Peer Review Article

Cleanroom Garments from a

Quality Risk Management
Approach
Authors: Matts Ramstorp, PhD, Professor, BioTekPro AB, Sweden

Introduction
Since the start of cleanroom technology, garment selection has been known to have a major impact on
the cleanliness of cleanrooms. In general, the ‘cleaner’ the cleanroom – the more covered the
cleanroom personnel must be; with garments acting like filters. Even though garments have been
recognized as important tools in cleanroom technology, during the past 20 years, little effort has been
put into the development and use of more modern and robust garments. The same applies to the
different test methods that are available to control the integrity of cleanroom garments. In fact,
nothing much has happened in these areas.

This article covers cleanroom garments, garment materials as well as

the different test methods available to study safety aspects, filtration
efficiency, and life cycle, in relation to Quality Risk Management - QRM.

The purpose of this article is to summarize the subject of cleanroom

garments related to historical and present safety demands, as well as
to future QRM demands. My intention is that the article will serve as a
basis of discussions in order to highlight the importance of garment
selection, and lead to a more scientifically based understanding and
use of cleanroom garments in the future.

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 “The primary barrier between
the personnel and the
cleanroom”

“Cleanroom clothing and gloves

are the primary barriers keeping
contaminants, generated by
personnel, from being emitted into
the cleanroom and deposited on
products”. This was stated by Mr
Alvin Lieberman in the
introduction of a book he wrote in
1992 (1).
It has long been established that
people are the biggest source of
contaminants (2), and
furthermore, in most cases the
source of the most critical
contaminants when working in
cleanrooms. There are many ways
to deal with this situation.
Examples include minimizing the
number of personnel in the
cleanroom, training the personnel
to behave in ways to minimize the
generation of contaminants
during work and dressing the
personnel in clean garments that
more or less acts as a barrier or a
filter between the personnel, the
surrounding environment and (or)
the product handled.
Thus, cleanroom garments play an
extremely important role when
creating and maintaining a desired
level of cleanliness, in order to
protect the final products, and
most importantly, when producing
medicinal products, in keeping the
patient safe.

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Demands on cleanroom garments
When cleanrooms were introduced in the air and space industry during the 1950s and 1960s, it was recognized
that contaminants, i.e. particles from various sources, had a major impact on the materials and equipment
handled. It was discovered early on that the personnel were the major source of contaminants comprising of
particles, such as skin flakes, microorganisms, hair, saliva, textile fibres from private clothing as well as clothing
worn during work. NASA, for example, generated numerous studies on personnel, resulting, among other
things, in the extensively recognized results shown in Table 1 (3).

Table 1. Results presented by NASA showing the number of particles generated by persons performing
different activities, measured as the number of particles with a size greater to and equal to 0.3 µm

Cleanroom garments are used in order to minimize the risk that particles, including microorganisms, from
operators, will negatively impact the cleanroom environment and ultimately, the products handled.

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 Cleanroom garment fabrics
Cleanroom garments are, from a general point of view, produced from two
different types of fabrics:
· Woven textile fabrics
· Non-woven fabrics
Woven textile cleanroom garments are intended for repeated use, need to
be washed, and in some cases, such as aseptic production, sterilized prior to
use. Non-woven garments, on the other hand, are generally intended for
single-use, and will only be subjected to washing and sterilization once,
since these garments are discarded after use. In this article, textile
cleanroom garments will be referred to as re-useable garments, and non-
woven cleanroom garments as single-use garments.
Cleanroom garment attributes
Cleanroom garments should perform four major and important functions:
· Act as a barrier or a filter
· Be sufficiently clean
· Retain their integrity over their entire lifecycle
· Supply operator comfort
“Sufficiently clean” means that garments should be cleaned in such a way
to not compromise the cleanliness of the cleanroom. Furthermore, they
should be manufactured of a material that will not, by itself, be a
contamination hazard. In other words, the garment should not generate
particles by itself.
Cleanroom garments should retain their integrity throughout the entire
lifecycle, since damaged garments can result in garment material being
released. Additionally, a damaged garment will have less possibility to act as
a barrier and will represent a risk of contamination of the environment.
In some cases, there is also a need to protect the operators from dangerous
compounds during cleanroom work. However, cleanroom garments used
for protection of operators are not covered in this context.

The balance between comfort and filtration efficiency

Many parameters are presented in commercial brochures when outlining
what type of cleanroom garment to use. Some of these parameters are
difficult to understand from an end-user point of view. The most difficult
parameter is comfort. Comfort is a subjective characteristic, which
contradicts the most important parameter in a cleanroom garment: the
capability of the garment to act as a barrier or a filter.

