This document summarizes the key points of a presentation on sterilization requirements and strategies for compliance. The presentation covered general sterilization requirements, radiation sterilization and its impacts, and EO sterilization and its impacts. It discussed the main changes in ISO 11137 for radiation sterilization and ISO 11135 for EO sterilization, and the impacts these standards have on sterilization contractors and medical device manufacturers.

1. Sterilization
requirements: Strategies
for Compliance
presented by
John Beasley
Owner & Sr. Consultant
MedTech Review

2. Topics
• General Requirements
• Radiation Sterilization
– Impact to Subcontractors
– Impact to Manufacturers
• EO Sterilization
– Impact to Subcontractors
– Impact to Manufacturers
• Summary

3. Introduction
• Presentation covers • Presentation does not
– Gap Analysis between cover
current version and – All differences – only
previous version of the most significant
standards – The steps for
– Compliance sterilization or
information validation of
– References sterilization processes
Copyright
laws
prevent
MedTech
Review
and
MEDTEC
China
Conferences
from
providing
copies
of
standards
to
conference
par;cipants.

4. Sterilization Processing by IR or EO

5. General Requirements
• Aligned somewhat with the requirements
of ISO 13485:2003
– Document and Record Retention
• Procedures for development, validation, routine
control and release (ISO 13485:2003, Clause 4)
– Management Responsibility
• Authority, responsibility, including contractors (ISO
13485:2003, Clause 5)

6. General Requirements
– Product Realization
• Procedures for purchasing, identification and
traceability, and calibration are required (ISO
13485:2003, Clause 7)
– Measurement and Improvement
• Controls for non-conforming material and
corrective actions (ISO 13485:2003, Clause 8)

7. Sterilization by Radiation
• ISO 11137:2006
– Part 1
• Requirements for development, validation, and
routine control of a sterilization process for medical
devices (approved 15 April 2006)
– Part 2
• Establishing the sterilization dose (approved 15
April 2006)
– Part 3
• Guidance on dosimetric aspects (approved 15 April
2006)

8. Sterilization by Radiation
• ISO 11137:2006 is now mandatory and
fully implemented in the EU (as of April
2009)
– The following standards are now OBSOLETE
• EN 552
• ISO 11137:1995
• AAMI TIR 27:2001
• ISO/TIR 13409:1996
• TIR 15844:1998

9. Certification
• Contract sterilization companies who carry
out irradiation processing can include
EN ISO 11137-1:2006 within the scope of
their ISO 13485 registration.
• EN ISO 11137 Parts 2 and 3 cannot be
included.

10. ISO 11137:2006 – Main Changes
• Clause 3 – Definitions
– Processing category
• Group of different products that can be sterilized
together, based on
– Composition
– Density
– Dose requirements

11. ISO 11137:2006 – Main Changes
– Product family
• Group of different products that can be given the
same sterilization dose based on the nature of the
– Raw materials
– Components
– Manufacturing processes
– Equipment
– Environment
– Location
It
would
be
helpful
for
the
manufacturer
to
develop
a
process
map
or
decision
tree
to
consistently
address
the
requirements
and
document
the
ra8onale
for
groupings.

12. ISO 11137:2006 – Main Changes
• Clause 5 – Sterilizing Agent
Characterization
– New requirements for environmental
considerations
Are
there
environmental
impacts
such
as
discharges
into
the
air
or
water
that
may
adversely
impact
the
environment?
How
are
these
controlled?

13. ISO 11137:2006 – Main Changes
• Clause 6 – Process and Equipment
Characterization
– Requirements have been expanded –
irradiator and its method of operation shall be
specified.
Can
be
addressed
under
vendor
contract
/
purchasing
control
/
internal
control
procedures
such
as
process
control,
equipment
valida8on
and
equipment
change
control.

14. ISO 11137:2006 – Main Changes
• Clause 7 – Product Definition
– New requirements emphasize control of product
AND packaging AND control of bioburden
– New requirements – defining product families in
establishing dose and dose audit based on
• Bioburden
• Representative product
• Master product
• Equivalent product
• Simulated product
Product
families
must
be
established
with
documented
criteria,
maintained
(i.e.,
reviewed)
and
risks
in
using
product
families
must
be
addressed

15. ISO 11137:2006 – Main Changes
• Clause 8 – Process Definitions
– Incorporates Method 1, Method 2 and Vdmax
Method (15 and 25)
– New Means for dose transference
SOPs
need
to
include
requirements
for
establishment
of
max
dose
and
steriliza8on
dose;
manufacturers
need
to
document
the
appropriate
method
used
and
process
for
valida8on.

