SIST EN 17141:2020
(Main)Cleanrooms and associated controlled environments - Biocontamination control
Cleanrooms and associated controlled environments - Biocontamination control
This European Standard establishes the principles and basic methodology of a formal system of biocontamination control in Cleanrooms and associated controlled environments. These principles are based on establishing control and then on demonstrating control.
This standard specifies the methods required for assessing risk monitoring risk zones in a consistent way and for applying control measures appropriate to the degree of risk involved.
It will also give guidance on the assessment and verification of microbiological sampling devices, with the aim of helping users standardize their monitoring so that results from one facility to another can be compared.
Within this standard, only microbiological hazards are addressed.
There is specific guidance given on common applications, including Food, Hospitals and Life Sciences (Pharma/Biopharma and Medical Devices).
Reinräume und zugehörige Reinraumbereiche - Biokontaminationskontrolle
Dieses Dokument legt die Anforderungen, Empfehlungen und Methodiken für die mikrobiologische Kontaminationskontrolle in auf Sauberkeit kontrollierten Bereichen fest. Darüber hinaus legt dieses Dokument die Anforderungen an die Erstellung und den Nachweis der mikrobiologischen Kontrolle in auf Sauberkeit kontrollierten Bereichen fest.
Dieses Dokument beschränkt sich auf lebensfähige mikrobiologische Kontamination und schließt alle Betrachtungen endotoxiner, proteinös-infektiöser und viraler Kontamination aus.
Es bestehen spezifische Leitfäden zu gemeinsamen Anwendungen, einschließlich Pharma/Biopharma, Medizinprodukte, Krankenhäuser und Lebensmittel.
Salles propres et environnements maîtrisés apparentés - Maîtrise de la biocontamination
La présente Norme européenne établit les principes et la méthodologie de base d’un système formalisé de maîtrise de la biocontamination dans les salles propres et les environnements maîtrisés apparentés. Ces principes s’appuient sur l’établissement et la démonstration d’une telle maîtrise.
La présente Norme spécifie les méthodes requises pour évaluer les risques, assurer une surveillance cohérente des zones à risque et appliquer les mesures de contrôle adaptées au niveau de risque concerné.
Elle fournit également des préconisations concernant l’évaluation et la vérification des dispositifs d’échantillonnage microbiologique, en vue d’aider les utilisateurs à normaliser leur surveillance de manière à faciliter la comparaison entre deux installations.
La présente Norme ne traite toutefois que des dangers microbiologiques.
Elle fournit des préconisations spécifiques concernant certaines applications courantes, comme l’agroalimentaire, les services hospitaliers et les sciences de la vie (pharmaceutique/ biopharmaceutique et dispositifs médicaux).
Čiste sobe in podobna nadzorovana okolja - Kontrola biokontaminacije
General Information
Relations
Buy Standard
Standards Content (Sample)
SLOVENSKI STANDARD
SIST EN 17141:2020
01-november-2020
Nadomešča:
SIST EN ISO 14698-1:2004
SIST EN ISO 14698-2:2004
SIST EN ISO 14698-2:2004/AC:2007
Čiste sobe in podobna nadzorovana okolja - Kontrola biokontaminacije
Cleanrooms and associated controlled environments - Biocontamination control
Reinräume und zugehörige Reinraumbereiche - Biokontaminationskontrolle
Salles propres et environnements maîtrisés apparentés - Maîtrise de la biocontamination
Ta slovenski standard je istoveten z: EN 17141:2020
ICS:
13.040.35 Brezprašni prostori in Cleanrooms and associated
povezana nadzorovana controlled environments
okolja
SIST EN 17141:2020 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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SIST EN 17141:2020
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SIST EN 17141:2020
EN 17141
EUROPEAN STANDARD
NORME EUROPÉENNE
August 2020
EUROPÄISCHE NORM
ICS 13.040.35
English Version
Cleanrooms and associated controlled environments -
Biocontamination control
Salles propres et environnements maîtrisés apparentés Reinräume und zugehörige Reinraumbereiche -
- Maîtrise de la biocontamination Biokontaminationskontrolle
This European Standard was approved by CEN on 4 November 2019.
CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this
European Standard the status of a national standard without any alteration. Up-to-date lists and bibliographical references
concerning such national standards may be obtained on application to the CEN-CENELEC Management Centre or to any CEN
member.
This European Standard exists in three official versions (English, French, German). A version in any other language made by
translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC Management
Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and
United Kingdom.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2020 CEN All rights of exploitation in any form and by any means reserved Ref. No. EN 17141:2020 E
worldwide for CEN national Members.
