Feature Article

Scope of the problem
Allergy to natural rubber latex proteins is a well recognised health issue, with a prevalence of 1% to 6% in the general population, and an increased incidence of 16% to 20% in healthcare workers. The allergic symptoms are immediate, IgE dependent, (type I), hypersensitivity ranging from local symptoms to systemic symptoms such as urticaria, angiodema, allergic rhinitis, asthma attacks and even life-threatening anaphylaxis. Allergic reactions occur in the great majority of reported cases when the subject is exposed to variety of medical devices that contain natural rubber latex (Table I). The potential risk of adverse allergic effects from latex proteins in the components of prefilled syringes fabricated from dry natural rubber (DNR) is reviewed, based on the published papers and post-market surveillance experience.

Natural rubber is a cis-1,4-polyisoprene natural polymer, called latex, that is processed from the sap of the Hevea Brasiliensis tree. Products that contain natural rubber are made using two manufacturing processes: the natural rubber latex (NRL) process and the DNR process. Immediate hypersensitivity to NRL appears to be caused by soluble allergic proteins found in latex.8 In the case of DNR, the manufacturing process is based on processing coagulated polyisoprene polymer in the form of dried or milled sheets coming from Hevea sap. Then, after several washing steps aimed at removing soluble coagulated materials, including residual proteins, the rubber is vulcanised in the presence of antioxidants and other processing chemicals such as benzothiazoles, carbamate chemicals, thiurams and methanamine. DNR may contain only trace amounts of protein from coagulated and washed latex biscuit. The antioxidants and some other hazardous processing chemicals used during the DNR manufacturing process are known to cause delayed hypersensitivity (type IV), clinically characterised as contact dermatitis. In contrast to immediate hypersensitivity, which could lead to potentially serious adverse reactions for subjects receiving drugs or vaccines, the type IV reaction does not expose latex immunised subjects to life-threatening clinical risks, and in most cases corresponds to occupational hazards for healthcare workers, but not for subjects receiving drugs or vaccines.

One way to assess the occurrence of the allergic reactions after vaccine injection related to latex allergy is to refer to the Vaccine Adverse Event Reporting System (VAERS) (www.vaers.org). This collates reports of suspected adverse events after administration of any vaccine licensed in the United States (US). It is a passive surveillance system: reports of events are voluntarily submitted by those who experience them.

Little scientific information exists regarding the safety of vaccination of latex-allergic individuals. A search of the VAERS database, which contains more than 160000 vaccine adverse event reports, revealed only 28 cases of possible, and not proven, immediate-type hypersensitivity reactions in vaccine recipients with a history of latex allergy. Given the large number of immunisations administered every year in the US, estimated to be in the range of 300 million per year, the reported risk of allergic reactions possibly as a result of latex protein contamination of vaccines appears to be extremely low. BD’s customer complaints tracking system indicates the absence of any reported cases of latex-related allergic reactions in the European and US markets in the past 10 years.

The DNR components

Vaccine products are marketed in vials and prefilled syringes. The DNR components in prefilled syringes are the needle shield when the needle is pre-attached to the syringe tip, the syringe tip cap and the plunger rod stopper. The rubber components, as part of primary packaging of drugs and the drug delivery system for parenteral route, ensure the integrity of closure of the container and that the plunger piston functions with low gliding force.

In contrast to NRL, DNR exposes subjects to the risk of trace amounts of latex derived proteins. The manufacturing process of DNR is initiated by a coagulation of Hevea brasilliensis soap, which results in a liquid portion corresponding to the latex, and a solid portion, which is washed to remove remaining soluble latex. Unlike NRL, the exposure risk to remaining trace contamination from latex proteins is deemed negligible by experts in this field.

Occurrence of allergic reactions
A total of 15 major and minor latex protein allergens among 35 identified proteins are designated by the International Allergen Nomenclature Committee (WHO/IUIS) (http://biobase.dk/pub/who-iuis/allerg.list). Among the major allergens the most sensitive test for detecting subjects with latex sensitisation uses recombinant Hev b 5, Hev b 6 and Hev b 7 latex antigens. The basic criteria for evaluating exposure to risks related to the trace contamination of latex major allergens in drugs or solutions in contact with DNR primary packaging components is the threshold of latex protein contamination that is able to induce an anaphylactic allergic reaction. Several risk groups for latex allergy have been identified; healthcare workers have the higher risk levels. Because an individual’s susceptibility to latex protein allergens is difficult to establish and also because the amount of latex protein materials able to induce local or/and systemic immediate allergic reaction remains unknown, the determination of threshold leachable latex protein materials from DNR components deemed acceptable is not yet established. Many foods, especially chestnuts, bananas and avocadoes could potentially cross-react with natural rubber latex.

