning techniques
• Contact times
• Rinsing
• Frequency of cleaning and disinfection
• Procedure for the transfer of cleaning
agents and disinfectants into and out
of clean areas
• Procedure for sterilization of disinfec-
tants
• Holding times for detergents and dis-
infectants.
ASSESSING SANITIZATION
EFFECTIVENESS
The effectiveness of cleanroom saniti-
zation is assessed through environmental
monitoring. Environmental monitoring
is a program which examines the numbers
and occurrences of viable micro-organ-
isms and non-viable particles such as dust
or skin cells. Environmental monitoring is
ideally targeted to those areas of the pro-
duction process where the risk cannot be
adequately controlled. Trend analysis of
environmental monitoring data provides
an indication if the cleanroom disinfection
program is moving out-of-control (13).
Viable monitoring of surfaces is the most
relevant approach for assessing the effec-
tiveness of surface sanitization.
Journal of GXP Compliance Volume 18 Number 3
Viable monitoring is designed to detect
levels of bacteria and fungi present in de-
fined locations during a particular stage in
the processing and filling of product. Vi-
able monitoring is designed to detect mi-
cro-organisms and answer questions such
as how many, how frequent, when do they
occur and why do they occur? (14)
Viable monitoring is undertaken using
microbiological growth medium (agar or
other substances) in different presenta-
tions. It is important that the culture media
used for environmental monitoring con-
tains a neutralizer to eliminate any residues
of the disinfectant.
The environmental monitoring program
is normally controlled by the site microbi-
ology department who establish the appro-
priate frequencies and durations for moni-
toring based on a risk assessment approach.
The sampling plan takes into account the
cleanliness level required at each site to be
sampled.
QUALIFICATION OF
DISINFECTANTS
Regulatory agencies expect the phar-
maceutical manufacturer to have evaluated
the efficacy of disinfectants. While suspen-
sion testing is useful for initial screening, it
is surface (or carrier) testing that is more
relevant. Qualification of a disinfectant is
demonstrated through performance testing
to show that the disinfectant is capable of
reducing the microbial bioburden found on
manufacturing area surfaces. Representa-
tive manufacturing surface samples are in-
oculated with a selection of microbial chal-
lenge organisms. A disinfectant is applied
to the inoculated surfaces and exposed for
a predetermined contact time after which
surviving organisms are recovered using a
qualified disinfectant-neutralizing broth
and test method (surface rinse, contact
plate, or swab). The number of challenge
organisms recovered from the test samples
(exposed to a disinfectant) is compared
to the number of challenge organisms re-
covered from the corresponding control
sample (not exposed to a disinfectant) to
determine the ability of the disinfectant to
reduce the microbial bioburden. Success-
ful completion of the validation qualifies
the disinfectant evaluated for use. The dis-
infectant efficacy validation should provide
documented evidence that the disinfectant
demonstrates bactericidal, fungicidal, and/
or sporicidal activity necessary to control
microbial contamination in the facility
(15).
The selection of surfaces to be assessed
for disinfectant efficacy is an important
consideration. Given the multitude of
available surfaces in a facility, a pragmatic
view should be taken. Where the surface
is considered critical in terms of cleaning
and disinfection, i.e., contact with product
and personnel, it should be considered for
disinfectant surface testing. USP chap-
ter <1072> lists common materials used
in clean rooms that should be considered
when developing disinfectant surface test-
ing. Stainless steel and other surfaces
within the manufacturing facility should
be tested such as different grades of vinyl
and stainless steel, different types of plastic,
glass from windows and vessels, and other
materials as appropriate.
The test involves examining prepa-
rations of micro-organisms dried onto
surfaces. A prepared sample of the disin-
fectant is added to the dried surface con-
taining and microbial suspension. The
surface is then transferred to a previously
validated neutralization medium and test-
ing performed to measure the reduction
in viable counts. One variation of the test
involves drying 0.05 ml suspensions of
the micro-organisms with interfering sub-
stances such as bovine serum albumin onto
different surfaces. The micro-organisms
should have a population range of 1.5 - 5.0
x 108 for bacteria and 1.5 - 5.0 x 107 for
fungi and are equilibrated to 25oC before
use. Once applied to the surface, the drying
of the micro-organisms maybe accelerated
using an incubator operating at 36-38oC.
Disinfectant solutions (where disinfectants
are made with Water of Standard Hard-
ness) are added to the surfaces. After the
specified contact time (five minutes is the
target), the surfaces are transferred to the
validated neutralization medium and then
pour plates are prepared for incubation and
counting. An alternative method is avail-
able using a soaked swab step (16).
To demonstrate the effectiveness of a
disinfectant, it must be challenged using a
panel of organisms that is reflective of the
natural microflora of the facility. The bio-
 Peer Reviewed: Facility Sanitation
cidal activity of the disinfectant should be
taken into account when selecting the panel
of organisms. Some organizations use type
cultures, some use environmental isolates,
and others a combination of the two. The
use of isolates from the manufacturing fa-
cility is increasingly becoming a regulatory
expectation.
The surface test described above cannot
demonstrate the effect of a range of envi-
ronmental factors like temperature, pH, de-
tergent residues, mechanical stress, and at-
tachment in the facility. For these reasons,
a disinfectant which appears effective for
the surface test can show marked variability
when applied to practical conditions. This
is due to problems in drying and differenc-
es between surfaces. In terms of drying
microbial suspensions, there is a marked
loss in the viability of a population when
dried onto a surface. Attempts to speed the
drying process do not significantly reduce
the variability of the actual number of mi-
cro-organisms challenged. Surfaces intro-
duce another variation because surfaces.
Surfaces of the same grade of material are
not truly identical. There have been marked
problems in achieving reproducibility and
repeatability for the surface test between
laboratories particular in estimating the
concentration of disinfectant required to be
effective. Some of these limitations can be
addressed through field trials.
Field trials (or in situ studies) are an im-
portant part of the qualification of a sani-
tizer. These trials determine if cleaning
techniques are suitable and if the cleaning
frequencies of cleanrooms require modifi-
cation. Filed trials involve a considerable
amount of environmental monitoring for
the counts before and after disinfection
and the types of microorganisms recovered
must each be evaluated (17).
SUMMARY
This paper has presented an overview
of the application of sanitization of phar-
maceutical facilities. Sanitization is a
key part of contamination control within
cleanrooms. It has examined some of the
techniques and control required, and has
compared different types of disinfectants
available for use. It has also emphasized
the importance of qualifying disinfectant
in order to demonstrate their effectiveness,
View publication stats
and for undertaking a vigorous monitoring
regime in order to show that the cleanroom
environment remains in control. The em-
phasis has been upon the assessment of
surfaces and the evaluation of disinfectants
in the field. While the article has focused
on microbiological assessments, there are
other variables at play including wiping
technique, expiry times, and chemical sta-
bility that must also be considered. This
acknowledged, it is hoped that this article
has provided information and advice useful
to compliance practitioners that can be ap-
plicable within the manufacturing facility.
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About the Author
Tim Sandle, Ph.D., is the head of the microbiology
department at Bio Products Laboratory Limited,
a pharmaceutical organization owned by the UK
Department of Health. Dr. Sandle is, additionally, a
visiting tutor at the School of Pharmacy, Manchester
University. E-mail: Tim.Sandle@bpl.co.uk
www.ivtnetwork.com