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SIST EN 17141:2020
EN 17141:2020 (E)
Contents Page
European foreword . 5
Introduction . 6
1 Scope . 8
2 Normative references . 8
3 Terms and definitions . 8
4 Establishment of microbiological control . 11
4.1 General . 11
4.2 Establishing a formal system for microbiological control . 11
4.3 Microbiological contamination control system quality attributes . 12
4.4 Identification of all potential sources and routes of microbiological contamination . 12
4.4.1 General . 12
4.4.2 Sources of microbiological contamination . 13
4.4.3 Routes of transfer of microbiological contamination . 13
4.5 Risk assessment . 14
4.6 Establishment of microbiological environmental monitoring plan . 14
4.6.1 General . 14
4.6.2 Monitoring locations . 14
4.6.3 Monitoring frequencies . 14
4.7 Establishment of alert and action limits . 15
4.8 Establishment of documentation system . 15
4.9 Personnel education and training . 15
5 Demonstration of microbiological control . 16
5.1 Trending . 16
5.2 Verification of the formal microbiological control system . 16
5.2.1 General . 16
5.2.2 Out of specification (OOS) investigation . 16
5.2.3 Records . 16
5.2.4 Sample tracking . 17
5.2.5 Integrity of results . 17
5.2.6 Data recording . 17
5.2.7 Data evaluation . 17
5.2.8 Trend analysis . 18
6 Microbiological measurement methods . 18
6.1 General . 18
6.2 Choice of sampling method. 18
6.3 Volumetric air samplers . 19
6.4 Culture media and incubation . 19
6.5 Incubators . 19
Annex A (informative) Guidance for life science pharmaceutical and biopharmaceutical
applications . 20
A.1 Introduction . 20
A.2 Risk/impact assessment . 21
A.3 Demonstrating control . 21
Annex B (informative) Guidance for life science medical device applications . 22
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B.1 Introduction . 22
B.2 Risk assessment . 22
B.2.1 General . 22
B.2.2 Example 1: Sterile - terminal sterilisation is possible from a packaged product . 24
B.2.3 Example 2: Sterile – No terminal sterilisation is possible due to product properties . 25
B.2.4 Example 3: Non-sterile products . 25
B.3 Establishing Microbiological Control . 26
B.3.1 Microbiological contamination limits . 26
B.3.2 Additional microbiological control considerations . 27
B.4 Demonstrating microbiological control . 27
B.4.1 Enumeration as part of measurement methods (Clause 6) . 27
B.4.2 Methods for sampling . 27
B.4.3 Microbiological Environmental Monitoring (EM) plan . 27
B.5 Other informative annexes for Medical Device applications . 29
Annex C (informative) Guidance for healthcare/hospital applications . 30
C.1 Introduction . 30
C.2 Establishing control in a healthcare/hospital application . 30
C.3 Risk assessment for operating room hospital applications . 30
Annex D (informative) Guidance for food applications . 31
D.1 Introduction . 31
D.2 Establishment of microbiological control . 31
D.3 Microbiological cleanliness levels for monitoring . 32
D.4 Demonstration of microbiological control . 33
D.5 Example for food manufacture . 33
Annex E (informative) Guidance on culture based microbiological measurement methods
and sampler verification . 35
E.1 General . 35
E.2 Air sampling . 35
E.2.1 Volumetric air samplers. 35
E.2.2 Settle plates. 37
E.3 Surface sampling . 37
E.3.1 General . 37
E.3.2 Contact plates and strips . 37
E.3.3 Swabs and sponges . 38
E.4 Microbiological growth media . 38
E.4.1 General . 38
E.4.2 Media suitability (media sterility and ability to support growth) . 38
E.4.3 Media dehydration . 39
E.4.4 Media disinfectant inhibition . 39
E.4.5 Plate incubation . 39
E.5 Validation of air samplers . 39
E.5.1 General . 39
E.5.2 Physical collection efficiency. 39
E.5.3 Biological collection efficiency . 40
E.6 Experimental method . 40
E.6.1 Aerosol chamber method . 40
E.6.2 Simplified laboratory method . 42
E.6.3 Incubation . 43
E.6.4 Collection efficiency calculations from testing results . 43
E.6.5 Air sampler revalidation . 44
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Annex F (informative) Rapid microbiological methods (RMM) and alternative real time
microbiological detection methods (AMMs) . 45
F.1 General . 45
F.2 Implementation of RMMs and AMMs . 45
F.3 Validation of RMMs and AMMs . 46
F.3.1 General . 46
F.3.2 Acceptance criteria considerations . 47
F.3.3 Verification test execution considerations . 47
F.4 Action and alert levels . 47
F.4.1 Setting action and alert levels . 47
F.4.2 Result outside of action and alert levels . 47
Bibliography . 48
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EN 17141:2020 (E)
European foreword
This document (EN 17141:2020) has been prepared by Technical Committee CEN/TC 243 “Cleanroom
technology”, the secretariat of which is held by BSI.
This European Standard shall be given the status of a national standard, either by publication of an
identical text or by endorsement, at the latest by February 2021, and conflicting national standards
shall be withdrawn at the latest by February 2021.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
This document supersedes EN ISO 14698-1:2003, EN ISO 14698-2:2003 and
EN ISO 14698-2:2003/AC:2006.
According to the CEN-CENELEC Internal Regulations, the national standards organisations of the
following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria,
Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of
North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and the
United Kingdom.
5
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EN 17141:2020 (E)
Introduction
Clean controlled environments are used to control and limit microbiological contamination where there
is a risk to product quality, patient or consumer.