Two methods of detection and measurement of leachable latex proteins from DNR components are available: the modified Lowry method, measuring the total amount of leachable proteins in the aqueous extraction solution (detection limit 1 mg/mL); and specific immunoassays detecting latex protein allergens using antibodies directed against major latex allergens (detection limit 15 ng/mL). Only specific tests are able to measure individual latex allergens responsible for sensitising and inducing immediate allergic reactions in exposed subjects.

A review of the VAERS data noted that there were no reported cases of allergic reactions related to DNR formulations between 1991 and 2003 in the US. Similarly, BD did not receive any customer complaints reporting cases of allergic reactions in the European and North America markets. Given the approximately
300 million immunisations each year in the US, the occurrence of an allergic reaction possibly as a result of latex protein contamination in vaccine solution appears to be below 0.001 ppm.

Health risk reduction
Studies conducted by an expert panel in Europe focusing on the health hazard related to medical gloves (NRL) strongly suggest a correlation between the level of leachable protein extracted from NRL and the risk of allergic reaction or sensitisation. The European expert panel recommends that reducing the level of available leachable protein will result in reduced risk. The same risk reduction strategy may be applied to DNR components of prefilled syringes: selecting DNR components with leachable latex protein below the most sensitive quantification limit. Because of the lack of substantial and consistent evidence of leachable latex protein content, it is necessary to reduce the allergic risk arising from DNR components to a level as low as is reasonably practicable, and consider the possible presence of protein residues below the detection limit of the most sensitive specific assay.

Regulatory compliance
DNR components combined with prefilled syringes are subjected to initial qualification testing as part of the drug primary packaging. The biological testing for preclinical qualification must comply with the US Pharmacopeia (USP) 381, USP 88, Japanese Pharmacopeia (JP) 59 and ISO 10993 Parts 1, 5, 4, 10 and 11; cytotoxicity, acute systemic toxicity, intra-cutaneous reactivity (USP 88, ISO 10993-10), implantation test (USP 88, ISO 10993-6) sensitisation by maximisation test on guinea pigs (ISO 10993-10) after saline, and cotton seed oil extraction; and physicochemical tests according to European Pharmacopeia (EP) 3.2.9. and JP 59.

The elastomeric closures are observed for any defects and have had functional testing for leakage of the drug around the stopper in conformity with EP 3.2.9. The materials are tested and must pass satisfactory USP requirements for leachable and extractables materials. Notably, total protein contamination in aqueous extraction solution using the modified Lowry test must be below the detection limit of the measurement methods. US 21 Code of Federal Regulations (CFR) Part 8001.437 requires medical devices and drug packaging containing DNR components to indicate on the product label: “This product contains Dry Natural Rubber.”

Managing risk
To properly manage the residual risks associated with DNR, users need to be informed about the nature of the residual health risk. Specific labelling information of prefilled syringes containing DNR components is a critical element of user information, as recommended in Guidance for Industry 21 CFR 801.437. To achieve effective risk reduction it is desirable to ensure that leachable latex protein is below the detection limit of the most sensitive LEAP or ELISA immunoassay and that this detects major latex allergens in aqueous extraction of DNR components in the range of 10 ng/mL. Selecting a synthetic elastomer in place of DNR will ensure optimal risk reduction. However, exposure to synthetic formulation chemicals and processing agents with the risk of extractable and leachable contamination from synthetic polymers still has to be carefully evaluated. All the data collected from the literature support the conclusion that exposure to DNR rubber components presents a residual health and hazard risk that is acceptable considering the benefits of prefilled syringes for drug delivery.

References
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Philippe E. Laurent* is Vice President Medical Affairs, BD Medical Pharmaceutical Systems, 11 rue Aristide Berges, F-38800 Le Pont de Claix France, tel. +33 476 68 3501, and Clinical Immunology and Allergic Disease Consultant General Hospital of Givors, Clinical Immunology and Allergic Disease Ward, Rue Pr. Fleming F-69700 Givors, France
e-mail: philippe_laurent@europe.bd.com
www.europe.bd.com

David Eacker is Director Corporate Pre-Clinical Development, BD Technology, Research Triangle Park North Carolina, USA

Frederic Boizet is Quality Engineer, Research and Development Department, BD Medical Pharmaceutical Systems, Le Pont de Claix, France

* To whom all correspondence should be addressed