Science Supporting Regulation: Process of setting exceptions in Allergen Regulations René Crevel ILSI Food Allergy Task Force - PDF

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Science Supporting Regulation: Process of setting exceptions in Allergen Regulations René Crevel ILSI Food Allergy Task Force VIII Updates on Food Safety Symposium Sao Paulo, Brazil November 10, 2016 Background:

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Science Supporting Regulation: Process of setting exceptions in Allergen Regulations René Crevel ILSI Food Allergy Task Force VIII Updates on Food Safety Symposium Sao Paulo, Brazil November 10, 2016 Background: Allergen labelling in the European Union Directive 2003/89/EC, amending Directive 2000/13/EC (Labelling Directive) Allergen labelling mandatory from 25 November 2005 Provided for exemptions Regulation 1169/2011 (Food Information for Consumers Regulation) Applicable from 14 December Exempted ingredients (1) Allergenic food Cereals containing Gluten, i.e. wheat, rye, barley, oats, spelt, kamut Exempted ingredient Wheat based glucose syrups inc. dextrose Wheat based maltodextrins Glucose syrups based on barley Cereals used for making distillates or ethyl alcohol of agricultural origin for spirit drinks and other alcoholic beverages. Fish Fish gelatine used as carrier for vitamin or carotenoid preparations Fish gelatine or Isinglass used as fining agent in beer and wine 3 Exempted ingredients (2) Allergenic food Soybeans Exempted ingredient Fully refined soybean oil and fat(1) including interesterified and partially hydrogenated soybean oil and fat Natural mixed tocopherols (E306), natural D-alpha tocopherol, natural D-alpha tocopherol acetate, natural D-alpha tocopherol succinate from soybean sources Vegetable oils-derived phytosterols and phytosterol esters from soybean sources Plant stanol ester produced from vegetable oil sterols from soybean sources 4 Exempted ingredients (3) Allergenic food Milk Exempted ingredient whey used for making distillates or ethyl alcohol of agricultural origin for spirit drinks and other alcoholic beverages. lactitol Nuts Nuts used for making distillates or ethyl alcohol of agricultural origin for spirit drinks and other alcoholic beverages (1) products derived from exempted ingredients are also exempted, in so far as the process that they have undergone is not likely to increase the level of allergenicity assessed by the EFSA for the relevant product from which they originated 5 Basis of Currently implemented exemptions The Directive (2003/89/EC) contained a provision for exempting derived ingredients: Updating could also be effected by the deletion from Annex IIIa of ingredients for which it has been scientifically established that it is not possible for them to cause adverse reactions. To this end, the Commission may be notified of the studies currently being conducted to establish whether ingredients or substances, derived from ingredients listed in Annex IIIa are not likely. to trigger adverse reactions. Directive 2003/89/EC: The Commission provided guidance for the contents of dossiers submitted in support of an exemption Initial focus was on temporary exemptions EFSA has subsequently developed guidance (later) Commission guidance (1) Who may notify? Producers or manufacturers of the derived substances, or of foodstuffs including such substances, or representative associations of those producers or manufacturers. What may be notified? Only derived ingredients or substances may be notified, not the original allergenic substance. So, peanut oil may be notified, but not peanuts (even when used in infinitesimal quantity). Notification is limited to generic derivatives, NO branded ingredients. Commission guidance (2) Content of dossier What is the substance and how is it used: A clear characterisation of the ingredient or substance for which a (temporary) deletion from Annex IIIa is sought, and of the method, as well as conditions under which the consumers are exposed to it. What is the scientific evidence for exemption: Arguments and data that support the claim that the ingredient or substance is not likely to trigger adverse reactions. What work is underway to support the scientific evidence: An overall description of the studies that the applicant is conducting to determine the allergic potential of the substance considered. Exemption dossiers in practice: highly refined soybean oil The soybean oil dossier: contents - Background - Recapitulation of temporary exemption dossier - Analysis of published data based on fully documented literature search - Initial EFSA conclusion - Characterisation of material - Oils refined according to FEDIOL specifications - Quantitative protein extraction and analytical methods specifically developed (not routinely available) - IgE-binding characteristics of extracted proteins - Clinical research - Double-blind placebo controlled challenges in peanut- and soy-allergic people - Characterised patients: full allergological screen - Soybean oil/rapeseed oil [placebo] mixed with mashed potato - Exposure assessment - Worst-case scenario Background: conclusions