Parameters such as air permeability, equivalent pore size diameter, water

vapour transmission, weight per unit surface area, and tear strength, impact
both filtration efficiency and comfort. When discussing the balance between
filtration efficiency and comfort, re-useable cleanroom garments can only be
compared with other re-useable garments, and, single-use cleanroom
garments can only be compared with other single-use garments. In each of
these fabric categories; the better the filtration efficiency, the more
uncomfortable the garment is to the user. Conversely, the better the
comfort for the user, the worse the filtration efficiency.

Many of these parameters are hard to translate when stating demands for
cleanroom garments. On the other hand, comfort is more easily
acknowledged, especially through operator verbal complaints.

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 Patient safety versus comfort of the personnel
Is it possible to balance these two aspects? In some cases, I get the
impression that comfort for the operators is more of a focus area than
filtration efficiency, and ultimately patient safety.
One of the largest and state-of-the-art hospitals in Sweden has 35 newly
built operating theatres with ventilation based on mixed or turbulent
airflow. Despite this, the general cleanliness demand of the room air has
been stated as < 5 CFU per cubic meter. This air cleanliness cannot be
obtained by this ventilation principle alone, demanding the personnel to
wear a specially designed and less porous surgical work suit in order to
minimize the CFUś generated.
The specialized surgical garment was purchased and used by the personnel,
but the garments turned out to be too impenetrable. In other words, the
barrier function was good enough for the desired cleanliness, but not for
the comfort of the personnel. The personnel were unable to wear the new
garments due to comfort and related skin problems, and thus continued to
use the traditional older-style garments. Thus, the cleanliness demands in
the operating theatre could not be obtained, and as a result, the hospital
was forced to decrease their cleanliness demands.

In the above case, operator comfort had a higher priority as compared to

patient safety. This shows the complex challenge between comfort for the
personnel versus patient safety.

Cleanroom garments in GMP operations

Different cleanroom cleanliness grades or classifications will require different
types of garments to be worn by personnel. In lower classification
cleanrooms, personnel often dress in less-covering garments and, to some
extent, in garments made from, for example, textile material that does not
fully comply with the attributes stated above. In the European GMP – Good
Manufacturing Practice, four different cleanroom cleanliness levels or
grades are defined: Grade A, Grade B, Grade C and Grade D, respectively.
Grade A is the cleanest and grade D the least clean (4). Each grade has a
different coverage requirement.
When working in a Grade D cleanroom, it is quite normal that the personnel
wear trousers and a coat. Moreover, personnel also use designated shoes or
shoe covers and cover hair with a bouffant. The material used for garments
in Grade D is not specified in the present Annex 1 of Volume 4, which in
practice means that blended textile materials, i.e. mixtures of cotton and
polyester, are used.
According to Annex 1, when working in the cleanest cleanroom, Grade B, the
following is specified: “The protective clothing should shed virtually no
fibres or particulate matter and retain particles shed by the body.” In
practice, this means that no natural fibre-based materials are to be used. In
other words, Grade B cleanroom garments are mostly made of 100 %
polyester or similar material.
Grade B cleanrooms are used together with Grade A clean zones when
performing aseptic filling or aseptic handling. This is the most critical
operation within the pharmaceutical industry, and it is also the operation
that puts the end-user, the patient, at highest risk, since there is no terminal
sterilization of the product in its sealed container after filling.
Quality Risk Management
QRM – Quality Risk Management – is not new. It has been around for a long
period of time and is also mentioned in the present Annex 1, in Volume 4 of
the Eudralex
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this However, the draft
article published AnnexV24No3,
in EJPPS 1 (2017)
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 introductory part: “This Annex provides general guidance that should be
used for all sterile medicinal products and sterile active substances, via
adaption, using the principles of Quality Risk Management (QRM), to
ensure that microbial, particulate and pyrogen contamination associated
with microbes is prevented in the final product”.
Although much “detailed” guidance is presented in the draft Annex 1
regarding cleanroom garments, in practice, both the handling and the use
of these important cleanroom tools always must be subjected to QRM.

Quality Risk Management Cleanroom garments

Even though QRM has been generally described and used for quite a long
period of time, cleanroom garments have not truly been subjected to risk
management principles in detail. Furthermore, the development of fabrics,
cleanroom garments and all the parts of a garment system, has not been
emphasized. The bottom line: Not much has happened during the last 20
years, when it comes to re-usable textile cleanroom garments.

