PARAMETRIC RELEASE COMES TO ETO STERILIZATION
Paul J. Sordellini
After decades of anguishing over long aeration times and interminable
incubation periods, manufacturers of medical devices sterilized with ethylene
oxide (EtO) may finally be getting something of a break. Thanks to the efforts
of industry experts in the United States and abroad, significant attention is
now being paid to the possible use of parametric release for EtO-sterilized
devices. Their work is providing industry with safe and complete guidance that
may soon make parametric release an everyday reality. As a result, companies can
expect to see a dramatic improvement in the turnaround times for products
sterilized in-house or out sourced to contractors.
It is estimated that approximately 45% of the medical devices manufactured in
the United States are sterilized using gamma irradiation. Another 45% of the
market is claimed to be held by EtO, while the remaining 10% is held by steam
and electron beam (E-beam).
When using any of these four sterilization methods, manufacturers must
validate the process in order to provide documented evidence that it will
consistently yield the desired sterility and sterility assurance level (SAL).
Upon completion of all stages of validation, routine control procedures for
gamma, E-beam, and steam consist of monitoring the physical parameters of the
process. Products may be released as soon as it has been confirmed that the
routine production cycle has fallen within the parameters established during
validation. For gamma and E-beam those parameters are exposure time and absorbed
dose; for steam, they are exposure time and temperature. In either case, the
time required before products can be moved out of the poststerilization phase
and shipped to market is generally dictated by the time necessary to perform a
routine quality assurance review of the physical process parameters verified
during the sterilization cycle. Release of products on this basis is called parametric
release.
While parametric release is the norm for most sterilization methods, however,
it has rarely been employed by contract EtO sterilizers. Following completion of
an extensive validation process, EtO sterilizers have continued to use
biological monitoring during routine production cycles as the basis for product
release. The typical process used for EtO sterilization includes initial
inventory control checks, placement of biological indicators (BIs),
preconditioning, time inside the sterilization vessel, aeration, retrieval of
BIs, shipment of BIs to the testing laboratory, BI preparation, as many as seven
days of BI incubation, compilation of the test result report, and communication
of test results to the manufacturer--who can only then arrange return shipment
of the lot to the manufacturing site for inspection and distribution. In some
cases the resident time of a given product lot within the walls of a contract
EtO facility can be as long as 11 days, and it can be even greater if weekends
intervene to hinder BI preparation or retrieval.
Just as the practice of parametric release by EtO contractors has been rare,
so has been the availability of related guidance documentation. The 1988
standard compiled by the Association for the Advancement of Medical
Instrumentation (ANSI/AAMI ST27) dedicated only one brief paragraph to the
subject of "process control release," stating that if controls are
sufficiently reliable, process control release may be considered.1
The absence of further detail-- together with the accompanying note that
regulatory authorities such as FDA may have to grant their approval for process
control release--undoubtedly prevented many EtO sterilizers from seeking to use
this technique.
In 1994, U.S. delegates voted to adopt a newer standard compiled by the
International Organization for Standardization (ANSI/ AAMI/ISO 11135) in place
of ANSI/AAMI ST27.2 This document contains updated ISO-compatible
requirements for validation, control, and conventional BI-based release of EtO-sterilized
product. But it goes beyond earlier standards by including a full section on
parametric release, which details what needs to be done differently during
validation and routine control in order to release product parametrically. Annex
D of the standard is also devoted to this subject and furnishes specifics
regarding management expertise, temperature spread across the load, monitoring
of effective recirculation, and performance qualification. In the hands of a
sterilization expert, ISO 11135 offers enough information for a contract
sterilizer to begin instituting parametric release and, in fact, industry
interest in this time-saving system has increased dramatically.
THE POTENTIAL OF PARAMETRIC RELEASE
The use of EtO for sterilization is as old as the equipment commonly
employed. Parametric release of devices processed with gamma radiation, E-beam,
and steam is also an old practice. However, because EtO sterilization requires
accurate control of a greater number of variables--thus making it somewhat of an
art rather than a pure science--industry has preferred to continue using BIs to
confirm the successful integration of all the critical parameters. In this
context, the routine use of parametric release would represent a significant
advance in the field of industrial EtO sterilization for medical devices.
The present push toward making parametric release a routine part of the world
of EtO sterilization is the result of two forces. First, by adopting ANSI/AAMI/ISO
11135, industry finally has an internationally recognized document that lists
the general requirements for parametric release. Second, to keep up with the
trend of cost cutting that is affecting all sectors of the health-care
marketplace, the medical device industry has a desperate need for greater
efficiency in all its processes.