from previously published work Highly refined soybean oil contains very small amounts of protein IgE binding was observed with a single sample of unrefined soybean oil. Only two cases of allergic responses to soybean oil have been reported: one from crude oil and one the oil was not characterised. Allergic reactions to soy require large amounts of protein Controlled clinical challenge studies showed that soybean oil was unable to provoke reactions in individuals with well-documented soybean allergy. Characterisation of soybean oil Samples of commercially-produced oils from different refiners, all produced according to FEDIOL Code of Practice Protein content measured: Crude soybean oil: 87000ng/g Fully refined soybean oil: 250ng/g Fully refined oils for challenges: 64ng/g Identification of extracted protein by mass spectrometry Identification of IgE-binding proteins by immunoblotting with IgE-positive sera from characterised soy-allergic individuals Lanes 3, 4 soybean meal Lanes 5, 6 N/RBD oil Lane 7: crude oil Clinical research (1) DBPCFC subjects 30 peanut- allergic (18-57, 13 males) (positive peanut DBPCFC) 32 soy-allergic (12-62, 10 males) (positive soy DBPCFC) DBPCFC materials Active: N/RBD soybean oil Placebo: N/RBD canola oil Protocol: escalating dose DBPCFC results (peanut-allergic) 28 completed full challenge with soy oil and 27 with canola oil; remainder stopped because of fullness. Reactions: all subjective and mild No reaction: 22/30 Soy oil only: 2/30 Placebo only: 4/30 Both soy and placebo: 2/30 Clinical research (2) DBPCFC results (soy-allergic) 31 completed full challenge with soy oil and 32 with rapeseed oil; one stopped the soy oil because of fullness. Reactions: all subjective and mild No reaction: 21/32 Soy oil only: 3/32 Placebo only: 6/32 Both soy and placebo: 2/32 Statistical analysis showed no difference in incidence of reactions between active and placebo groups Exposure assessment Used worst-case scenario, which was also the basis for the design of the challenge studies For comparison, the VITAL 2.0 reference dose for soy is 1mg (1000µg) of soy protein. The worst case scenario, by definition, vastly overestimates likely exposure. EFSA PANEL conclusions Taking into account all the information available, the Panel considers that it is not very likely that N/RBD soybean oils will trigger a severe allergic reaction in susceptible individuals under the conditions of production and use stated by the applicant Exemption dossiers in practice: Wheat starch hydrolysates (prepared and submitted by AAF) AAF File: contents Literature review Code of good practice on purification of Wheat Starch Hydrolysates Analytical studies review by external expert Exposure assessment Clinical studies review by external expert 19 Code of good practice on purification of Wheat Starch Hydrolysates To guarantee consistency in time and throughout industry Industry commitment to implement Code in Quality Management Systems New quality parameter defined to guarantee maximum residual gluten content Initially set at 100 ppm N/ds Finally set a maximum 20 ppm gluten/ds based on R5 ELISA assay (now Codex and EU limit for gluten-free ) 20 Analytical - General considerations High carbohydrate matrix Low residual protein / gluten content Non-protein nitrogen constituents Residual protein / gluten expected to be partially hydrolysed. different analytical approaches needed 21 Identification and quantification of residual N- components in Wheat Starch Hydrolysates N-content mostly below 100 ppm/ds (adapted Kjeldahl, chemiluminescence) N mainly explained by presence of phospholipid residues (NMR, ICP-OES) Less than 100 ppm true protein = limit of detection with direct HPLC amino acid analysis True protein content highly overestimated by N-measurement 22 Structural characterisation of residual proteins and peptides in Wheat Starch Hydrolysates Extraction and concentration protocol based on reversed phase chromatography good recovery ( 90%) Different approaches based on MS: MALDI TOF, LC/ES- MS/MS Semi quantification by use of different calibrators/internal standards: European gliadin standard, synthetic peptides Trace amounts of native gliadin (1-15 ppm) and gliadin/glutenin peptides ( ppm) commonly present 23 Immunochemical determination of residual gluten (1) R5 ELISA (E.Mendez, National Center for Biotechnology, Madrid, Spain) Presence of hydrolyzed protein: both sandwich (3.1 ppm) and competitive (2.4 ppm) R5 ELISA used Industry samples ( ): mainly below detection limit, exceptionally above 20 ppm gluten Study samples: mainly below detection limit, all below 5 ppm No higher levels detected with competitive R5 24 Immunochemical determination of residual gluten (2) Specific detection of toxic peptides (F. Koning, LUMC, Leiden, The Netherlands) T-cells based assay: difficult to standardize limited use mabs based assay mabs against 3 gliadin epitopes, calibrated with European gliadin standard Highest results with gliadin-γ1 mab Study samples mainly below 5 ppm, all below 12 ppm gluten mabs against LMW and HMW glutenin epitopes, calibrated with (synthetic) peptides: result cannot be converted