Cleanroom use and cleanroom garments in the future

The new demands stated in the draft Annex 1, indicate the need to look
more thoroughly at all aspects on cleanroom garments. Longstanding and
well-known test methods must be scientifically judged, to determine if, and
in what respect, they can be used in the context of QRM, and (or) if new test
methods or totally new approaches must be developed and adopted for
cleanroom garments.

The part covering Aseptic Preparation (5), section 8.9 states: “Where
possible, the use of equipment such as RABS, isolators or closed systems,
should be considered in order to reduce the need for interventions into the
grade A environment and minimize the risk of contamination”. The intent of
this guidance is to minimize the potential risk of contamination from
operators during interventions.

Isolators as well as closed systems, for aseptic production, can be placed in a

surrounding cleanroom with lower cleanliness, whereas RABS (Restricted
Access Barrier Systems) must be used in Grade B cleanrooms, the same
cleanliness level needed when using open clean zones, UDF- and (or)
microbial safety cabinets class II.

When working in lower classification cleanrooms, (Grade C or Grade D), and

using isolators and closed process systems, a lower degree of body
coverage could be considered. However, Grade B garments will still be used
to a very large extent, since all processes cannot be performed in isolators
or closed systems, and RABS will still demand a Grade B background. In sum,
the demand of the Grade B cleanroom garment system will remain strong,
even in the future.

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 Testing cleanroom garments
Since cleanroom garments are of fundamental importance for the
outcome of the manufacturing process, the quality of the final
products, and hence patient safety, different test methods have
been developed. The overall purpose of these test methods can be
divided into two parts:
· To obtain information of the performance of the garment
· To give the end-user guidance on which garments to chose
The Institute of Environmental Sciences and Technologies (IEST) has
published several Recommended Practices that are to be used as
practical tools when getting cleanrooms working to desired
specifications. In the Recommended Practice covering cleanroom
garments, (IEST-RP-CC 003.4) (6) different test methods are
specified, focusing on the garment material, the fabric, and on
ready-made garments, respectively. The different tests described in
this document, shown in respect to their purpose, are:
Cleanliness of fabric and (or) garment:
· Releasable large particles test
· The Helmke drum test
Filtration efficiency
· The particle penetration test
· The microbial penetration test
· The body box test
Test for equivalent pore size diameter
· The bubble point method

Filtration efficiency testing

The three tests normally used to study the filtration efficiency of
cleanroom fabrics are:
· The particle penetration test
· The microbial penetration test
· The body box test
The two penetration tests above are not subjected to undesired
variations, such as using different test persons, differences in
movement pattern of the test persons, etc. This might be a problem
when performing the body box test. The body box test is performed
on persons dressed in different cleanroom garments, and
performing different movements in a test chamber, in which the
particles generated during test are measured.
The particle and microbial penetration test give an idea of the
quality of the fabric, whereas the body test is a tool to compare the
different garments and (or) garment systems in an environment
that comes closer to real use. For comparison purposes body box
testing should, however, be done with the same operator and
under exactly the same test conditions. The body box test gives an
idea on how the garment is performing as a whole.

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Equivalent pore size diameter
The bubble point test is used to determine the equivalent pore
size diameter of a fabric. This term is normally used to describe
the filtration efficiency of the fabric. This is not fully accepted,
since the filtration efficiency is not based on “pore size” only, but
also on the thickness of the fabric. When performing the bubble
point test on a single as compared to a double layer of fabric, the
same equivalent pore size diameter will be obtained, even
though double layers of fabric will enhance the filtration
efficiency enormously.

Use the correct cleanroom garment parameters

All the different tests have one thing in common: they serve as
means to describe different aspects of the garment material, the
fabric and (or) the cleanroom garment. However, the problem
remains that these results are not easily understood by the end-
user. This is troublesome, since many of these parameters are
not discussed with end-users, making it extremely hard to
understand the properties of cleanroom garments, and
ultimately to produce a User Requirement Specification (URS).

Cleanroom garment end-users normally reference the

recommendations stated in the Recommended Practice from
IEST when choosing the correct garment system, which outlines
the recommended choice of different apparel. By combining this
information with, for example, the Annex 1 of Volume 4 in the
EudraLex, the end-user can be confident that they have chosen a
cleanroom garment system that is in “compliance” with the
stated demands.

