Eucomed Position paper: Natural rubber latex gloves and latex allergy

EUCOMED Position Paper
Natural Rubber Latex Gloves and Latex Allergy
This position paper has been prepared by the EUCOMED Latex Task Group upon
which are represented many of the most important suppliers of Natural Rubber Latex
(NRL) and synthetic gloves in Europe and worldwide.
EUCOMED is the major European medical technology industry association with a
membership comprising companies with European operations together with national
and pan-European organizations in the medical technology sectors.
Currently, EUCOMED represents more than 2,500 companies employing
approximately 300,000 EU citizens that provide tens of thousands of different types
of healthcare products within the EU and globally.
EXECUTIVE SUMMARY
Over the past few years, EUCOMED and its members have been closely involved in
discussions concerning natural rubber allergy. In 1998-1999, EUCOMED participated in
an Ad Hoc Working Group charged by the European Commission with examination of
the issue. In response to a series of questions formulated by this group, the Scientific
Committee on Medicinal Products and Medical Devices (SCMPMD) recently adopted its
opinion on natural rubber latex allergy. The SCMPMD opinion identified a number of
areas for further study as well as certain practical steps that could be considered to
minimize risk.
EUCOMED believes that it is now appropriate to consider follow-up actions based on
the work of the SCMPMD. The European harmonized standard EN 455-3 has already
been agreed and published to address the biocompatibility of NRL medical gloves.
However, further recommendations for NRL gloves should be considered at the
European level, to avoid unilateral action by Member States that could fragment the
internal market. This paper explores the options for a way forward based on the current
state of the science reflected in the opinion of the SCMPMD. In particular, EUCOMED
believes that the Commission and the Member States could consider the following
further recommendations for NRL gloves:
• Recommended limits on water-extractable proteins for NRL medical gloves of 200
micrograms/dm²
EUCOMED Position Paper – Natural Rubber Latex Gloves and Latex Allergy
EUCOMED Latex Task Group – May 14 th 2001

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• Recommended limits on glove powder of 30 milligrams/dm² for powdered NRL
medical gloves, along with a definition of powder-free gloves limiting residual powder
to 2 milligrams, regardless of glove size;
• Specification of either the modified Lowry assay or amino acid analysis as
appropriate testing methods, with further support for development of an appropriate
allergen assay; and
• A labeling requirement.
EUCOMED hopes that the proposals contained in this paper will contribute to the
formulation and establishment of an achievable and uniform set of recommendations
throughout Europe, taking into account the critical role NRL gloves play in the
healthcare setting and the state of the art in glove manufacturing.
DISCUSSION
Regulation of NRL gloves to date
NRL gloves are medical devices regulated by Directive 93/42/EEC, as amended (the
Medical Devices Directive or MDD). The MDD is a New Approach directive that is
confined to defining the essential requirements that medical devices must meet.
Manufacturers of medical devices may demonstrate conformity with the essential
requirements by complying with voluntary harmonized European standards. A number
of standards pertain to NRL medical gloves, in particular the harmonized European
standard EN 455-3 on the biocompatibility of NRL medical gloves (EN 455 “Medical
gloves for single use - Part 3: Requirements and testing for biological evaluation,”
published 14 October 2000, O.J. No. C 293/9).
NRL gloves play a key role in barrier protection, both in the operating room and the
patient care setting. NRL glove use has increased dramatically since the mid-1980s as
a result of the universal precautionary principle, implemented to prevent the spread of
HIV. NRL gloves also protect healthcare workers and patients against other bloodborne
pathogens such as Hepatitis B and C.
In addition to irritant dermatitis reported by healthcare workers who wear gloves, allergic
reactions to NRL proteins and to the chemical constituents used in the manufacturing
process of NRL have been reported. These concerns prompted the Commission to
examine further the issues surrounding latex allergy.
The Commission has funded a study on the measurement and testing of allergologically
relevant compounds in disposable gloves. The study aimed to evaluate the significance
of the various testing methods used with regard to determining the allergenicity of NRL
gloves. 1 In 1998, the Commission’s DG Enterprise set up the Ad Hoc Working Group on
Medical Devices manufactured of Natural Rubber Latex (Ad Hoc Group). The Ad Hoc
1
European Commission. Determination of allergological relevant compounds in disposable gloves.
Correlation of chemical, allergological and immunological data. Final report MAT1 - CT 940060. European
Commission, Directorate General XII Science, Research and Development. Brussels, Belgium 1998.
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Group surveyed the issues raised by NRL gloves 2 in order to develop a series of
questions for the SCMPMD. The Ad Hoc Group referred these questions to the
SCMPMD in April 1999.
Opinion of the Scientific Committee
The SCMPMD adopted its opinion on natural rubber latex allergy on 27 June 2000. The
opinion was posted on the Internet at the end of July 2000. The following is a brief
summary of several of the key findings.