to gluten protein 25 HPLC amino acid analysis Preparative extraction based on reverse phase chromatography (see MS study) Limited data: 0.5 to 1.4 ppm protein 26 Conclusion - Analytical Taking into account complexity of the problem, best available technologies have been used. Based on immunological and HPLC data Study samples: generally 1-5 ppm, all below 12 ppm Industry samples ( , R5): mainly below detection limit, exceptionally above 20 ppm. Industry commitment for max. 20 ppm gluten/ds Industry to further optimize refining where necessary 27 Exposure to gluten from Wheat Starch Hydrolysates Based on food consumption data from Ireland, Italy and NL Main application areas based on AAF data Total population and population groups (children-adults and malefemale) Daily (coeliac disease) and single meal (wheat allergy) consumption Realistic and worst case scenario (gluten content based on MS analysis) Daily exposure: worst case (P95) 4.3 mg Single meal exposure: worst case (P95) 1.7 mg 28 Clinical studies Two DBPCFC studies: coeliac disease and wheat allergy Wheat-based glucose syrup and maltodextrin separately evaluated Study product Same type of product for glucose syrup, maltodextrin and placebo group Taking into account exposure data Long duration CD clinical study: stability and acceptability Small scale production according to food industry standards Powdered soft drink in single dose sachets, in two flavors, adjusted to same sweetness level by the use of sucrose and intense sweeteners 29 Coeliac disease clinical study Design 90 well-characterized CD patients on a gluten-free diet Randomized in 3 groups: glucose syrup, maltodextrin and placebo Daily use over 24 weeks Parameters evaluated: mucosal morphology (biopsy), serology, gastrointestinal symptoms, malabsorption, quality of life Results Good compliance to study protocol Premature withdrawals (8) equally spread No significant difference between product and placebo groups 30 Wheat allergy clinical study Design Aiming to enroll 60 individuals with clinically proven wheat allergy Randomized in two product groups 2-days DBPCFC in clinic and 20-days reintroduction at home Parameters: clinical symptoms typical for food allergy Results 36 patients finally enrolled, 32 completing the study: limited availability, some refused to participate, children under age of 2 years not allowed to participate 2-days challenge at clinic: limited symptoms, no significant difference between product and placebo 20-days challenge: high rate of symptoms, both to product and placebo less controlled conditions in home testing or other factors (milk proteins in flavourings)? difficult to interpret 31 EFSA final opinion (3 May 2007) 32 Coeliac disease wheat-based glucose syrups, dextrose and maltodextrins are unlikely to cause an adverse reaction in individuals with coeliac disease provided that the (provisional) value of gluten considered by Codex Alimentarius for foods rendered gluten-free is not exceeded. Wheat allergy Wheat-based glucose syrups, dextrose and maltodextrins may contain levels of proteins and peptides. It is not known at which levels of intake these products would cause allergic reactions to wheat-allergic individuals. Nevertheless, taking into account all the scientific information provided and in particular the levels of wheat proteins reported in these products, the Panel considers that it is not very likely that this product will trigger a severe allergic reaction in susceptible individuals. https://www.efsa.europa.eu/en/efsajournal/pub/3417 Purpose of the guidance To update the Commission guidelines and help applicants prepare well-structured applications To provide a common format for the organisation of the information: To outline the required information and scientific data To describe the hierarchy of different types of data and study designs reflecting the relative strength of evidence highlighting the key issues which should be addressed in the application Guidance: what is required To allow a scientific evaluation...the application must contain: information on the characteristics of the food allergen-derived preparation all pertinent scientific data. Pertinent data means all human and non-human studies, published or unpublished, in favour and not in favour. where any of the required data are not relevant for a particular application, reasons/justification must be given for absence Pertinent published human data should be identified through a comprehensive review. Guidance: what type of data is required Data from food challenge studies.may provide important information regarding allergenicity. Double-blind placebo controlled food challenges (DBPCFC) are less subject to bias than single-blind challenges or open challenges. Sufficient characterisation of the study population regarding the diagnosis of food allergy is important. The selected sample size should be adequately justified within the context of each application. Data from studies in animals or other model systems alone cannot substitute for human data as evidence of non-allergenicity For more information
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