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The standards for
sterilisation of medical
devices have been
revised in the past few
years. Henry Sibun,
manager of Medical &
Health Services for
TÜV Product Service
gives an overview of
what a Notified Body
auditor looks for in a
company’s sterilisation

Setting new standards
for medical devices
   n 600 BC Homer wrote in The Odyssey             These new versions replaced and combined         defines the content and structure for all

I  that on Odysseus’s return he fumigated his
   home, saying: “Bring me sulphur, which
cleanses all pollution, and fetch fire also that
                                                   the old standards at European and
                                                   International level into single standards.
                                                   They are much more detailed and longer
                                                                                                    future standards covering sterilisation and
                                                                                                    gives a much more consistent basis from
                                                                                                    which to work for those companies that
I may burn it, and purify the cloisters”           than those they have replaced (see Table 2).     apply more than one method of sterilisation.
(burning sulphur produces sulphur dioxide).                                                         The requirements for the different
   The writings provide a good indication          Recent changes                                   sterilisation methods are now all specified to
that the need to protect ourselves from            All standards are reviewed on a regular basis    the same level of detail.
unseen micro-organisms and the diseases            – usually every five years. The old standards       The clauses of the three part-one
they cause has been known for millennia.           (see Table 2) were mostly published in 1994      requirement standards are now the same
However, it was not until 1875 that Louis          or 1995 and it was decided in 1999 to revise     and are shown in Table 3. All three printed
Pasteur developed pasteurisation and our           jointly the European and International           standards now take up many more pages,
understanding of the causative agents              versions and issue a combined standard.          being 30-60% longer. In the case of both EtO
progressed significantly.                          Although the old EN and ISO standards were       and Moist Heat a “part 2” of the standards
   There are many methods to produce               technically the same, there were editorial       will be published in the form of a “Technical
sterile products, including physical methods       differences and manufacturers selling into       Specification” rather than a standard itself.
such as radiation or heat (dry/moist) and          both the US and Europe had to work with          These will give comprehensive guidance on
chemical methods such as ethylene oxide,           and show compliance with both versions.          application of the requirements in the Part 1
glutaraldehyde, formaldehyde, hydrogen             The wording in some parts of the guidance        standards as well as general information in
peroxide, ozone and peracetic acid .               annexes was also open to different               support of the sterilisation method.
   Ensuring medical products are sterile is a      interpretations.
complex process and the standards for the             The most obvious change is that all three     Validation
three main commercially used processes             requirement standards (the part-one              The new standards give a much more
were all revised in 2006 and 2007. These           standards) have a common structure and           detailed and clearer explanation of
include the standards for ethylene oxide           format and use the same terminology. This is     validation. They also use the international
(EtO), radiation and moist heat (see Table 1).     based on the ISO 14937 standard, which           terminology of Installation Qualification