Leachable protein levels. The SCMPMD reports that a relationship between leachable
protein levels in NRL and the risk of allergic reaction or sensitization has been
demonstrated in several studies, either directly or indirectly. The SCMPMD thus
suggests that this risk can be reduced by minimizing the level of leachable proteins.
Using this approach relies on protein levels as a proxy for allergen levels in NRL
medical gloves. The SCMPMD notes that “at the moment measurement of total protein
is the best available way to monitor the allergenic properties of latex products, but it may
not be sufficient” because the “total protein content is not necessarily equivalent to
allergen content.” The SCMPMD also points out that “at present, there is no method
routinely available that can reliably evaluate the allergen content of NRL products.”
Glove powder. The SCMPMD’s opinion states that “it has not been demonstrated that
powdered gloves are more likely to induce sensitization than powder-free gloves,
provided the protein content of the gloves is identical.” The SCMPMD’s opinion further
states that “the glove powder acts as a protein carrier resulting in airborne allergens.”
However, the SCMPMD also notes that “the reaction to glove powder is not dependent
on the powder but on the proteins carried by the powder.”
The case for developing further product recommendations for NRL gloves
EUCOMED welcomes the SCMPMD’s opinion concerning the science of rubber allergy.
As such, the opinion forms a reference point for scientific discussions at the European
level and can provide the basis for any recommendations governing NRL products.
EUCOMED believes that the Commission and the Member States should now consider
appropriate recommendations that respond to the findings of the SCMPMD. In past
comments, EUCOMED has indicated its willingness to work with the regulatory
authorities to this end. EUCOMED believes that any additional product
recommendations established in response to the SCMPMD’s findings should be
informed both by the current state of knowledge on latex allergy issues as well as the
continual progress made in glove manufacturing.
This is consistent with the risk/benefit analysis required by the Medical Devices
Directive. The first essential requirement of the directive is that “devices must be
designed and manufactured in such a way that they will not compromise the safety and
health of patients and users . . . provided that any risks which may be associated with
their use constitute acceptable risks when weighed against the benefits . . . .” Given this
2
EUCOMED took an active role in this process, including the submission of detailed industry
comments.
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clear principle, any regulation of NRL medical gloves must balance the potential risk of
allergic reaction against the unique and primary role played by NRL gloves in controlling
the spread of infectious disease. Such regulation should take account of the following
key factors:
• Access and affordability -- Billions of pairs of NRL gloves are required every
year in the healthcare setting. The ready availability of cost-effective NRL
gloves must be guaranteed, notably for national healthcare reimbursement
systems.
• Safety -- NRL gloves are crucial to healthcare workers and patients in the
fight against deadly blood-borne pathogens, such as HIV, as well as Hepatitis
B and C.
• Manufacturing technology issues -- NRL proteins cannot be completely
eliminated from finished NRL products. Powder is also used in the
manufacturing process of nearly all NRL gloves. Overly restrictive protein
and powder level limits may compromise barrier qualities and increase cost.
• Low prevalence of allergic reactions -- Allergies to NRL proteins are rare.
Most people who are sensitized to NRL never develop an allergic reaction,
and the great majority of allergic reactions are mild. The most common
reactions to NRL are irritant rather than allergic responses.
• The ubiquity of NRL in medical devices and consumer products -- NRL
gloves are not the sole source of exposure to NRL. Hundreds of medical
devices contain NRL, including catheters, bandages, syringes, and
anesthesia masks. Thousands of consumer products also contain NRL, such
as condoms, balloons, rubber bands, athletic shoes, carpeting, and tires.
Regulating the use of NRL gloves will not resolve latex allergy issues.
EUCOMED wishes to emphasize the need for a uniform approach at the EU level in line
with the approach adopted by the Medical Devices Directive. Member States should
not take unilateral measures grounded in individual, and perhaps outdated assessments
of the risks posed by NRL gloves. Such measures threaten the single market in medical
devices, which the Medical Devices Directive is intended to achieve.
Last, it should be noted that the major suppliers of NRL gloves produce for the world
market. For years, many responsible manufacturers of NRL medical gloves have
attempted to lower total protein and powder levels in their NRL gloves. It is in the
interest of all to harmonize regulatory approaches related to these efforts while holding
costs to a minimum. EUCOMED believes that the European Union should focus on an
approach that could provide the basis for global harmonization, while at the same time
satisfying the requirements of the MDD.
Possible ways forward
EUCOMED believes that the Commission and the Member States should consider the
following:
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• Achievable limits on water-extractable protein levels and powder
Protein. A practical approach in the current state of science could be to
recommend reasonable limits on the amount of water-extractable protein for NRL
medical gloves (see Opinion of the SCMPMD on natural rubber latex allergy
adopted on 27 June 2000, Doc. SANCO/SCMPMD/2000/0009 Final, p. 2 and p.