In this document the term “clean controlled environments” is used to cover cleanrooms, clean zones,
controlled zones, clean areas and clean spaces.
This document gives guidance on best practice for establishing and demonstrating control of airborne
and surface microbiological contamination in clean controlled environments. This document describes
the requirements for microbiological contamination control and provides guidance on the qualification
and verification of clean controlled environments.
In order to establish microbiological control, it is important to understand the risks of microbiological
contamination. This is achieved by considering the sources of microbiological contamination, the
associated microbiological concentrations and the likelihood of transfer and the impact on product
quality, the patient or the consumer.
A formal system of microbiological control identifies, controls and monitors microbiological
contamination on an ongoing basis. This is a process of continuous improvement and the principles of
Plan – Do – Check – Act (PDCA) apply, as shown in Figure 1.
Figure 1 — Application of PDCA as the system for microbiological control
This document provides general guidance and considerations for a number of different applications. It
is expected to have particular use in the Pharmaceutical, Biopharmaceutical, Medical Devices and other
Life Science industries, as well as in Healthcare and Hospitals, Food, and related applications which use
clean controlled environments.
In the regulated Pharmaceutical and Biopharmaceutical manufacturing sector there are already many
applicable standards and regulatory guidelines. These include the EU Annex 1 GMP [31] guidance on the
manufacture of Sterile Medicinal products and the FDA Aseptic Processing guidance [32]. The European
and United States Pharmacopoeias also provide some guidance on certain related topics. There are
numerous other documents and technical papers available from industry associations including the
Parenteral Drugs Association (PDA), International Society of Pharmaceutical Engineering (ISPE) and
Pharmaceutical Healthcare Sciences Society (PHSS). While there are regulations and standards on risk
management of medical devices, for example EN ISO 14971 [2], there is less guidance on the
microbiological control of clean controlled environments.
In the Healthcare and Hospital sector there are EU Directives, including the Tissue and Blood Directives
for specialist and similar clean controlled environments. There are national standards and guidelines
for specialised Operating Theatres, Isolation units, Immuno-compromised wards as part of infection
6
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EN 17141:2020 (E)
control. In addition, Hospital Pharmacy aseptic compounding units, Radiopharmacies and specialist
laboratories such as Stem Cell typically refer to Life Science industry guidance documents.
In the Food and consumer related industries, while there are regulations and standards on food,
beverages and cosmetics for example there is insufficient guidance regarding microbiological control in
clean controlled environments.
This document includes a number of informative annexes that provide further guidance on
biocontamination control in specific applications, and includes, for example:
— tables of microbiological cleanliness levels for monitoring of microbiological contamination in
certain types of clean controlled environments;
— guidance in specific areas of microbiological control relating to the choice of environmental
monitoring (EM) sampling methods, the management and trending of collected data and the role of
alternative and real time microbiological detection systems;
— appropriate methods for establishing control, selecting appropriate alert and action levels and
target levels as necessary;
— establishing a microbiological environmental monitoring plan as part of demonstrating control of
the clean controlled environment.
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1 Scope
This document establishes the requirements, recommendations and methodology for microbiological
contamination control in clean controlled environments. It also sets out the requirements for
establishing and demonstrating microbiological control in clean controlled environments.
This document is limited to viable microbiological contamination and excludes any considerations of
endotoxin, prion and viral contamination.
There is specific guidance given on common applications, including Pharmaceutical and
BioPharmaceutical, Medical Devices, Hospitals and Food.
2 Normative references
The following document is referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
EN ISO 14644-1:2015, Cleanrooms and associated controlled environments — Part 1: Classification of air
cleanliness by particle concentration (ISO 14644-1:2015)
3 Terms and definitions
For the purposes of this document, biocontamination control and microbiological control are
synonymous, and the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia. available at http://www.electropedia.org/
— ISO Online browsing platform: available at http://www.iso.org/obp
3.1
action level
level set by the user in the context of controlled environments, which, when exceeded, requires
immediate intervention, including investigation of cause, and corrective action
3.2
alert level
level set by the user in the context of controlled environments, giving early warning of a drift from
normal conditions, which, when exceeded, should result in increased attention to the process
3.3
clean controlled environment
defined zone in which microbiological contamination is controlled by specified means
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3.4
cleanroom
room within which the number concentration of airborne particles is controlled and classified, and
which is designed, constructed and operated in a manner to control the introduction, generation, and
retention of particles inside the room
Note 1 to entry: The class of airborne particle concentration is specified.
Note 2 to entry: Levels of other cleanliness attributes such as chemical, viable or nanoscale concentrations in
the air, and also surface cleanliness in terms of particle, nanoscale, chemical and viable concentrations may also be
specified and controlled.
Note 3 to entry: Other relevant physical parameters may also be controlled as required, e.g. temperature,
humidity, pressure, vibration and electrostatic.
[SOURCE: EN ISO 14644-1:2015, 3.1.1, [1]]
3.5
clean zone
defined space within which the number concentration of airborne particles is controlled and classified,
and which is constructed and operated in a manner to control the introduction, generation, and
retention of contaminants inside the space
Note 1 to entry: The class of airborne particle concentration is specified.