22                                                                  October 2008   CLEANROOM TECHNOLOGY
                                                                                                           the product;
 Table 1: Current standards for the three main methods for sterilising                                     ■ Definition of what constitutes non-
 medical devices                                                                                           conformance for both measurable and
 Sterilisation                                                                                             subjective criteria;
 method          Standards                                                              Date               ■ Statistical methods for data collection and
 Ethylene        EN ISO 11135-1, Sterilisation of health care products                  May 2007
                                                                                                           ■ Consideration of maintenance and repairs
 oxide           – Ethylene oxide – Requirements for the development, validation
                                                                                                           of manufacturing equipment;
                 and routine control of a sterilisation process for medical devices
                                                                                                           ■ Criteria for revalidation.
 Ethylene        EN ISO/PDTS 11135-2, Sterilisation of health care products             Publication
 oxide           – Ethylene oxide – Part 2: Guidance on the application of
                 ISO 11135-1
                                                                                        pending 2008       Validation reports
                                                                                                           The validation report allows a simple review
 Radiation       EN ISO 11137-1, Sterilisation of health care products – Radiation –    April 2006         of the results of the actual activities
                 Part 1: Requirements for the development validation and routine                           undertaken against what had been planned.
                 control of a sterilisation process for medical devices                                    This report should be factual and brief with
 Radiation       EN ISO 11137-2, Sterilisation of health care products – Radiation –    May 2007           the minimal information necessary to
                 Part 2: Establishing the sterilisation dose                                               record how the protocol was met. All
 Radiation       EN ISO 11137-3, Sterilisation of health care products – Radiation –    April 2006         deviations from the protocol requirements
                 Part 3: Guidance on dosimetric aspects                                                    must be listed, discussed and justified.
 Moist heat      EN ISO 17665-1, Sterilisation of health care products – Moist heat –   August 2006           The test results should be summarised
                 Requirements for the development, validation and routine control                          against the acceptance criteria (preferably in
                 of a sterilisation process for medical devices                                            a table) so that the reviewers can easily see if
 Moist heat      ISO/PDTS 17665-2, Sterilisation of health care products –              ISO final          these have been met. Statements on whether
                 Moist heat – Part 2: Guidance on the application of ISO 17665-1        confirmation       they have been met or not should be made
                                                                                        ballot underway    and any non-conforming results discussed,
                                                                                                           leading to a suitable justification of accep-
(IQ), Operational Qualification (OQ) and              include the following:                               tance or corrective action. A conclusion
Performance Qualification (PQ).                       ■ Identification of the process to be                must be made that clearly states whether the
   Detailed protocols for performing                  validated;                                           validation requirements have been met.
validations are essential to ensure that the          ■ Identification of device(s) to be sterilised          Appendices with all raw data should be
process is adequately validated. Much time            using this process;                                  attached. The final report should be
can be saved by putting the majority of the           ■ Objective and measurable criteria for a            reviewed and approved by the validation
effort of the validation into developing and          successful validation;                               team and appropriate management.
writing the protocol rather than the report.          ■ Length and duration of the validation;
The protocol:                                         ■ Shifts, operators, equipment to be used in         Regular review
■ helps to define the process and make sure           the process;                                         The validation process has not been
that all important parameters are identified          ■ Identification of utilities for the process        completed until the re-qualification require-
for monitoring;                                       equipment and quality of the utilities;              ments have been defined and documented.
■ makes the review at the end of the                  ■ Identification of operators and required           Requalification requirements include a
validation simple and objective (pre-defined          operator qualification;                              regular review of the sterilisation process at
acceptance criteria);                                 ■ Complete description of the process;               defined intervals according to documented
■ reduces the need to repeat parts (or all) of        ■ Relevant specifications that relate to the         procedures. The statement “the sterilisation
the validation because important aspects are          product, components, manufacturing                   load has not changed” is not a sufficient
missed out.                                           materials etc;                                       justification for not conducting any
   Although the standards give details of the         ■ Any special controls or conditions to be           requalification activities!
activities within the validation they are not         placed on preceding processes during the               The procedure should summarise and
prescriptive about the contents of the                validation;                                          discuss all changes including:
protocol. Detailed information on validation          ■ Process parameters to be monitored, and            ■ product changes during the year (e.g. new
protocols is provided by the Global                   methods for controlling and monitoring;              products, physical changes to existing
Harmonization Task Force (GHTF Study                  ■ Product characteristics to be monitored            products, new raw material suppliers, etc.);
Group 3).2                                            and method for monitoring;                           ■ product bioburden levels;
   Validation protocols are recommended to            ■ Any subjective criteria used to evaluate           ■ environmental monitoring results;

 Table 2: Old and new standards for the sterilisation of medical products
 Sterilisation Method                            Old European Standard              Old International Standard         New Standards (not all published)
 Ethylene Oxide                                  EN 550                             ISO 11135                          EN ISO 11135 -1, -2
 Radiation                                       EN 552                             ISO 11137                          EN ISO 11137-1, -2, -3
 Moist Heat:                                                                                                           EN ISO 17665 -1, -2
 Industrial                                      EN 554                             ISO 11134
 Healthcare                                                                         ISO 13683

CLEANROOM TECHNOLOGY               October 2008                                                               23

