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A new European standard for Biocontamination Control - EN 17141 will replace

EN ISO 14698 Parts 1 and 2:2003

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Standards

A new European standard for Biocontamination

Control – EN 17141 will replace EN ISO 14698
Parts 1 and 2:2003
Conor Murray and Roland Durner

Abstract to ISO 14644-1:2015 3 by the maximum of the application of ISO 14698 in

Cleanrooms and clean controlled concentration of particles of a given member countries the following
environments are classified based size. For certain critical processes, points with potential for improvement
on airborne particle concentrations. microbiological parameters are also were identified:
Depending on the purpose, further crucial, because biocontamination leads • does not include clear enough
characteristics or contaminants can be to unacceptable quality losses. guidance on risk and impact
considered. Biocontamination plays an Biocontamination control revolves assessments with a focus on the
important role in microbiological control around living micro-organisms, mostly different needs and types of
in many applications in a cleanroom bacteria or fungi that are difficult to applications;
or clean controlled environment. The detect and identify. In addition,
• does not fit into the pattern of the ISO
existing standard for Biocontamination biological contamination can multiply
14644 series, which differentiates
control in cleanrooms and associated itself through growth. For this reason,
between classification and monitoring;
controlled environments, ISO 14698 biocontamination control is a critical
Parts 1 and 2 from 2003, has had limited monitoring parameter, especially in the • does not clearly differentiate
application. The European Committee manufacture of pharmaceuticals, between aseptic and non-sterile
for Standardization (CEN), through an medical devices and combinational applications;
initiative of Technical Committee (TC) products. Biocontamination is life
• does not provide enough help on
CEN/TC 243/WG5 (Working Group 5), threatening in environments that are
airborne versus surface
has been working on revising and not classified as cleanrooms, such as
biocontamination risks and controls;
updating the ISO 14698 standard since operating theatres, intensive care units
2016. The new EN 17141 standard, which and isolation wards in hospitals. These • has unclear boundaries between
is based on this work, will be published are now considered as clean controlled normative and informative sections;
in the summer of 2020. Recently countries environments in the new EN 17141 4
• is, by general consensus, difficult
voted unanimously to withdraw the ISO standard. In food it is pathogens that
to read and use;
14698 Parts 1 and 2 standards as part of are of concern and can cause sickness
the ISO systematic review process. CEN/ and even lead to death without • is presented as two Parts when it
TC 243 is now putting forward EN 17141 immediate treatment. Common sources only needs to be one;
for inclusion in the ISO 14644 family include bacteria such as Campylobacter
• does not reflect the current state of
of standards in order to harmonise the which comes from raw and undercooked
rapid and real-time measurement
approach to contamination control of poultry and other meat, raw milk
technologies.
micro-organisms in air and on surfaces, and untreated water. One of the most
with that of particles and other common causes of foodborne illnesses Between 2009 and 2014, WG2 of
contaminants in air and on surfaces. is Salmonella which comes from raw and ISO/TC 209 found no consensus on
undercooked eggs, undercooked poultry modernising ISO 14698 – yet the need for
Biocontamination control and meat, fresh fruits and vegetables, relevant guidelines on biocontamination
in cleanrooms and clean and unpasteurized dairy products. control remained. That is why CEN
controlled environments TC/243 set up Working Group 5 with a
People are the main source of What is the need for a new clear direction and a task list to complete
biocontamination on both air and or revised standard for as part of revising ISO 14698. In 2016,
surfaces. While technology has developed biocontamination control? a group of European experts in
significantly since ISO 14698 Parts 11 and Since the publication of ISO 14698 microbiology, engineering, and related
22 were published in 2003 and has helped Parts 1 and 2 in 2003, the application scientific disciplines started work under
to limit the number of people and the of a quality risk-based approach has the convenorship of Conor Murray with
intervention of people, the human element become well established, especially the secretariat provided by BSI (British
is unlikely to be replaced completely. in pharmaceutical production and Standards Institution).
Cleanrooms are classified according food processing. Based on a survey

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 Standards

Table 1: Comparison of the existing ISO 14698 parts 1 and 2 with the new EN 17141