Note 2 to entry: Levels of other cleanliness attributes such as chemical, viable or nanoscale concentrations in
the air, and also surface cleanliness in terms of particle, nanoscale, chemical and viable concentrations may also be
specified and controlled.
Note 3 to entry: A clean zone(s) may be a defined space within a cleanroom or may be achieved by a separative
device. Such a device may be located inside or outside a cleanroom.
Note 4 to entry: Other relevant physical parameters may also be controlled as required, e.g. temperature,
humidity, pressure, vibration and electrostatic.
[SOURCE: EN ISO 14644-1:2015, 3.1.2, [1]]
3.6
colony forming unit
formation of a single macroscopic colony after the introduction of one or more microorganisms to
microbiological growth media
Note 1 to entry: One colony forming unit is expressed as 1 cfu.
3.7
critical control point
specific point, procedure, or step in the process at which control can be exercised to reduce, eliminate,
or prevent the possibility of microbiological contamination
3.8
critical zone
designated space within the clean controlled environment used to control microbiological
contamination
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3.9
culturable
having the ability to grow and form colony forming units (cfu), using microbiological culturing
techniques
3.10
environmental monitoring
EM
measurement of specified parameters at periodic intervals within a clean controlled environment
3.11
microorganism
entity of microscopic size encompassing bacteria fungi protozoa and viruses
Note 1 to entry: Microbe is synonymous with microorganism.
Note 2 to entry: The use of the term microorganism in this standard includes bacteria, yeast and moulds only.
[SOURCE: ISO 17665-1:2006, 3.25, [50]]
3.12
microorganism of interest
microbiological contamination
...
SLOVENSKI STANDARD
oSIST prEN 17141:2018
01-november-2018
ýLVWHVREHLQSRGREQDQDG]RURYDQDRNROMD.RQWURODELRNRQWDPLQDFLMH
Cleanrooms and associated controlled environments - Biocontamination control
Reinräume und zugehörige Reinraumbereiche - Biokontaminationskontrolle
Salles propres et environnements maîtrisés apparentés - Maîtrise de la biocontamination
Ta slovenski standard je istoveten z: prEN 17141
ICS:
13.040.35 Brezprašni prostori in Cleanrooms and associated
povezana nadzorovana controlled environments
okolja
oSIST prEN 17141:2018 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN 17141:2018
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oSIST prEN 17141:2018
DRAFT
EUROPEAN STANDARD
prEN 17141
NORME EUROPÉENNE
EUROPÄISCHE NORM
September 2018
ICS 13.040.35
English Version
Cleanrooms and associated controlled environments -
Biocontamination control
Salles propres et environnements maîtrisés apparentés Reinräume und zugehörige Reinraumbereiche -
- Maîtrise de la biocontamination Biokontaminationskontrolle
This draft European Standard is submitted to CEN members for second enquiry. It has been drawn up by the Technical
Committee CEN/TC 243.
If this draft becomes a European Standard, CEN members are bound to comply with the CEN/CENELEC Internal Regulations
which stipulate the conditions for giving this European Standard the status of a national standard without any alteration.
This draft European Standard was established by CEN in three official versions (English, French, German). A version in any other
language made by translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC
Management Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and United Kingdom.
Recipients of this draft are invited to submit, with their comments, notification of any relevant patent rights of which they are
aware and to provide supporting documentation.
Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without
notice and shall not be referred to as a European Standard.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2018 CEN All rights of exploitation in any form and by any means reserved Ref. No. prEN 17141:2018 E
worldwide for CEN national Members.
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oSIST prEN 17141:2018
prEN 17141:2018 (E)
Contents Page
European foreword . 6
Introduction . 7
1 Scope . 9
2 Normative references . 9
3 Terms and definitions . 9
4 Establishment of microbiological control . 12
4.1 General . 12
4.2 Establishing a formal system for microbiological control . 12
4.3 Microbiological contamination control system quality attributes . 12
4.4 Identification of all potential sources and routes of microbiological contamination . 13
4.4.1 General . 13
4.4.2 Routes of transfer and sources of microbiological contamination . 14
4.4.3 Routes of transfer of microbiological contamination . 14
4.5 Risk assessment . 14
4.6 Establishment of microbiological environmental monitoring plan . 15
4.6.1 General . 15
4.6.2 Monitoring locations . 16
4.6.3 Monitoring frequencies . 16
4.7 Establishment of alert and action limits . 16
4.8 Establishment of documentation system . 17
4.9 Personnel education and training . 17
5 Demonstration of Microbiological Control . 17
5.1 Trending . 17
5.2 Verification of the formal microbiological control system . 17
5.2.1 General . 17
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5.2.2 Out of specification (OOS) investigation . 18
5.2.3 Records . 18
5.2.4 Sample tracking . 18
5.2.5 Integrity of results . 18
5.2.6 Data recording . 18
5.2.7 Data evaluation . 19
5.2.8 Trend analysis . 19