One response to the need to reduce health-care costs has been to eliminate
massive stockpiles of medical products and switch to just-in-time (JIT)
inventory systems. This changeover applies both to hospitals, which now order
only what they need and only when they need it, and to manufacturing companies,
which now regulate their production according to immediate market demand. To
implement a JIT system, the manufacturing sector must upgrade its ability to
respond efficiently to periods of increased market demand for its devices. For
many device manufacturers this has meant switching to gamma, E-beam, or steam
sterilization, where the opportunity to use parametric release translated into
quicker response time and reduced costs. But for other manufacturers whose
devices suffer from material incompatibility with those methods, EtO has
remained the only viable sterilization option. And with it has come long
turnaround times and limited flexibility in responding to market demands.
The technique of releasing EtO-sterilized product based on process parameter
review has the potential to revolutionize the EtO industry. Once validation of
the process has been completed, use of parametric release will streamline the
EtO sterilization process to initial inventory control checks, preconditioning,
sterilization, and aeration, followed by direct shipment to distribution sites.
Allowing a few hours for initial and final inventory control, and 12 hours each
for preconditioning, sterilization, and aeration, it is conceivable that a
product lot could enter and exit an EtO sterilization facility in about 40
hours--thus rivaling the turnaround times offered by other sterilization
methods. Other products may require more time, depending on their resistance to
the process, vacuum sensitivity, and aeration requirements.
Added advantages of parametric release are less product handling and related
damage. Many manufacturers have experience with the damage and delays associated
with cutting open boxes to place BIs, reopening the same boxes after processing
to retrieve the indicators, lost or incorrectly placed BIs, and laboratory
errors in handling or incubating BIs. There is also the expense of purchasing,
placing, retrieving, and testing the BIs to consider. In addition, once a
contract sterilizer has handled a product lot so extensively, manufacturers
usually require that the load be returned to the manufacturing site for a
careful quality inspection.
By contrast, a load that is going to be released parametrically can be net
wrapped by the manufacturer and processed without ever having a single carton
removed or opened. Net wrapping permits temperature probes to be inserted
between cartons at sites appropriate for monitoring validated temperature
parameters. The load can then remain intact throughout the sterilization phase
and be confidently shipped from the sterilization site directly to a
distribution center--thus avoiding the time and expense of bringing it back to
the manufacturer. In harmony with JIT, some manufacturers could have products
EtO-sterilized and on their way to market less than 48 hours after they come off
the assembly line.
To be sure, implementation of parametric release will require EtO
sterilization firms to make substantial financial and professional commitments.
The costs of installing and operating the additional gas analysis equipment
required for parametric release can be considerable. Company management will
require additional training, validation protocols will have to be reworked, and
standard operating procedures will need to be upgraded. And, most important, the
company will need to establish clear and efficient channels of communication
with its customers, so that all parties can review the process data before the
end of the aeration phase, thereby taking full advantage of the potential for
timely product release.
For manufacturers, there may be a slight disadvantage to the implementation
of parametric release, since EtO sterilizers may seek to recoup the costs of
their new equipment by charging higher fees for each load released
parametrically. On balance, however, the benefits of parametric release should
justify these charges, which should contribute to the overall reduction of
health-care costs.
AAMI'S TIR
A key element in the movement toward parametric release of EtO-sterilized
products was put in place at AAMI's June 1995 meeting in Washington, DC, where
three task groups were formed for the purpose of writing a technical information
report (TIR) concerning various parts of ISO 11135. One of these groups is
dedicated to writing a report on the engineering aspects of industrial EtO
sterilization, which will include a section of complete guidance for anyone
intent on initiating parametric release of EtO-sterilized devices. As currently
conceived, this section is expected to discuss requirements for equipment,
validation, routine controls and monitoring, release of product, and contract
sterilization.
A first draft of the entire TIR--including the section on parametric
release--was presented for committee review at another AAMI meeting last
September. While there is still a great deal to be discussed--and the document
is sure to undergo many more changes before final presentation to the full
committee--it is not too early to discern some of the key issues related to
parametric release now under discussion.
The September draft of the TIR stresses the importance of ensuring even
distribution of moisture and sterilant, and emphasizes the need to monitor the
actual functioning of recirculation systems during the preconditioning,
sterilization, and aeration phases. In a related discussion, members of the task
group questioned the recommendations of ISO 11135, Annex D (an informative
appendix, and therefore not part of the standard's requirements), which suggests
that product temperature across the load be permitted to vary only 3°C (5.4°F)
above the minimum acceptable validated temperature. This means that if the
sterilization cycle is validated to a run at a minimum of 120°F, the product
temperature spread across the load should be controlled to a range of 120°125.4°F
in order to satisfy the requirements for parametric release. Such a tight
temperature range is realistic provided that the sterilization vessel is small,
but members of the group noted that achieving such a tight product temperature
spread in large industrial vessels would render parametric release prohibitively
expensive or even impossible. As an initial solution, the task group proposed
that its draft recommend a slightly higher acceptable temperature spread than
that suggested by ISO 11135, Annex D. Whether this proposal will withstand
further discussion remains to be seen.