16. ISO 11137:2006 – Main Changes
• Clause 9 – Validation
– IQ / OQ / PQ requirements have been
expanded
– Dose mapping (both container and product)
– Process specifications established directly
from validation; requirements detailed
– Defined sample sizes required

17. ISO 11137:2006 – Main Changes
• Clause 12 – Maintaining process
effectiveness
– Standard defines a more flexible approach for
maintaining effectiveness of process
• Bioburden specifications (number and type)
– 1 month, 3 month, each batch
• Dose audits – frequency; rationale
• Failure Investigation and actions

18. Impact to Sterilization Contractor
• Requirements for environmental
considerations
“The
poten8al
effect
on
the
environment
of
the
opera8on
of
the
radia8on
steriliza8on
process
shall
be
assessed
and
measures
to
protect
the
environment
shall
be
iden8fied.
This
assessment,
including
poten8al
impact
(if
any)
shall
be
documented
and
measures
for
control
(if
iden8fied),
shall
be
specified
and
implemented.

19. Impact to Sterilization Contractor
• Think about all of the possible environmental
impacts that might occur in the event of a
failure of the radiation control system.
– Maintenance of the source material and its
storage (pool water levels, alarms, testing)
– Control of access to the cell
– Care and maintenance of the source racks/
carriers
– Control room alarms These
items
can
be
reviewed
and
covered
during
preven8ve
– Auditing for safety maintenance
ac8vi8es
and
supplier
audits.

20. Impact to Sterilization Contractor
• Process interruptions
– What happens when there is an interruption in the
exposure?
– What is the impact of stopping and restarting the
cycle and the timing? How are under-dosing and
overdosing prevented?
– What is the additional exposure to the product
resulting from the travel time of the source material
rising up and lowering down, possibly multiple times?
– Is there a risk of product or package degradation
caused by the changes in temperature while in the
cell due to the interruptions?

21. Impact to Sterilization Contractor
• Partial containers – dose mapping
“If
par8ally-­‐filled
irradia8on
containers
are
to
be
used,
the
effect
of
par8al
filling
on
dose
distribu8on
within
irradia8on
containers
or
in
other
irradia8on
containers
present,
shall
be
determined
and
recorded.
When
a
carrier
is
not
completely
full,
the
density
of
the
load
becomes
inconsistent,
and
therefore
the
delivered
dose
can
vary.
By
properly
mapping
par8al
carrier
loads,
equivalent
dose
distribu8on
can
be
assured.”

22. Impact to Sterilization Contractor
• Procedures for review and product release
• 11.1 – Any specific periodic tests, calibrations,
maintenance tasks and necessary re-qualifications
need to be documented.
• 11.2 – Procedures for review of records and
product release from sterilization need to be
written.
When
a
steriliza8on
process
is
found
to
not
meet
specifica8ons,
taking
into
account
the
uncertainty
of
the
measurement
system(s),
then
the
product
shall
be
handled
as
nonconforming.

23. Impact to Sterilization Contractor
• Each of the previous items must be
audited in addition to
– Personnel training
– Dosimetery
– Radiation cell refueling

24. Impact to Manufacturer
• VDMax 25
– Bioburden testing unchanged (<1000 CFU per
device); verification does set to 10-1; sterility
testing on 10 units
• VDMax 15
– Bioburden control limits extremely low (<1.5
CFU per device)
• ISO 15843 – Dose audit frequency
– Quarterly -> Semi-annually -> Annually

25. Regarding China
• GB18280-2007 - Sterilization of health
care products requirements for
validation and routine control of
radiation sterilization
– idt ISO 11137:2006

26. Sterilization by EO
• ISO 11135-1:2007
– Requirements for development, validation,
and routine control of a sterilization process
for medical devices (approved 01 May 2007)
• ISO 11135-2:2008
– Guidance on the application of ISO
11135-1:2007

27. Sterilization by EO
• ISO 11135 is now mandatory and fully
implemented in the EU (as of May 2010)
– The following standards are now OBSOLETE
• EN 550:1994
• ISO 11135:1994

28. Certification
• Contract sterilization companies who carry
out EO processing can include
EN ISO 11135-1:2007 within the scope of
their ISO 13485 registration.
• EN ISO 11135-2:2008 cannot be included.

