Quality control of the diagnostics for occupational type I allergies

Status:

completed 11/2023

Aims:

The objectives of the research project were standardization, continuous documentation and quality assurance as well as making allergy testing for occupational type I allergies available in order to ensure meaningful diagnostics for each insured person suspected of having an occupational allergy. The present research project FB 317a aimed to explore strategies to counteract the diagnostic gap that already existed at the start of the project due to the lack of test allergens and to achieve an improvement and standardization of the diagnosis of work-related type I allergies.

Activities/Methods:

Based on a survey of priority needs of the German accident insurance institutions (UVT) for occupationally relevant skin test allergens for the diagnosis of work-related type I allergies, in cooperation between the Paul-Ehrlich-Institut (PEI) and the Institute for Prevention and Occupational Medicine (IPA) of the German Social Accident Insurance a list of the priority test allergens to work on was defined. For these, quality standards were developed taking into account the European Pharmacopoeia (Ph. Eur.), the German Ordinance on the Operation of Pharmacies (ApBetrO) and the German Medicinal Products Act (AMG), which are required for the production of sensitive and specific skin test solutions. Although permitted, the preparation of test allergens had not been established in pharmacies before the start of the research project. A two-stage process was used to develop pharmacy-adapted standard operating procedures (SOPs) for the preparation of skin prick test solutions. Validation experiments were planned with the assistance of a biostatistician and carried out at two sites (IPA and PEI), each with two employees, to check the robustness of the quality when the SOPs were applied by different people, at different times, at different sites and using different batches of allergen starting material from the same allergen source. In addition, stability and sterility data were obtained. Initial transfer attempts were made to a public pharmacy. In addition, protein-chemical and immunological testing of commercially available diagnostics relevant for the testing of occupational type I allergies was carried out.

Results:

The survey amongst the UVT revealed 20 priority occupational allergen sources for which the availability of high-quality test allergens for the diagnosis or exclusion of work-related type I allergies and consequently for the German accident insurance institutions´ mission is essential. At the start of the project, no authorized or marketable test allergens were available for 8/20 allergen sources and only one for 5/20 allergen sources. At the end of the project period, no authorized or marketable test allergens are available for 11/20 allergen sources and only one for 3/20 allergen sources. Allergen starting materials could be obtained for 18 of the 20 allergen sources. For 13 allergen sources, 16 certified allergen starting materials from certified suppliers could be acquired. Two of the non-certified allergen source materials proved to be qualitatively unsuitable due to an insufficient protein content. For the remaining 16 allergen sources with available starting materials, quality criteria and pharmacy-adapted SOPs were created based on laboratory protocols, taking into account the special pharmacy conditions and legal requirements. For 16 allergen sources, qualitatively suitable test allergens could be prepared from the allergen starting materials using these pharmacy SOPs. The stability and sterility of the analyzed skin prick test solutions was maintained during storage (4-8° C) and after opening during the study period of 1 year. Validation experiments showed significant differences when using different batches of starting material from the same allergen source and when produced at different sites; despite these differences, the protein content of most test allergens (87%) was still within the Ph. Eur. specified 80-120% limit. The transfer attempt to a public pharmacy with practical application of the established SOPs was successfully demonstrated using the preparation of four different test allergens as an example. The preparation of skin prick test solutions by public pharmacies represents a legally permitted alternative for supply assurance of occupational allergy test allergens in the face of a continuing shortage of commercial test allergens. This option which has been successfully investigated within this project can make an important contribution to closing the existing diagnostic gap for work-related type I allergies.

Outlook: On the way to a widespread pharmacy supply of occupationally relevant test allergens, in addition to the clarification of a few remaining medicolegal aspects several subsequent steps are necessary. These include for example additional biostatistically monitored validation experiments with different starting material batches of further allergen sources and stability and sterility tests of the corresponding skin prick test solutions over 1 year in order to ensure the conformity of all SOP-based skin prick test solutions with the qualitative requirements of Ph. Eur. prior to their validation by in vivo skin prick testing and attracting further pharmacies interested in the SOP-based production of test allergens.

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