6 Microbiological measurement methods. 20
6.1 General . 20
6.2 Choice of sampling method . 20
6.3 Volumetric air samplers. 20
6.4 Culture media and incubation . 20
6.5 Incubators . 21
Annex A (informative) Guidance for life science pharma/biopharma applications . 22
A.1 Introduction . 22
A.2 Risk/impact assessment . 23
A.3 Demonstrating control . 23
Annex B (informative) Guidance for life science medical device applications . 25
B.1 Introduction . 25
B.2 Risk assessment . 25
B.2.1 General . 25
B.2.2 Example 1: Sterile - terminal sterilisation is possible from a packaged product . 27
B.2.3 Example 2: Sterile – No terminal sterilisation is possible due to product properties, . 28
B.2.4 General . 28
B.2.5 Example 3: Non-sterile products . 28
B.3 Establishing Microbiological Control . 29
B.3.1 Microbiological contamination limits . 29
B.3.2 Additional microbiological control considerations . 30
3
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B.4 Demonstrating microbiological control . 30
B.4.1 Enumeration as part of measurement methods (Clause 6) . 30
B.4.2 Monitoring using air sampling . 30
B.4.3 Microbiological Environmental Monitoring (EM) plan - Number of measuring
locations . 30
B.5 Other informative annexes for Medical Device applications . 31
Annex C (informative) Guidance for healthcare/hospital applications . 32
C.1 Introduction . 32
C.2 Establishing control in a healthcare/hospital application . 32
C.3 Risk assessment for Operating Room hospital applications . 32
Annex D (informative) Guidance for food applications . 34
D.1 Introduction . 34
D.2 Establishment of microbiological control . 34
D.3 Microbiological Cleanliness Levels for Monitoring . 35
D.4 Demonstration of microbiological control . 36
D.5 Example for food manufacture . 37
Annex E (informative) Guidance on culture based microbiological measurement methods
and sampler verification . 39
E.1 General . 39
E.2 Air sampling . 39
E.2.1 Volumetric air samplers . 39
E.2.2 Settle plates . 41
E.3 Surface sampling . 41
E.3.1 General . 41
E.3.2 Contact plates and strips . 41
E.3.3 Swabs and sponges . 42
E.4 Microbiological growth media . 42
E.4.1 General . 42
E.4.2 Media sterility and fertility . 42
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E.4.3 Media dehydration . 42
E.4.4 Media disinfectant inhibition . 43
E.4.5 Media incubation . 43
E.5 Incubators . 43
E.6 Validation of air samplers . 43
E.6.1 General . 43
E.6.2 Physical collection efficiency. 43
E.6.3 Biological collection efficiency . 44
E.7 Experimental method . 44
E.7.1 Aerosol chamber method . 44
E.7.2 Air sampler revalidation . 47
Annex F (informative) Rapid microbiological methods (RMM) and alternative real time
microbiological detection methods (AMMs). 48
F.1 General . 48
F.2 Implementation of RMMs and AMMs . 48
F.3 Validation of RMMs and AMMs . 49
F.3.1 General . 49
F.3.2 Acceptance criteria considerations . 49
F.3.3 Verification test execution considerations . 50
F.4 Action and alert levels . 50
F.4.1 Setting action and alert levels . 50
F.4.2 Result outside of action and alert levels . 50
Bibliography . 51
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prEN 17141:2018 (E)
European foreword
This document (prEN 17141:2018) has been prepared by Technical Committee CEN/TC 243
“Cleanroom technology”, the secretariat of which is held by BSI.
This document is currently submitted to the second CEN Enquiry.
The first Enquiry was approved in September 2017 but with such a large number of comments and
recommendations relating to both the content and structure of the standard it was decided to prepare a
second publication in response.
6
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oSIST prEN 17141:2018
prEN 17141:2018 (E)
Introduction
Clean controlled environments are used to control and limit microbiological contamination where there
is a risk to product quality, patient or consumer.
In this standard the term “clean controlled environments” is used to cover cleanrooms, clean zones,
controlled zones, clean areas and clean spaces.
This standard gives guidance on best practice for establishing and demonstrating control of airborne
and surface microbiological contamination in clean controlled environments. This standard describes
the requirements for microbiological contamination control and provides guidance on the qualification
and verification of clean controlled environments.
In order to establish microbiological control, it is necessary to understand the risks of microbiological
contamination. This is achieved by considering the sources of microbiological contamination, the
associated microbiological concentrations and the likelihood of transfer and the impact on product
quality, the patient or the consumer.
A formal system of microbiological control identifies, controls and monitors microbiological
contamination on an ongoing basis. This is a process of continuous improvement and the principles of
Plan – Do – Check – Act (PDCA) apply, as shown in Figure 1.
Figure 1 — Application of PDCA as the system for microbiological control
This standard provides general guidance and considerations for a number of different applications. It is
expected to have particular use in the Pharmaceutical, Biopharmaceutical, Medical Devices and other
Life Science industries, as well in Healthcare and Hospitals, Food, and related applications which use
clean controlled environments.
