S. May

Determination of the allergenic activity of birch pollen and apple prick test solutions by measurement of β-hexosaminidase release from RBL-2H3 cells. Comparison with classical methods in allergen standardization

Background: A murine in vitro model of the allergic type I reaction was set up to determine the biologic activity of extracts without involvement of human beings. It is based on β‐hexosaminidase release from passively sensitized RBL cells after allergen challenge. The intended application of this RBL cell assay in the field of quality control of allergenic extracts requires its comparison with established methods.

Regulatory environment for allergen‐specific immunotherapy

To cite this article: Kaul S, May S, Lüttkopf D, Vieths S. Regulatory environment for allergen‐specific immunotherapy. Allergy 2011; 66: 753–764.

The Principle of Homologous Groups in Regulatory Affairs of Allergen Products – A Proposal

Among other legal regulations, the Note for Guidance on Allergen Products CPMP/BWP/243/96 released by the European Medicines Agency provides regulatory instructions regarding the quality of allergen extracts for diagnostic or therapeutic purposes. The current revision of this guideline intends to transform the so-called ‘principle of taxonomic families’ to the ‘principle of homologous groups’. According to this concept, the data of one allergen extract demonstrating stability, efficacy and safety can, to a limited extent, be extrapolated to other allergen extracts belonging to the same homologous groups. The present work proposes the formation of homologous groups for pollen species and animal-derived materials on the basis of similar biochemical composition and homology/cross-reactivity of allergens or allergen sources. Some tree pollen species could be assigned to three different homologous groups, some weed pollen species to one homologous group and numerous grass pollen species to one homologous group on condition that data rely on single defined representative species. A homologous group for mites is limited to the Dermatophagoides species and the grouping of vertebrate-derived materials such as dander could be possible under restrictions. The criteria for the formation of the proposed homologous groups are illustrated in detail to provide an opportunity for extending existing homologous groups by further species in case of new insights in allergens and cross-reactivity of allergen sources. In this way, the concept of homologous groups could serve as a dynamic tool in the regulation of allergen products.

Regulatory aspects of specific immunotherapy in Europe.

Purpose of reviewThe recent developments in the regulation of allergen products and their impact on specific immunotherapy (SIT) in Europe are summarized, and unmet needs are discussed. Recent findingsNew guidance on the quality, the clinical development, and marketing authorization status of allergen products for SIT has been released. The most important documents are Guidelines from the European Medicines Agency, a revision of the European Pharmacopoeia Monograph on Allergens, regulations, and position papers of scientific societies. SummaryThe increased demands on quality, safety, and efficacy will lead to allergen products being better characterized and with enhanced proof of efficacy and safety. In addition, national activities to regulate the existing broad spectrum of named patient allergen products have been started. At the same time these developments represent a challenge to manufacturers to meet all new requirements. Some problems, for example regarding patient-tailored products containing recombinant allergens remain and may require novel regulatory approaches.

Die individuelle Rezeptur in der spezifischen Immuntherapie Notwendigkeit und Fehlerquellen

ZusammenfassungEine kausale Behandlung der Typ-I-Allergien mittels der spezifischen Immuntherapie (SIT) ist unumgänglich, um dem “Etagenwechsel” von einer Rhinitis zum Asthma bronchiale entgegenzuwirken. Dafür stehen Therapie-Allergene als (zugelassene und der staatlichen Chargenprüfung unterworfene) Fertigarzneimittel oder als individuelle Rezepturen (IR) zur Verfügung. 60 bis 80 % aller Präparate für die SIT werden als IR vom Arzt für einen bestimmten Patienten zusammengestellt. Wegen der sehr großen Zahl potenzieller Allergie-Auslöser kommt die SIT nicht ohne IR aus, da die chargenmäßige Herstellung eines Fertigpräparates für ein u.U. sehr kleines Patientenkollektiv nicht sinnvoll wäre. IR können zu einer Fehlerquelle in der Behandlung allergischer Erkrankungen werden durch die Zusammenstellung von Therapiemischungen, die auf eine durch allergologisch unerfahrene Ärzte nicht adäquat erhobene Anamnese zurückgehen, die Zusammenstellung von Mischungen nicht miteinander kreuzreagierender Allergene, die Stabilität und Wirksamkeit einer solchen Mischung durch proteolytischen Abbau bis zur vollständigen Wirkungslosigkeit negativ beeinflussen können und durch das Nichterreichen der für einen klinischen Effekt notwendigen Konzentration jedes Einzelallergens in einer Mischung. Alle Faktoren können derzeit nur durch eine gründliche Schulung allergologisch tätiger Ärzte und deren Zusammenarbeit mit verantwortungsvoll agierenden Herstellern beherrscht werden, da bisher Bemühungen, IR verbindlichen Regelungen vergleichbar denen für zugelassene Präparate zu unterwerfen, nicht zum Ziel geführt haben.AbstractThe causal treatment of type I allergies by specific immunotherapy (SIT) is absolutely essential to counter the transformation of rhinitis into bronchial asthma. There are therapy allergens available for this purpose as finished drugs (with marketing authorization and subject to official batch testing) or as named patient products (NPP). Sixty to eighty percent of all preparations for SIT are compounded as NPP for a specific patient by his physician. Because of the enormous number of potential allergens, SIT also requires NPP, as the batchwise production of finished drugs would not be practical for possibly very small groups of patients. However, NPP may become a source of error in treating allergic diseases due to the compilation of mixtures for therapy being attributed to an inadequate anamnesis obtained through physicians without allergological experience, the compilation of mixtures of non cross-reacting allergens that may negatively influence the stability and efficacy of such a mixture, up to total ineffectiveness by proteolytic degradation, and the failure to reach the concentration essential for a clinical effect of each single allergen in a mixture. All these factors can only be controlled by intensive training of practising allergists and their cooperation with responsible acting manufacturers, since up till now efforts to subject NPP to binding regulations, comparable to those existing for preparations with marketing authorization, have failed.