The life cycle of cleanroom garments - Practical approach

today
At present textile cleanroom garments are used to a major
extent. The use of textile garments demands that these are
repeatedly used which means that these garments must be
washed, or washed and subsequently sterilized, when used in
Grade B cleanrooms for aseptic production. The process of
washing and even more sterilization will have a negative impact
on the function of the garments and must be considered when
discussing the life cycle of the garment.
Re-usable cleanroom garments are washed and, if to be used in
Grade B/A applications, also sterilized. From a general point of
view, the “cleanroom” laundry companies around the world
have full control of their washing process, and in most cases the
washing processes and the sterilization processes are validated.
In some parts of the world, cleanroom garments are washed in
“in house” laundries or “industrial” laundries, where chemicals,
temperatures as well as air cleanliness used for washing and
drying also have an impact om the life span of the garments, and
not always considered in quality performance of laundries.
Many of the “cleanroom” laundry suppliers also have historical
knowledge of the impact of these processes regarding the
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garments used by the end-users, have not been subjected to a
full validation.

Contamination Control Strategy – CCS

In the draft to Annex 1 (2017) a new term is introduced –
Contamination Control Strategy – CCS, which is explained in the
following way:

“Quality Assurance is particularly important, and manufacture of

sterile products must strictly follow carefully established and
validated methods of manufacture and control. A contamination
control strategy should be implemented across the facility in order to
assess the effectiveness of all the control and monitoring measures
employed. This assessment should lead to corrective and
preventative actions being taken as necessary.

The strategy should consider all aspects of contamination control

and its life cycle with ongoing and periodic review and update of the
strategy as appropriate.

Contamination control and steps taken to minimise the risk of

contamination from microbial and particulate sources are a series of
successively linked events or measures. These are typically assessed,
controlled and monitored individually but these many sources
should be considered holistically.”

One way to explain the purpose of a Contamination Control

Strategy is to detect and fill gaps that are identified when
assessing the system and controlling and monitoring individual
events from a holistical point of view.
A Contamination Control Strategy must, therefore, incorporate
cleanroom garments, the production of the garment, and all the
different treatments that the garment is subjected to, such as
washing and sterilization, packaging, transportation, use, … etc.
In other words, suppliers’ recommendations on garment life, in
respect to repeated washing and sterilization is not good
enough. A proper validation based on scientific evidence is the
only way to ensure patient safety.

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 Cleanroom garment supplier’s recommendation

In the Nordic countries there is a widespread

understanding that traditional cleanroom garments
made from 100 % polyester can withstand 150 washing
cycles, or 50 washing cycles followed by sterilization in
an autoclave. This has been known for over 25 years.
However, to my knowledge, the end-users or wearers of
cleanroom garments do not perform their own tests to
validate whether or not this is true. Instead, they rely on
the supplier of laundered and in some cases sterilized
garments for this validation.
In a warning letter (FDA) from 2016 (7) the following was
stated:
“In response to this letter, provide an action plan that
describes how your firm will do the following.
Select appropriate gown suppliers. Include the role of
the quality unit in making supplier selection and
ongoing qualification decisions.
Reduce your maximum number of gown sterilizations
to ensure that gowns are discarded before they show
signs of breakdown. Provide the maximum number of
re-sterilizations you will allow and describe how you
will document and validate this procedure.
Correct your visual inspection procedures for sterile
garments to improve detection and rejection of
defective garments.
Ensure that the quality unit makes final decisions
relating to release of raw materials and supplies
(e.g.,garments) you use in production.
Conduct a risk assessment of the effects of damaged
garments on your drugs. “

In two Inspection Reports from FDA from 2017 (8) the

following is stated:

“… the QA department has not validated the number of

cleaning and sterilization cycles through which the
garments and goggles can be processed without
compromising the integrity of the sterile equipment”.
“However, you have not validated the number of cleaning
and sterilization cycles through which the garments can be
processed and are relying on the supplier's
recommendation of cycles.”
These report findings, together with the wording found in
the draft Annex 1 (2017) of the Eudralex, Volume 4, stating
“After washing and before sterilization, garments should be
checked for integrity” confirm that the integrity of
cleanroom garments over time, is quite significant!
The key points are: How is a cleanroom garment to be
integrity tested? Is it even possible to integrity test
cleanroom garments?
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Single-use or re-usable cleanroom garments?

From a quality risk management perspective, the use of re-usable cleanroom garments, that have been
used in operation and washed and sterilized up to 50 times, is a big challenge. The impact of multiple use
in operation, repeated laundering and repeated sterilization will negatively influence the filtering and
barrier performance of re-usable garments. Furthermore, it is impossible to integrity-test cleanroom
garments individually, in order to confirm the protective ability of the garment, due to lack of practically
approved technologies, as well as time constraints.