Other issues of importance include product load configuration and the
presence of "cold spots" within the load. Because a
lower-than-validated product temperature would compromise the SAL delivered by
the process, all members of the task group agreed that the minimum specified
product temperature must be validated, maintained, and monitored at all times.
But there was disagreement over the question of whether the product temperature
range specified by previous standards (AAMI ST27 accepted a range of 18°F)
needed to be narrowed for parametric release. Those favoring a less restrictive
range reasoned that only the minimum temperature needed to be defined in order
to ensure the product's SAL; the maximum temperature need only be governed by
the thermal sensitivity of the product and packaging. Since higher temperatures
accelerate and benefit the sterilization process, they should not be discouraged
unless the product or packaging integrity are at risk. Although this question is
yet to be resolved, one proposal was for the TIR to require only that the load
be kept above the minimum validated temperature, without specifying a particular
product temperature range.
Because product load configuration is an important element in the success of
parametric release, the AAMI task group determined that manufacturers should be
given more guidance on this subject than has previously been available. In the
case of a load made up of only one type of product, it often happens that a
certain location inside the vessel consistently yields lower temperatures. Such
cold spots are typically found in pallets placed next to sterilizer doors, and
may be due to recirculation factors affecting that particular area. In such
cases, the group agreed that it is essential to identify such cold spots during
the validation phase (using both empty-chamber qualifications and
product/process validation cycles), and that additional probes be inserted in
these locations during all routine production cycles.
In the case of loads made up of many different products (i.e., custom kits)
the committee insisted that there be clear guidance regarding the management of
cold spots. The validation should be engineered in such a way as to identify not
only "fixed" cold spots (consistent with sterilizer location), but
also "wandering" cold spots that originate from the presence of
certain types of product within the load. Although the nature of the TIR's
guidance is not yet determined, one proposal is to require that manufacturers
conduct a comparative thermal study of all items composing the product family in
order to determine which products show slow heat absorption or poor heat
retention. Subsequent validation would then be engineered to include a
worst-case load configuration of products deemed to be the most difficult to
heat. Later, if a routine processing configuration contained a significant
number of these worst-case products, additional temperature probes would be used
to ensure compliance with the minimum validated temperature.
CONCLUSION
It is expected that the AAMI TIR will be published sometime in 1996, and it
will be interesting to see how the document develops and what effect it will
ultimately have on industry. Parametric release is not the only subject dealt
with in the engineering TIR. Guidance will also be provided for all equipment
necessary for proper EtO sterilization, for methods of calculating the relative
humidity inside a vessel, and for dealing with issues of process equivalency
among multiple vessels. There are many other ideas that may find their way into
the document or into practice:
* Using a period of conventional product release with extensive temperature
probing in order to accumulate thermal profiles of diverse product lot
configurations.
* Employing various methods of gas analysis (flame ionization detector gas
chromatography, Fourier-transform infrared spectroscopy, microwave molecular
rotational spectrometry).
* Employing various methods of moisture analysis (electronic humidity
sensors, thermal conductivity detector gas chromatography, Fourier-transform
infrared spectroscopy, microwave molecular rotational spectrometry).
* Implementing a required frequency for headspace analyses (e.g., once at the
beginning and once at the end of dwell, at five-minute intervals during the
entire dwell).
* Requiring sterilizers to correlate calculated gas and moisture measurements
with those verified through direct analysis.
* Establishing the need to monitor and control the quality of steam used
during the conditioning phase.
The ultimate evolution in modern EtO sterilization of medical devices,
however, is still some way off. This will come when routine parametric release
is combined with in-chamber dynamic environmental conditioning, a process that
bypasses the time-consuming phase of external preconditioning. When that
practice becomes routine, products that are able to withstand a deep vacuum
cycle will be transferred directly from the truck to the vessel, sterilized,
aerated, and shipped to market--sometimes in less than 24 hours. The current
developments in EtO sterilization are a small step forward along the path to
such a future.
REFERENCES
1. Guideline for Industrial Ethylene Oxide Sterilization of Medical
Devices, ANSI/AAMI ST27, Arlington, VA, Association for the Advancement of
Medical Instrumentation (AAMI), 1988.
2. Medical Devices--Validation and Routine Control of Ethylene Oxide
Sterilization, ANSI/AAMI/ISO 11135, Arlington, VA, AAMI, 1994.
Paul J. Sordellini is a sterilization consultant with Quality Solutions,
Inc. (Annandale, NJ).
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