9).
NRL glove manufacturers have already considerably reduced the level of
extractable proteins in their products. Any limit that would be set would have to
take into account existing glove manufacturing technology. In particular, the
significant lot-to-lot variations that inevitably exist in manufacturing, and the
limitations and interlaboratory variations of the assays used to measure protein
levels must be considered. In view of these issues, the across-the-board level of
30 micrograms/g that has sometimes been advocated would not be workable. A
more realistic limit value would be on the order of 200 micrograms/dm². 3
In this respect, EUCOMED notes that the Medical Devices Directive itself
provides that the essential requirements must be interpreted and applied in such
a way as to take account of technology and practice existing at the time of
design and of technical and economic considerations that are compatible with a
high level of protection of health and safety.
Powder. As noted above, the SCMPMD report observed that it has not been
demonstrated that powdered gloves are more likely to induce sensitization than
non-powdered gloves, assuming equal levels of protein. Since EUCOMED
strongly supports a uniform approach to regulation of NRL gloves, it believes that
workable recommended limits on powder could nevertheless be considered to
discourage unilateral measures at national level. EUCOMED would also
propose a uniform standard for what constitutes a powder-free glove. Relevant
limits could be as follows: 4
• Powdered NRL medical gloves would be limited to no more than 30
milligrams of powder per dm²; and
• Trace or residual powder in powder-free gloves would be limited to no more
than 2 milligrams particulate weight per glove, regardless of glove size.
• Testing methods
The testing method applied to NRL gloves is of overarching importance. This is
confirmed by the fact that the European Commission commissioned a study on
3
For medical devices such as gloves, which are in temporary contact with the skin, EUCOMED believes that
recommended limits are more appropriately expressed in terms of unit of surface area (dm 2 ) than unit of weight
(g)(in contrast to implantable medical devices). This is consistent with the approach developed by the American
Society for Testing and Materials (ASTM). A limit of 200 micrograms/dm 2 is in fact roughly equivalent to 200
micrograms/g. This figure takes account of variations in the characteristics of rubber (a natural product), in
production processes, and in the test methods used to measure total protein levels.
4
These levels are consistent with the initial standard being formulated by ASTM.
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this specific issue in 1998. Any limits imposed must be based on a reliable
assay capable of generating reproducible results.
Two methods are used to measure protein -- the modified Lowry method and
amino acid analysis. 5 Both methods measure the total amount of protein, and
not just allergenic protein. The modified Lowry method is relatively simple to
use. However, the modified Lowry assay has a relatively high quantification limit.
In addition, certain chemicals, including those used in the manufacture of NRL
products, can interfere with the results of the assay. As a result, the modified
Lowry method is viewed with skepticism by a significant segment of industry.
Both the 1998 Commission-funded study and the SCMPMD opinion find that
amino acid analysis (e.g., by HPLC) is a sensitive and specific method for
determining protein content. Amino acid analysis should be accepted as an
alternative to the modified Lowry method. In addition, consideration could be
given to an approach suggested in the opinion of the SCMPMD. Amino acid
analysis could be used as a reference method to determine total protein levels in
finished products during process validation. The modified Lowry method,
calibrated by amino acid analysis, might then be useful as a low-cost standard
method of manufacturing process control.
In any event, EUCOMED strongly believes that future action should address the
need, identified by the SCMPMD, for the availability of allergenic protein assays,
e.g., validated, commercially available competitive IgE inhibition assays such as
DPC AlaSTAT, Upjohn-Pharmacia and RAST-type tests. Unlike assays that
measure total leachable proteins, assays measuring allergens come closer to
measuring what matters -- clinically relevant allergens, not all proteins. As
needed, the Commission should support further work to standardize and
promote the availability of such assays.
• Labeling requirements
EUCOMED submits that labeling is a central part of the way forward, in particular
in light of the overall low level of risk posed by natural rubber allergy when
weighed against the benefits provided by latex gloves (low prevalence of latex
allergy in population at large; unique barrier protection function of NRL medical
gloves; extremely rare incidence of life-threatening allergic reaction to NRL).
Clear labeling requirements would provide a means of alerting allergic individuals
to the risk of an allergic reaction, without compromising the need for affordable
and effective barrier protection, in accordance with the MDD’s Essential
Requirement 13(3)(k).
EUCOMED and its members welcome the opportunity to provide ongoing support to the
Commission and national regulatory authorities in developing appropriate
recommendations for NRL gloves.
* * *
5
Powder testing methods are already standardized and do not present an issue.
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For further information on this Position Paper or questions please contact:
EUCOMED
Tel: +32 2 772 22 12
Fax: +32 2 771 39 09
Email: eucomed@eucomed.be
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