Single-use garments do not suffer from these drawbacks, since these are only washed and sterilized
once, and discarded after use. From a historical point of view, when facing the option of selecting single-
use versus re-usable garments, re-usable garments where often the simpler choice, due to lack of good
enough alternatives. However, from a quality risk management perspective, together with the wording
stated in draft Annex 1 (2017), from a patient risk perspective, single-use garments might be a better
and much safer option in Grade B/A in the future.

The raw material used in single-use cleanroom garments as well as the preparation of the garment,
should be produced under controlled conditions, and the garment must offer consistent properties.

What differentiates single-use from re-usable cleanroom garments is that these garments are only used
once, and subjected to washing and subsequent sterilization only one time. Therefore, when using
single-use garments, the impact of repeated use, repeated washing as well as repeated sterilization are
not issues.

End-user responsibility for the future

Until now, many end-users have been relying on the recommendations of their supplier regarding the
use of re-usable cleanroom garments. When working with aseptic production in Grade B cleanrooms
and Grade A clean zones, this will be a challenge for the future. Contamination Control Strategy – CCS,
which is the holistical evidence, including the scientifically based validations obtained through QRM,
shows that the operation is in total control. In this context, suppliers’ recommendations will not be
good enough.

The end-user must therefore put much stronger demands on their supplier for validation data, and not
only rely on their recommendations. The challenge for re-useable cleanroom garments is to give proof
of the performance during its full life cycle. Today the life cycle of re-usable garments is much too long.

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 Summary and thought
Cleanroom garments have been used for many years, without much
adaption to general developments in the industry. Patient safety is
the main objective when producing medicinal products and medical
devices, and this emphasizes the need to keep operators as far away
from the product and the process as possible. As suggested in draft
Annex 1, the patient safety objective is obtained by increasing use of
isolators, closed process systems and RABS (Restricted Access
Barrier Systems).

In some cases, this development will result in use of cleanrooms

with lower cleanliness grades; but in many cases, Grade A and Grade
B will still be used with operators present. Cleanroom garments will
be needed in the future to a high extent. The performance demands
on cleanroom garments will increase, in order to provide the
ultimate and necessary patient safety. Re-usable cleanroom
garments pose a major risks to patient safety, since the repeated
use, wash and sterilization of textile garments is not fully validated
throughout the entire value-chain and lifecycle. Suppliers
recommendations, without validation, is not enough.

Operator comfort will be of great importance even in the future.

Therefore, end-users must, not only specify garment performance
from a barrier point of view, but also include operator comfort in
their User Requirement Specification – URS.

Conclusion
As stated in the introduction, the purpose of this article to serve as a
basis of discussion. Moreover, this article is intended to be a “wake-
up call”, especially for businesses working with aseptic production,
since there is no terminal sterilization of the product before patient
use. Cleanroom garments play a critical role in this context.

From a QRM – Quality Risk Management and a CCS - Contamination

Control Strategy point of view, end-users must demand scientifically
based validation and testing data from their suppliers of re-usable
cleanroom garments or consider using single-use cleanroom
garments as the alternative to ensure the safety of the patient.

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 References

1. Lieberman, A. (1992) “Contamination Control and

Cleanrooms – Problems, Engineering Solutions and
Applications”, Van Nostrand Reinhold, New York, USA
2. Ramstorp, M. (2000) “Introduction to Contamination
Control and Cleanroom Technology”, Wiley-VCH, Weinheim,
Germany
3. Austin, R.P. and Timmerman, S.W. (1965) “Design and
Operation of Cleanrooms”, Business News Publishing Co.,
Detroit, USA
4. The Role Governing Medicinal Products in the European
Union, Volume 4 – Guidelines for Good Manufacturing
Practice for medicinal Products for Human and Veterinary
Use, “Annex 1 – Manufacture of Sterile Medicinal Products”
(2008), the European Commission, Brussels, Belgium
5. The Role Governing Medicinal Products in the European
Union, Volume 4 – Guidelines for Good Manufacturing
Practice for medicinal Products for Human and Veterinary
Use, “Draft Annex 1 – Manufacture of Sterile Medicinal
Products” (2017), the European Commission, Brussels,
Belgium
6. “Garment System Considerations for Cleanrooms and
other Controlled Environments”, IEST-RP-CC-003.4 (2011),
Institute of Environmental Sciences and technologies (IEST),
Schaumburg, USA
7. FDA Warning Letter, https://www.fda.gov/inspections-
compliance-enforcement-and-criminal-
investigations/warning-letters/wockhardt-ltd-495920-
12232016
8. FDA.org

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journal, PHSS cannot accept any responsibility for the accuracy
of the advice or information in the journal. Statements and
opinions expressed in the articles and communications are those
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