Section ISO 14698-1:2003 ISO 14698-2:2003 EN 17141

(2020 expected)
Title Cleanrooms and associated Cleanrooms and associated Cleanrooms and associated
controlled environments - controlled environments - controlled environments -
biocontamination control biocontamination control biocontamination control
Part 1: General principles Part 2: Evaluation and
and methods interpretation of
biocontamination data
Total number of 32 11 51
pages
Normative pages 11 11 19
Introduction General information on the - Classification into higher-level
importance of biocontamination risk management systems and
control in various areas of a PDCA (plan - do - check - act)
application system of continuous
improvement.
Scope Principles and basic methodology Guidance on methods for the This document establishes the
of a formal system of evaluation of microbiological requirements, recommendations
biocontamination control for data and the estimation of and methodology for
assessing and controlling results obtained from sampling microbiological contamination
biocontamination when for viable particles in risk zones control in clean controlled
cleanroom technology is used for biocontamination control. environments. It also sets out the
for that purpose. It should be used, where requirements for establishing and
This part of ISO 14698 specifies appropriate, in conjunction demonstrating microbiological
the methods required for with ISO 14698-1. control in clean controlled
monitoring risk zones in a environments.
consistent way and for applying This document is limited to viable
control measures appropriate to microbiological contamination.
the degree of risk involved. In There is specific guidance given
zones where risk is low, it can be on common applications,
used as a source of information. including Pharmaceutical and
BioPharmaceutical, Medical
Devices, Hospitals and Food.
Excluded scope Application-specific - Any considerations of endotoxin,
requirements; fire and prion and viral contamination.
safety issues
Normative ISO 14644-4: 2001: Cleanrooms ISO 14698-1: 2003: Cleanrooms ISO 14644-1:2015, Cleanrooms and
references and associated controlled and associated controlled associated controlled environments
environments - Part 4: Design, environments - Biocontamination — Part 1: Classification of air
construction, and start-up control – Part 1: General principles cleanliness by particle concentration
ISO 14698-2: 2003: Cleanrooms and and methods
associated controlled environments
- Biocontamination control - Part 2:
Evaluation and interpretation of
biocontamination data
Definitions Added: Micro-organisms of
interest, clean-controlled
environment, culturable
Removed as unnecessary:
bioaerosol, formal system, contact
device, audit trail, data stratification,
estimate, estimation, estimator, as
built, at rest, operational

www.cleanairandcontainment.com Clean Air and Containment Review | Issue 42 | 2020 Number Two 25
Standards

Section ISO 14698-1:2003 ISO 14698-2:2003 EN 17141

(2020 expected)
Normative section Principles of biocontamination Evaluation and interpretation of Establishment of microbiological
control biocontamination data control
Establishing the Formal System Demonstration of microbiological
Expression, interpretation and control
reporting of results Microbiological measurement
Verification of the Formal System methods

ISO 14698-1:2003 EN 17141 (2020 expected)

Annex 22 28
(informative) pages
Annex A Guidance on determining airborne biocontamination. (Moved to Guidance for life science
Normative Section 6 in EN 17141). pharmaceutical and
biopharmaceutical applications
Annex B Guidance on validating air samplers. (Moved to EN 17141 Annex E). Guidance for life science medical
device applications
Annex C Guidance on determining biocontamination of surfaces. (Moved to Guidance for healthcare/hospital
Normative Section 6 in EN 17141 with additional instructions in EN applications
17141 Annex E for culture-based methods and Annex F for Rapid
Microbiological Methods (RMM) and Alternative Microbiological
real-time detection Methods (AMM)).
Annex D Removed: Guidance on determining biocontamination of textiles Guidance for food applications
(Not within the scope of EN 17141 as already addressed in EN
14065:2016)
Annex E Removed: Guidance for validating of laundering processes. (Not Guidance on culture based
within the scope of EN 17141 as already addressed in ISO 14644- microbiological measurement
5:2004). methods and sampler verification
Annex F Removed: Guidance for determining biocontamination of liquids. Rapid microbiological methods
(Not within the scope of EN 17141). (RMM) and alternative
microbiological real-time
detection methods (AMM)
Annex G Removed: Guideline for training. (This is already addressed in many Not used
other standards and guidelines. The importance of training is
highlighted in Normative Section 4.9 in EN 17141).