A new in vitro model for testing of food allergens: Allergen‐specific mediator release of passively sensitized rat Basophil Leukaemia cells

An assay based on allergen‐specific mediator release of rat basophil leukaemia cells (RBL cells) was investigated as a possible new tool for the in vitro testing of food allergens. The RBL‐2H3 cells were sensitized passively with diluted murine pool sera containing IgE specific for food and pollen allergens. These sera were obtained from BALB/c mice after low‐dose intraperitoneal injection of birch pollen, celery and peanut extracts. Comparative immunoblotting with murine and human IgE demonstrated that the murine IgE response was directed predominantly against known major allergens. Subsequent to sensitization of the RBL cells with antiserum against birch pollen allergens, apple allergy was used as an immunological model of birch pollen related food hypersensitivities. The known cross‐reaction of the major allergens of birch pollen and apple was reproduced completely by the mediator release measured in the murine in vitro assay. The ranking of allergenic potency obtained for these allergens agreed closel...

[Allergens for specific immunotherapy: authorization and quality criteria of the Paul-Ehrlich-Institut].

ZusammenfassungDie Zulassung von Allergenextrakten für die spezifische Immuntherapie (SIT) zur subkutanen Injektion (SCIT) bzw. zur sublingualen Applikation (SLIT) beim Paul-Ehrlich-Institut (PEI) sorgt für Präparate, deren Qualität, Sicherheit und Wirksamkeit belegt sind. Die staatliche Chargenprüfung, der diese Präparate als Fertigarzneimittel unterliegen, schafft den Nachweis, dass nur Präparate in Verkehr gebracht werden, die den im Zulassungsverfahren festgelegten Spezifikationen entsprechen. Präparate für die SIT, die auf persönliche Verschreibung des Arztes für einen Patienten hergestellt werden – sog. individuelle Rezepturen –, sind nicht zulassungsfähig und werden daher hinsichtlich ihrer Qualität, Sicherheit und Wirksamkeit auch nicht durch das PEI überwacht. Es werden die verschiedenen Zulassungsverfahren in der Europäischen Union (EU) beschrieben sowie problematische Aspekte der Zulassungsanforderungen dargestellt.AbstractThe marketing authorization of allergen preparations for specific immunotherapy (SIT) for subcutaneous injection (SCIT) and sublingual immunotherapy (SLIT) at the Paul-Ehrlich-Institut (PEI) insures that the quality, safety, and efficacy of these medicinal products is proven. As finished products, these medicinal products are subject to official batch control tests, which provide evidence that only those products are marketed which conform to the specifications laid down in the marketing authorization procedure. Products for SIT prepared for a patient on the basis of the physician’s prescription – so-called named patient products – cannot be subjected to a marketing authorization review. Therefore, they are not subject to the pharmaco-surveillance by the PEI regarding quality, safety and efficacy. This article describes the different marketing authorization procedures in the European Union (EU) and addresses the problems related to the marketing authorization requirements.

Therapieallergene zur spezifischen Immuntherapie

ZusammenfassungDie Zulassung von Allergenextrakten für die spezifische Immuntherapie (SIT) zur subkutanen Injektion (SCIT) bzw. zur sublingualen Applikation (SLIT) beim Paul-Ehrlich-Institut (PEI) sorgt für Präparate, deren Qualität, Sicherheit und Wirksamkeit belegt sind. Die staatliche Chargenprüfung, der diese Präparate als Fertigarzneimittel unterliegen, schafft den Nachweis, dass nur Präparate in Verkehr gebracht werden, die den im Zulassungsverfahren festgelegten Spezifikationen entsprechen. Präparate für die SIT, die auf persönliche Verschreibung des Arztes für einen Patienten hergestellt werden – sog. individuelle Rezepturen –, sind nicht zulassungsfähig und werden daher hinsichtlich ihrer Qualität, Sicherheit und Wirksamkeit auch nicht durch das PEI überwacht. Es werden die verschiedenen Zulassungsverfahren in der Europäischen Union (EU) beschrieben sowie problematische Aspekte der Zulassungsanforderungen dargestellt.AbstractThe marketing authorization of allergen preparations for specific immunotherapy (SIT) for subcutaneous injection (SCIT) and sublingual immunotherapy (SLIT) at the Paul-Ehrlich-Institut (PEI) insures that the quality, safety, and efficacy of these medicinal products is proven. As finished products, these medicinal products are subject to official batch control tests, which provide evidence that only those products are marketed which conform to the specifications laid down in the marketing authorization procedure. Products for SIT prepared for a patient on the basis of the physician’s prescription – so-called named patient products – cannot be subjected to a marketing authorization review. Therefore, they are not subject to the pharmaco-surveillance by the PEI regarding quality, safety and efficacy. This article describes the different marketing authorization procedures in the European Union (EU) and addresses the problems related to the marketing authorization requirements.