29. Sterilization by EO
• Cycle Development
– Several methods for cycle development
offered in Annex
– Use of developmental chambers as well as
production chambers for process
development expanded
– Chamber and process equivalency
– Clarification of microbiological and physical
PQ provided

30. Sterilization by EO
• Main Changes
– Clause 5 – Sterilizing Agent Characterization
• New requirements for microbicidal effectiveness if
EO outside range of widely recognized
compositions or if novel diluents are to be used
• Effects of EO on the product to be documented
• Environmental considerations

31. Sterilization by EO
– Clause 6 – Process and Equipment
Characterization
• Generally relates to the requirements of the
contractor; responsibility lies with the manufacturer
to ensure contractor sterilizer complies with these
specific requirements
• Process Characterization is a result of the OQ
• Equipment Characterization is a result of the IQ

32. Sterilization by EO
– Clause 7 – Product Definition
• Product and packaging must meet the specified
requirements for safety, quality, and performance
following the sterilization process at the most
challenging process parameters
– Useful Standards
• ISO 10993 (relevant parts) for biological safety and
EO residuals following exposure
• AAMI TIR 28:2001; Product Adoption and Process
Equivalency for EO Sterilization

33. Sterilization by EO
• ISO 11737-1:2006 specifies requirements and provides
guidance for the enumeration and microbial
characterization of the population of viable micro-
organisms on or in a medical device, component, raw
material or package.
• ISO 17664:2004 specifies the information to be
provided by the medical device manufacturer on the
processing of medical devices claimed to be
resterilizable, and medical devices intended to be
sterilized by the processor.
• ISO 11607-1:2006 specifies the requirements and test
methods for materials, preformed sterile barrier
systems, sterile barrier systems and packaging
systems that are intended to maintain sterility of
terminally sterilized medical devices until the point of
use.

34. Sterilization by EO
– Clause 8 – Process Definition
• Process parameters clearly defined
• Appropriateness of BI and process challenge
device to be defined and documented to
demonstrate and support SAL

35. Sterilization by EO
– Clause 9 – Validation
• The number of sensors in PQ (temperature,
humidity, BIs) in the load is based on product load
volume as opposed to usable chamber volume.
• The number of sensors in IQ/OQ is based on
chamber volume.
– Clause 10 – Routine Monitoring and Control
• New requirements for additional levels of reviews
when parametric release is to be used

36. Sterilization by EO
– Clause 11 – Product Release
• Conventional release and parametric release are
more harmonized
– Clause 12 – Maintaining Process
Effectiveness
• Justification for requalification requirements /
intervals of requalification

37. Sterilization by EO
– Requalification Review to include
• Verify appropriateness of BIs
• Verify loading patterns remain unchanged
• Verify no changes to design, materials, load
configuration or manufacturing process
• Verify no change in bioburden or characterization has
occurred
• Verify temperature distribution and chamber operation
remain unchanged
• Review of sterilization process history demonstrates
repeatability
• Review of preventive maintenance programs
demonstrate no change to sterilizing equipment
Recommended
reduce
microbial
performance
qualifica;on
studies
are
performed
at
least
every
two
years
to
verify
the
documented
paperwork
review
has
captured
any
changes
in
the
product
or
steriliza;on
review

38. Regarding China
• GB 18279-2000 ethylene oxide
sterilization of medical equipment
validation and routine control
– idt ISO 11135:1994

39. Summary
• While techniques of sterilizing medical
devices have not changed much over the
past 25 years, the levels at which
sterilization processes are monitored and
controlled have changed significantly.

40. Summary
• Sterilization Validation is DYNAMIC
– ISO 14937:2009 specifies the elements of a
Quality Management System which are
necessary to assure the appropriate
characterization of the sterilizing agent,
development, validation and routine
monitoring and control of a sterilization
process.
• It provides a standardized procedure for validating
new sterilization technologies.

41. Thank You
John Beasley
Owner & Sr. Consultant
MedTech Review, LLC
www.medtechreview.com
Email: john@medtechreview.com
SKYPE: medtechreview