Working Group 5 task list 5. Provide an overview of various 10. Consider the role and practical use
from CEN/TC 243 industries, including food, life sciences of scientific/technical progress,
This was the list of tasks approved in and healthcare, and deciding whether especially the possible application of
the new work item proposal approved classification tables are possible and AMM/RMM measurement methods.
by the TC: appropriate in each case.
1. Retain the relevant parts of the
6. Develop application-related
existing ISO 14698 Parts 1 and 2. The new EN 17141:2020
checklists of relevant topics
The aim of the standard is to provide the
2. Review and limit scope to remove in biocontamination control.
user with guidelines for first establishing
viruses, prions, endotoxins and
7. Improve the structure to make and then demonstrating microbiological
water based biocontamination
it easier to use the standard and control. For this purpose, the normative
control. The use of the term
improve readability. part adopted the Quality Risk
micro-organism in this standard
Management (QRM) approach of the EU
applies ONLY to bacteria, yeast 8. Include how to set Alert and Action
GMP Annex 1,7 which is currently in
and spores/moulds. limits, where appropriate.
consultation. EN 17141 deals exclusively
3. Include implementation of risk 9. Carry out an independent review with monitoring and not classification,
management and control (including and comparison of alternative since today’s methods only allow indirect
ICH QRM 5 and HAACP 6). real-time microbiological measurements of biocontamination.
measurement methods (AMMs) These are carried out using growth-
4. Follow the principle of first
and rapid microbiological based methods, which result in a delay
establishing and then demonstrating
measurement methods (RMMs) between sampling and results. In
microbiological control
and sampling technology. addition, the sensitivity of the
(environmental monitoring).

26 Clean Air and Containment Review | Issue 42 | 2020 Number Two www.cleanairandcontainment.com
 Standards

measurement is not remarkably high, an effective environmental monitoring as part of a harmonised approach to
since not all viable germs can be program for biocontamination control in contamination control in cleanrooms
propagated by incubation. clean controlled environments. and clean controlled environments.
Large parts of ISO 14698 are still A final bibliography enables easy As part of this alignment the term
relevant according to the working location of further literature on the “Biocontamination control” will be
group. However, it decided to remove various issues. changed to “Microbiological control”
unnecessary parts (or those described A glimpse into the future: rapid and align with other parts of ISO
in other standards). To emphasize and alternative microbiological 14644 which address total particles,
continuity, the term ‘biocontamination methods (RMM/AMMs) micro-organisms, chemicals,
control’ remains in the name, although The working group concluded that nanoparticles and macroparticles
the standard takes into account RMMs and AMMs are not yet mature in air and on surfaces. A new work
micro-organisms, but not viruses, enough to replace conventional growth- item application to this effect will be
endotoxins, prions, or pollen. based microbiological detection submitted to the next plenary meeting
Table 1 gives a headline comparison methods. However, the technology is of ISO/TC 209 in October 2020.
between ISO 14698 Parts 1 and 2 and rapidly evolving and holds the prospect The ISO 14644 series of standards is
EN 17141. of immediate actionable monitoring designed to support a contamination
The different requirements of different results. This view was reflected by control plan that first establishes control
fields of application for biocontamination including Annex F with general and then demonstrates control of
control are a challenge. For example, guidance on implementation and specified contaminants in cleanrooms
microbial steps in the food industry can validation of these technologies. and clean controlled environments. This
be part of a production process, whereas
the complete absence of micro-organisms
in aseptic production is a crucial quality “This document establishes the requirements,
feature. In addition, the new standard
should not be in conflict with existing
recommendations and methodology for microbiological
industry-specific regulations. contamination control in clean controlled environments.”
A lot of consideration was given to
microbiological surface and air sampling
methods and their validation. For What are the next steps? is a central principle of the new EN
example, the d50a number was EN 17141:2020 was adopted by the 17141 and follows on from risk and
introduced as a parameter for the member states on October 3, 2019 with impact assessments.
physical collection efficiency of active air 20 votes in favour, no rejection and 13 Furthermore, it is one of the key
samplers so the results from different abstentions. The amendments tabled, objectives of CEN/TC 243 that EU
active air samplers with the same d50 along with some editorial changes have Directives refer to EN 17141 (or a
number are comparable. now been processed by the CEN central future ISO 14644-??) for guidance
Secretariat. The agreed English version on cleanrooms and clean controlled
Industry-specific checklists of EN 17141 is going through the final environments. The current revision and
facilitate the application translation stage (into German and update of EU Annex 1 GMP guidance
Particular attention was paid to the French) and is expected to come into is an example, where it already refers
informative annexes (listed in Table 1). force in all CEN affiliated countries in to ISO 14644-1 for total airborne
Simple checklists, flowcharts and, in the summer of 2020. particles. A reference to EN 17141
some cases, warning and action limits As part of the standard ISO (or the equivalent ISO 14644-??) for
were compiled based on the current systematic review process, countries microbiological control would be a
state of technology and science. voted unanimously to withdraw (vs welcome scientific addition.
Some applications, such as medical retain or update) the existing ISO 14698
device manufacture, are discussed in Parts 1 and 2:2003. The next step in the References
more detail than those with already ISO process is a formal vote to withdraw 1. ISO 14698-1:2003 Cleanrooms and
well-established regulatory guidance. ISO 14698 Parts 1 and 2:2003. This vote associated controlled environments
The guidance for Medical Devices in is scheduled for some time later in 2020 — Biocontamination control — Part 1:
informative Annex B occupies nearly half and is expected to complete the formal General principles and methods
of the entire informative section. Three withdrawal process of this standard. For
2. ISO 14698-2:2003 Cleanrooms and
examples are given and Table B1 in the Europe, the EN ISO 14698 version will
associated controlled environments
Annex aligns with the corresponding be automatically withdrawn with the
— Biocontamination control — Part 2:
table in EU GMP Annex 1. publication of EN 17141.
Evaluation and interpretation of
With detailed checklists for different It is the intention of CEN/TC 243 to
biocontamination data
areas of application, EN 17141 gives integrate the new EN 17141 standard
informative guidance on how to establish into the ISO 14644 family of standards