   ■ changes to the manufacturing facility;     (e.g. load volume, usable chamber volume,          probes, the report stated 15 were needed,
■ changes to personnel in the product           total chamber volume, etc.);                       location map showed 11 probes & the data
realisation process;                            ■      Sterilisation     cycle   development       traces for 13!);
■ changes to the steriliser (including          conducted simultaneously to the validation         ■ Deviations from the requirements of the
maintenance, repair, etc.)                      activities – the specification including           protocol are not identified or discussed in
  Depending on the outcome of this review,      tolerances for all parameters should have          the report;
a decision can be made on what level of re-     been determined prior to starting PQ;              ■ The validation report (ethylene oxide)
validation is necessary.                        ■ Validation protocol has insufficient detail      does not summarise all of the points listed in
  There are a number of non-conformities        to allow the validation results to be judged       section 9.5.4 of ISO 11135-1 and tolerances
found during audits of companies                against it;                                        are not given for all of them;
manufacturing sterile medical devices that      ■ Validation report indicates that protocol        ■ Compliance with the Standard is claimed
are very common, including:                     was not followed but there is no explanation       but not all requirements met or followed;
■ No summary description of the steriliser      of this (e.g. protocol required 21 temperature     ■ No traceability from results to steriliser

  SABIC Innovative Plastics’ Ultem resin helps Biorep
  Technologies bring diabetes treatment to market
 SABIC Innovative Plastics has helped Biorep Technologies, a device
 manufacturer specialising in tools used in diabetes research and
 treatment, to develop a new system for isolating insulin-producing
 cells faster and more efficiently.
    Biorep’s technology enables islets – insulin-producing cells from
 a donor’s pancreas – to be isolated and purified for transplantation
 in patients whose Type-1 diabetes cannot be controlled with
 insulin injections.
    The Ricordi Chamber, invented by Dr Camillo Ricordi of the
 Diabetes Research Institute in Miami, is used to break down the
 pancreas mechanically and chemically to isolate the islets. The
 chamber was originally custom-made from stainless steel, which
 was quite heavy to shake during the 30-45 minute isolation process
 and prevented doctors from visually assessing the progress of the
 breaking down of the pancreas.
    By injection moulding the Ricordi Chamber from Ultem HU
                                                                         Biorep’s Ricordi Chambers moulded with Ultem Resin
 polyetherimide (PEI) resin, a translucent, high-temperature,
 autoclavable material, Biorep achieved several key objectives.
 According to Ramon Poo, president, Biorep Technologies, the main        and companies to purchase and use the Ricordi Chamber.”
 benefit of finding a suitable autoclavable plastic is mass                 Ultem resin is a rigid, high-strength thermoplastic that can
 production.                                                             withstand prolonged exposure to high temperatures and repeated
    “By using Ultem resin, we can provide chambers to the doctors        sterilisation by autoclaving. It has a translucent, light amber colour
 quickly, instead of the two weeks that it takes to produce a custom     that allows the doctors to see the pancreas inside the chamber. The
 stainless steel chamber. The use of Ultem resin to mould chambers       excellent chemical resistance of the resin was also critical, since the
 also reduces our manufacturing costs. The lower price of the            enzymes used during the digestion process are extremely caustic.
 chamber makes it possible for more research centres, universities          A disposable perfusion tray, also offered by Biorep for use in
                                                                         transplant procedures, is injection moulded in SABIC Innovative
                                                                         Plastics’ Cycolac HM acrylonitrile-butadiene-styrene (ABS) resin,
                                                                         which offers excellent toughness, chemical resistance, and bonding
                                                                         ability. This biocompatible material was custom-coloured white
                                                                         using SABIC Innovative Plastics’ ColorXpress service.
                                                                            Many facilities do not have the expensive, certified, sterilisation
                                                                         equipment and approved processes that are required when reusing
                                                                         items for isolations. The option to buy a disposable, sterile
                                                                         perfusion tray made from Cycolac ABS resin will assisted facilities
                                                                         with the approval of their isolation protocols.
                                                                            SABIC adheres to stringent healthcare product requirements
                                                                         covering resin biocompatibility in accordance with either USP
                                                                         Class VI biological or the ISO 10993 “Biological Evaluation of
                                                                         Medical Devices” standards, as well as food contact compliance
                                                                         according to EU and US FDA standards.
   A perfusion tray made with Cycolac Resin                              ■