In the regulated Pharmaceutical and Biopharmaceutical manufacturing sector there are already many
applicable standards and regulatory guidelines. These include the EU PIC/S Annex 1 GMP guidance
documents on the manufacture Sterile Medicinal products, the FDA Aseptic Processing guidance
document and the WHO GMP guidance on good manufacturing practice. The European and United
States Pharmacopoeias also provide some guidance on certain related topics. And there are numerous
other documents and technical papers available from industry associations including the PDA, ISPE and
PHSS. While there are regulations and standards on risk management of medical devices, for example
EN ISO 14971, there is less guidance on the microbiological control of clean controlled environments.
In the Healthcare and Hospital sector there are EU Directives, including the Tissue and Blood Directives
for specialist Labs and similar clean controlled environments. There are national standards and
guidelines for specialised Operating Theatres, Isolation units, Immuno-compromised wards as part of
infection control. In addition, Hospital Pharmacy aseptic compounding units, Radiopharmacies and
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specialist laboratories such as Stem Cell Labs typically refer to Life Science industry guidance
documents.
In the Food and consumer related industries, while there are regulations and standards on food,
beverages and cosmetics for example there is insufficient guidance regarding microbiological control in
clean controlled environments.
Informative annexes give tables of microbiological cleanliness levels for monitoring of microbiological
contamination in certain types of clean controlled environments. Other informative annexes offer
additional guidance in specific areas of microbiological control relating to the choice of environmental
monitoring (EM) sampling methods, the management and trending of collected data and the role of
alternative and real time microbiological detection systems, as well as guidance on appropriate
methods for establishing control, selecting appropriate alert and action levels and establishing a
microbiological environmental monitoring plan as part of demonstrating control of the clean controlled
environment.
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1 Scope
This document establishes the requirements, recommendations and methodology for microbiological
contamination control in clean controlled environments. It also sets out the requirements for
establishing and demonstrating microbiological control in clean controlled environments.
This document is limited to viable microbiological contamination and excludes any considerations of
endotoxin, prion and viral contamination.
There is specific guidance given on common applications, including Pharma/BioPharma, Medical
Devices, Hospitals and Food.
2 Normative references
The following document is referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
EN ISO 14644-1, Cleanrooms and associated controlled environments — Part 1: Classification of air
cleanliness by particle concentration (ISO 14644-1:2015)
3 Terms and definitions
For the purposes of this document, biocontamination control and microbiological control are
synonymous, and the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia. available at http://www.electropedia.org/
— ISO Online browsing platform: available at http://www.iso.org/obp
3.1
aseptic
conditions and procedures used to exclude the introduction of microbial microbiological contamination
[SOURCE: ISO 14161:2009]
3.2
clean controlled environment
defined zone in which microbiological contamination is controlled by specified means
3.3
cleanroom
room within which the number concentration of airborne particles is controlled and classified, and
which is designed, constructed and operated in a manner to control the introduction, generation, and
retention of particles inside the room
Note 1 to entry: The class of airborne particle concentration is specified.
Note 2 to entry: Levels of other cleanliness attributes such as chemical, viable or nanoscale concentrations in
the air, and also surface cleanliness in terms of particle, nanoscale, chemical and viable concentrations may also be
specified and controlled.
Note 3 to entry: Other relevant physical parameters may also be controlled as required, e.g. temperature,
humidity, pressure, vibration and electrostatic.
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[SOURCE: ISO 14644-1:2015, 3.1.1]
3.4
clean zone
defined space within which the number concentration of airborne particles is controlled and classified,
and which is constructed and operated in a manner to control the introduction, generation, and
retention of contaminants inside the space
Note 1 to entry: The class of airborne particle concentration is specified.
Note 2 to entry: Levels of other cleanliness attributes such as chemical, viable or nanoscale concentrations in
the air, and also surface cleanliness in terms of particle, nanoscale, chemical and viable concentrations may also be
specified and controlled.
Note 3 to entry: A clean zone(s) may be a defined space within a cleanroom or may be achieved by a separative
device. Such a device may be located inside or outside a cleanroom.
Note 4 to entry: Other relevant physical parameters may also be controlled as required, e.g. temperature,
humidity, pressure, vibration and electrostatic.
[SOURCE: ISO 14644-1:2015, 3.1.2]
3.5
colony forming unit
formation of a single macroscopic colony after the introduction of one or more microorganisms to
microbiological growth media
Note 1 to entry: One colony forming unit is expressed as 1 cfu.
3.6
controlled zone
designated space in which the concentration of at least one contamination category (particles, chemical,
biocontamination) in air and/or on surfaces is controlled and specified and which is constructed and
used in a manner to minimize the introduction and impact of contamination
Note 1 to entry: Levels of cleanliness attributes such as viable concentrations in the air or cleanliness in terms
of particle and viable concentrations on surfaces may be specified by class(es).
Note 2 to entry: Other relevant parameters may also be controlled as necessary, e.g. temperature, humidity and
pressure, vibration and electrostatic.
Note 3 to entry: A controlled zone can be a defined space within a cleanroom or may be achieved by a
separative device, such a device may be located inside or outside a cleanroom.
Note 4 to entry: The term biocontamination is synonymous with microbiological contamination.
[SOURCE: ISO 14644-15:2017, 3.9.]