a. The physical collection efficiency is the cut-off size (d50 value) which defines the aerodynamic equivalent
particle diameter size at which the sampler collects 50 % of the particles in the air

www.cleanairandcontainment.com Clean Air and Containment Review | Issue 42 | 2020 Number Two 27
 Standards

3. ISO 14644-1:2015, Cleanrooms and

Conor Murray is Convener of CEN/TC 243/WG5. Conor has
associated controlled environments
over 30 years’ experience in design and construction of
— Part 1: Classification of air
cleanrooms and biosafety labs and, since 2007 independently
cleanliness by particle concentration
as 3dimension Cleanrooms Limited, in an oversight and
4. EN 17141:2020 Cleanrooms and auditing role. Conor represents the National Standards
associated controlled environments - Authority of Ireland (NSAI), as Head of Delegation and a SME
Biocontamination control (Subject Matter Expert) at ISO/TC 209 and the European
mirror, CEN/TC 243, on cleanroom standardisation. Conor is the Chairperson
5. ICH guideline Q9 on quality risk
of the Healthcare Services Committee advising the Irish Health Service
management (2015)
Executive on standards compliance. Conor is Chairperson of the Irish
6. Pierson. M.D., Corlett, D.A. (eds.). Cleanrooms Society (ICS). He lectures internationally and gives cleanroom
HACCP — Principles and training and education courses on behalf of the ICS.
applications. New York Van conor@3dimension.ie
Nostrand Reinhold, 1992
Dr. Roland Durner is responsible for sales and marketing at
7. European Commission EudraLex
MBV AG, the manufacturer of the MAS-100 air sampler. With
“The Rules Governing Medicinal
his training in environmental microbiology and biotechnology
Products in the European Union”
at ETH Zurich, he supports customers in the planning and
Volume 4, EU Guidelines for Good
implementation of microbiological air surveillance projects.
Manufacturing Practice, Medicinal
More than twenty years of experience in sales and product
Products for Human and Veterinary
management of laboratory equipment enable him to support
Use, Annex 1 - Manufacture of
the in-house development team in product development projects by ensuring
Sterile Medicinal Products, 25Nov08.
the transfer of knowledge from practice to development. In addition, he is a
technical expert on CEN/TC 243/WG5.
roland.durner@mbv.ch

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