24                                                                October 2008    CLEANROOM TECHNOLOGY
number or cycle number;
■ Steriliser timer is not calibrated or checked
  Unexpected results or errors during the
                                                    Anville Instruments wins major MoD
validation are common – as long as they are
acknowledged and discussed, this is not a           contract for steriliser validation kits
problem.                                            The Ministry of
                                                    Defence in the UK
Summary                                             has placed an
The standards for ethylene oxide, moist heat        order      for     50
and radiation sterilisation have been               new        steriliser
substantially revised and re-issued with a          validation       kits
common structure. The international and             from      the     UK
European standards have been combined               company Anville
into one.                                           Instruments based
   The Validation Protocol should be a              in Aldershot.
detailed “meaty” document defining all of              The order is set
the     expected    outcomes      (including        to provide valid-
tolerances) and what to do if they are not          ation teams with
met. The Validation Report should                   advanced equip-
summarise the parameters observed (and              ment for checking
their ranges) and compare them with those           the accuracy of One of 50 steriliser validation kits to be used by the Ministry of Defence
expected in the protocol.                           sterilisers      and
                                                    washer-disinfectors in defence medical facilities.
Regular review                                         With responsibility for tri-service hospital, dispensary and dental facilities, the MoD’s
All deviations to the Protocol, however small,      validation teams carry out a continuous programme of steriliser and washer-disinfector
must be documented and justified in the             validation and calibration around the world, both on land and at sea.
report. The sterilisation process should               Calibration equipment by definition has to be robust, portable, easy to use and most
undergo a regular documented review                 importantly highly accurate. The existing paper chart recorder and logging technology
according to a defined procedure. The               was more than 10 years old and the Ministry decided to open tendering for a replacement
procedure should define the inputs to the           system.
sterilisation process that could influence its         Because of the value of the contract, EU regulations demanded the bidding was opened
adequacy.                                           throughout Europe. The contract was awarded to Anville, who met all the MoD
   Time and effort invested in getting the          requirements both technically and commercially.
protocol right will save time when reporting           The fifty steriliser validation kits currently on order each consist of an Anville Series 825
and trying to make sense of data if it was not      data logger, Anville EaziVal software, Anville Series 275 UKAS temperature reference,
as expected. A well-documented (but                 Anville Series 300 dry-block temperature bath, pressure transducer, thermocouple set,
concise) validation will be simpler to review       autoclave fittings and carrycase with software training provided by Anville.
and approve internally. It will also speed up       ■ T +44 1252 351030 ■ ■
Notified Body reviews and reduce the risk of
non-conformities being raised.
   Compliance with the EN55X standards            with the Medical Devices Directive on the             Make sure staff in R&D are aware of the
will cease to be a presumption of conformity      following dates: EN552 on 30 April 2009,            new standards so that they are taken into
                                                  EN554 on 30 August 2009 and EN550 on 31             account in the development process.     ■
                                                  May 2010.
 Table 3: Common clauses for ISO                     A greater expertise in sterilisation is          References
                                                                                                      1 EN ISO 14937: 2000 Sterilisation of health care products - General
 11135-1, ISO 11137-1 and ISO                     needed; if this is not available in-house, buy      requirements for characterisation of a sterilising agent and the
 17665-1                                          in this expertise. Don’t rely on external           development, validation and routine control of a sterilising agent
                                                                                                      2 – SG3/N99-10 (Edition 2) Quality Management
                                                  sterilisation companies to tell you what to do
 1. Foreword                                                                                          Systems – Process Validation Guidance, 22 January 2004
                                                  – they are a knowledgeable source of
 2. Introduction                                  information but you need the ability to
 3. Scope                                         independently review the validations. Obtain         CONTACT
 4. Normative References                          copies of the new standards (discuss these as        Henry Sibun
 5. Terms & Definitions                           part of management review).                          Manager of the Medical & Health
 6. Quality Management System Elements                Three-year transition periods were given         Services
 7. Sterilising Agent Characterisation            before the previous versions become                  TÜV Product Service Ltd
 8. Process & Equipment Characterisation          obsolete but these are now down to ~7                Octagon House
                                                  months (irradiation), ~12 months (moist              Concorde Way
 9. Product Definition
                                                  heat) and ~21 months (EtO). Start working            Segensworth North
 10. Process Definition
                                                  now to ensure all processes are updated and          Fareham
 11. Validation
                                                  revised in accordance with the new                   Hampshire PO15 5RL
 12. Routine Monitoring & Control                 standards – conduct a gap analysis on your           UK
 13. Product Release & Sterilisation              procedures and prepare an action plan with           T +44 1489 558217
 14. Maintaining Process Effectiveness            timescales for compliance with the revised 

CLEANROOM TECHNOLOGY              October 2008                                                                             25

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