3.7
critical control point
specific point, procedure, or step in the process at which control can be exercised to reduce, eliminate,
or prevent the possibility of microbiological contamination
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3.8
critical zone
designated space within the clean controlled environment used to control microbiological
contamination
3.9
culturable
having the ability to grow and form colony forming units, using microbiological culturing techniques
3.10
environmental monitoring, EM
measurement of specified parameters at periodic intervals within a clean controlled environment
Note 1 to entry: Environmental monitoring can include measurements such as particle counts and
microbiological sampling methods such as airborne, settle plates, swabs, etc.
3.11
microorganism
entity of microscopic size encompassing bacteria fungi protozoa and viruses
Note 1 to entry: Microbes is synonymous with microorganism.
Note 2 to entry: The use of the term microorganism in
...
SLOVENSKI STANDARD
oSIST prEN 17141:2017
01-september-2017
ýLVWHVREHLQSRGREQDQDG]RURYDQDRNROMD.RQWURODELRNRQWDPLQDFLMH
Cleanrooms and associated controlled environments - Biocontamination control
Reinräume und zugehörige Reinraumbereiche - Biokontaminationskontrolle
Salles propres et environnements maîtrisés apparentés - Maîtrise de la biocontamination
Ta slovenski standard je istoveten z: prEN 17141
ICS:
13.040.35 Brezprašni prostori in Cleanrooms and associated
povezana nadzorovana controlled environments
okolja
oSIST prEN 17141:2017 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.
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oSIST prEN 17141:2017
DRAFT
EUROPEAN STANDARD
prEN 17141
NORME EUROPÉENNE
EUROPÄISCHE NORM
June 2017
ICS 13.040.35
English Version
Cleanrooms and associated controlled environments --
Biocontamination control
Salles propres et environnements maîtrisés apparentés Reinräume und zugehörige Reinraumbereiche -
- Maîtrise de la biocontamination Biokontaminationskontrolle
This draft European Standard is submitted to CEN members for enquiry. It has been drawn up by the Technical Committee
CEN/TC 243.
If this draft becomes a European Standard, CEN members are bound to comply with the CEN/CENELEC Internal Regulations
which stipulate the conditions for giving this European Standard the status of a national standard without any alteration.
This draft European Standard was established by CEN in three official versions (English, French, German). A version in any other
language made by translation under the responsibility of a CEN member into its own language and notified to the CEN-CENELEC
Management Centre has the same status as the official versions.
CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, Former Yugoslav Republic of Macedonia, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania,
Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland,
Turkey and United Kingdom.
Recipients of this draft are invited to submit, with their comments, notification of any relevant patent rights of which they are
aware and to provide supporting documentation.
Warning : This document is not a European Standard. It is distributed for review and comments. It is subject to change without
notice and shall not be referred to as a European Standard.
EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION
EUROPÄISCHES KOMITEE FÜR NORMUNG
CEN-CENELEC Management Centre: Avenue Marnix 17, B-1000 Brussels
© 2017 CEN All rights of exploitation in any form and by any means reserved Ref. No. prEN 17141:2017 E
worldwide for CEN national Members.
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Contents Page
European foreword . 7
Introduction . 8
1 Scope . 10
2 Normative references . 10
3 Terms and definitions . 10
4 Establishment of control requirements . 12
4.1 Formal system of microbiological control . 12
4.2 Formal system quality attributes . 12
4.3 Impact assessment . 12
4.4 Verification . 14
4.5 Establishing the formal system . 14
4.5.1 General requirements . 14
4.5.2 Processing of samples . 14
4.5.3 Culturing methods . 15
5 Demonstrating control . 16
5.1 Establishing an environmental monitoring program through impact assessment . 16
5.2 Trending . 17
5.3 Action and alert levels . 17
5.3.1 Setting action and alert levels . 17
5.3.2 Result outside of action/alert . 17
5.4 Sampling (as part of an environmental monitoring plan) . 18
5.4.1 General . 18
5.4.2 Sampling plan . 18
5.4.3 Design of the sampling plan . 18
5.4.4 Frequency of sampling . 19
5.4.5 Sampling sites . 20
5.5 Verification of the formal system . 20
5.5.1 General . 20
5.5.2 Corrective action . 21
5.5.3 Records . 21
5.5.4 Sample tracking . 21
5.5.5 Collection of results . 21
5.5.6 Data recording . 22
5.5.7 Data evaluation . 23
5.6 Verification . 24
5.7 Out-of-specification results . 24
5.8 Verification of results . 25
6 Metrology . 26
6.1 General . 26
6.2 Sampling devices . 26
6.2.1 Processing of samples . 26
6.2.2 General . 26
6.2.3 Selection of a sampling device (impaction) . 26
6.3 Filtration air samplers . 28
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6.4 Liquid impingement air samplers and cyclonic samplers . 28
6.5 Viable surface sampling . 29
6.5.1 Principles . 29
6.5.2 Expression of results . 29
6.5.3 Surface sampling devices . 29
6.6 Settle plates . 30
6.6.1 Principle . 30
6.6.2 Use of settle plates . 30
6.7 Culturing methods of analysis . 30
6.7.1 General . 30
6.7.2 Culture media . 30
6.7.3 Transportation . 31
6.7.4 Incubation . 31
6.7.5 Enumeration . 31
6.7.6 Characterization . 31
6.8 Expression, interpretation and reporting of results . 31
7 Training . 32
7.1 General . 32
7.2 Documentation . 32
Annex A (informative) Guidance for life science pharma/biopharma applications . 33
A.1 Introduction. 33
A.2 Notes on risk/impact assessment . 34
A.3 Notes on establishing control requirements . 34
A.4 Notes on demonstrating control . 34
Annex B (informative) Guidance for life science medical device applications . 35
B.1 Introduction for life science medical device applications . 35
B.2 Impact assessment for life science medical device applications . 36
B.3 Establish control for life science medical device applications . 36
B.4 Demonstrating control for life science medical device applications . 37
B.4.1 General . 37
B.4.2 Processing of samples . 37
B.4.3 Enumeration . 37
B.4.4 Monitoring frequencies (daily/shift, weekly, monthly) as part of establishing
control. 37
B.4.5 Sampling . 37
B.4.6 Environmental monitoring sampling plan - Number of measuring points . 38
B.5 Other informative annexes for life science medical device applications . 38
Annex C (informative) Guidance for healthcare/hospital applications . 39
C.1 Introduction. 39
C.2 Notes on impact/hazard assessment for healthcare application . 39
C.3 Notes on establishing control in a healthcare application . 40
Annex D (informative) Guidance for food applications . 41
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D.1 Introduction . 41
D.2 Establishment of control requirements . 41
D.2.1 Formal system of microflora control . 41
D.2.2 Formal system quality attributes . 41
D.2.3 Risk assessment . 41
D.2.4 Verification . 41
D.3 Establishing the formal system . 42
D.3.1 General requirements . 42
D.3.2 Processing of samples . 42
D.3.3 Culturing methods . 42
D.4 Demonstration of control . 42
D.4.1 General . 42
D.4.2 Trending . 44
D.4.3 Action and alert levels . 44
D.4.4 Sampling . 45
Annex E (informative) Evolving metrology of biocontamination control . 46
E.1 Introduction - Why an organization should consider rapid microbiological methods
(RMM) . 46
E.2 Requirements for validation - an alternative method regarding compendial methods . 46
E.3 Need to establish alert and action levels for the new validated method . 46
E.4 Quantitative rapid methods description . 46
E.4.1 General . 46
E.4.2 Growth dependent rapid methods . 46
E.4.3 Growth independent rapid methods . 50
Annex F (informative) Guidance on determining airborne microbiological levels . 52
F.1 Introduction . 52
F.2 Culturable airborne sampling . 52
F.2.1 Principle . 52
F.2.2 Expression of results . 52
F.3 Culturable surface sampling . 52
F.3.1 Principles . 52
F.3.2 Expression of results . 52
F.4 Settle plates . 53
Annex G (informative) Guidance on verifying samplers used for evaluating airborne
microbiological levels . 54
G.1 Introduction . 54
G.2 Quantifying the physical cut-off size and collection efficiency . 54
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G.2.1 General . 54
G.2.2 Physical efficiency . 54
G.3 Experimental methods . 55
G.3.1 Aerosol chamber method . 55
G.3.2 Simplified laboratory method (PQ) . 57
G.4 Incubation . 58
G.5 Interpretation of results . 58
Annex H (informative) Guidance on determining microbiological contamination of surfaces . 59
H.1 Introduction. 59
H.2 Principles . 59
H.3 Sampling devices . 59
H.3.1 Contact sampling devices . 59
H.3.2 Swabs . 59
H.3.3 Settle plates . 60
H.4 Expression of results . 60
Annex I (informative) Guidance on determining microbiological contamination of textiles . 61
I.1 Introduction. 61
I.2 Principle . 62
I.3 Contact sampling devices . 62
I.4 Expression of results . 62
Annex J (informative) Guidance on verifying laundering processes . 63
J.1 Introduction. 63
J.2 Test method . 63
J.2.1 Principle . 63
J.2.2 Microorganisms. 63
J.2.3 Microbiological suspensions . 64
J.2.4 Control and test pieces . 64
J.2.5 Preparation of the inoculum . 64
J.2.6 Procedure . 65
J.2.7 Interpretation of results . 66
Annex K (informative) Guidance on training . 67
K.1 Introduction. 67
K.2 Elements for standardized training programs . 67
K.2.1 General . 67
K.2.2 Training documents . 67
K.2.3 Training manual . 68
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K.2.4 Microbiological control procedures . 68
K.3 Training verification . 69
K.3.1 General . 69
K.3.2 Assessment tools . 69
K.3.3 Documentation . 69
K.4 Evaluation and interpretation of microbiological contamination data . 70
K.4.1 General . 70
K.4.2 Significance of microbiological contamination . 70
Annex L (informative) Typical sources of microbiological contamination . 71
L.1 Introduction . 71
L.2 People . 71
L.3 Physical conditions of the facility and surrounding environment .
...
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