The History, Present and Future of Allergen Standardization in the United States and Europe

Zimmer, Julia; Bridgewater, Jennifer; Ferreira, Fátima; Ree, Ronald van; Rabin, Ronald L.; Vieths, Stefan

doi:10.3389/fimmu.2021.725831

Cited by 27 publications

(50 citation statements)

References 86 publications

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“…The European Pharmacopoeia specifies quality requirements including processes and methods on manufacturing and analysis of medicinal products (38). As such, allergen standardization requires a reference standard(s) as well as a thorough confirmation of its identity, quality, potency, and safety through all phases of product development (12). The reference standard is used to ensure lot-to-lot consistency of allergenic potency.…”

Section: Discussionmentioning

confidence: 99%

“…A drug substance reference standard is rigorously qualified using all the tests on the drug substance manufacturer’s COA, as well as highly characterized using additional analytical methods (US Pharmacopeia or European Pharmacopoeia) that are a necessary activity in the process of drug standardization. As mentioned previously, when preparing allergen for use as subcutaneous immunotherapy treatment, practice guidelines and regulatory authorities suggest choosing standardized allergens when available because of the safety and efficacy advantages of limiting potency variation (8, 12). No such guidelines currently exist for allergens used as food OIT, but the regulatory pathway for the commercial development of an OIT for food allergy has been clarified.…”

Section: Discussionmentioning

confidence: 99%

“…Allergen standardization refers to maintaining consistency within manufacturing process and analytical capabilities between lots of allergen products and between products from different manufacturers; it is intended to improve both safety and efficacy of allergen immunotherapy (12). This requires the use of rigorously qualified and highly characterized reference standards against which each lot must be measured for potency (i.e., allergenic activity) as well as other quality attributes (e.g., identity).…”

Section: Introductionmentioning

confidence: 99%

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Manufacturing Processes of Peanut (Arachis hypogaea) Allergen Powder-dnfp

Leonard

Ogawa

Jedrzejewski

et al. 2022

Preprint

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Background: Important components of drug safety, efficacy, and acceptability involve manufacturing and testing of the drug substance and drug product. Peanut flour sourcing/processing and manufacturing processes may affect final drug product allergen potency and contamination level, possibly impacting drug safety, quality, and efficacy. We describe key steps in the manufacturing processes of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Palforzia®), a drug used in oral immunotherapy (OIT) for the treatment of peanut allergy. Methods: Established criteria for source material must be met for manufacturing PTAH drug product. Degree of roasting was determined with a Hunter colorimeter. Protein/allergen content, identity, potency, safety, and quality of each batch of PTAH drug substance were assessed with a combustion analyzer, allergen-specific Western blot (immunoblotting), ELISA, and HPLC; contaminants (i.e., aflatoxin) were measured by UPLC. Results: Roasting degree beyond ″light roast″ was associated with variable degrees of protein allergen degradation, or potentially aggregation, particularly for Ara h 1 and Ara h 3. Relative potency and amounts of protein allergens showed variability due in part to seasonal/manufacturing variability. Proportion of lots not meeting aflatoxin limits has increased in recent years. Up to 60% of peanut flour source material failed to meet screening selection acceptance criteria for proceeding to drug substance testing, mostly because of failure to meet potency acceptance criteria. Other lots were rejected due to safety and quality. Influence of potency variation, within specification parameters, on safety/tolerability observed in trials was considered low, in part due to stringent controls placed at each step of manufacture. Conclusions: Extensive variability in allergen potency is a critical issue during immunotherapy, particularly during OIT initial dose escalation and up-dosing, as it may result in lack of efficacy or avoidable adverse allergic reactions. Based on EU and US regulatory requirements, the production of PTAH includes manufacturing controls to ensure drug product safety, potency, and quality. For example, although PTAH contains all peanut allergens, each lot has met strict criteria ensuring consistent allergenic potency of Ara h 1, Ara h 2, and Ara h 6. The rigor of PTAH manufacturing process ensures reliable dose consistency and stability throughout its shelf life.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Manufacturing Processes of Peanut (Arachis hypogaea) Allergen Powder-dnfp

Leonard

Ogawa

Jedrzejewski

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In other words, to meet acceptance criteria, peanut flour lots A drug substance reference standard is rigorously qualified using all the tests on the drug substance manufacturer's COA, as well as highly characterized using additional analytical methods (US Pharmacopeia or European Pharmacopoeia) that are a necessary activity in the process of drug standardization. As mentioned previously, when preparing allergens for use as subcutaneous immunotherapy treatment, practice guidelines and regulatory authorities suggest choosing standardized allergens when available because of the safety and efficacy advantages of limiting potency variation (8,12). No such guidelines currently exist for allergens used as food OIT, but the regulatory pathway for the commercial development of an OIT for food allergy has been clarified.…”

Section: Discussionmentioning

confidence: 99%

Manufacturing processes of peanut (Arachis hypogaea) allergen powder-dnfp

Leonard

Ogawa²,

Jedrzejewski³

et al. 2022

Front. Allergy

View full text Add to dashboard Cite

BackgroundImportant components of drug safety, efficacy, and acceptability involve manufacturing and testing of the drug substance and drug product. Peanut flour sourcing/processing and manufacturing processes may affect final drug product allergen potency and contamination level, possibly impacting drug safety, quality, and efficacy. We describe key steps in the manufacturing processes of peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; Palforzia®), a drug used in oral immunotherapy (OIT) for the treatment of peanut allergy.MethodsEstablished criteria for source material must be met for manufacturing PTAH drug product. Degree of roasting was determined with a Hunter colorimeter. Protein/allergen content, identity, potency, safety, and quality of each batch of PTAH drug substance were assessed with a combustion analyzer, allergen-specific Western blot (immunoblotting), ELISA, and HPLC. Contaminants (ie, aflatoxin) were measured by UPLC.ResultsRoasting degree beyond “light roast” was associated with variable degrees of protein allergen degradation, or potentially aggregation. Relative potency and amounts of protein allergens showed variability due in part to seasonal/manufacturing variability. Proportion of lots not meeting aflatoxin limits has increased in recent years. Up to 60% of peanut flour source material failed to meet screening selection acceptance criteria for proceeding to drug substance testing, mostly because of failure to meet potency acceptance criteria. Other lots were rejected due to safety (ie, aflatoxin) and quality. Influence of potency variation, within specification parameters, on safety/tolerability observed in trials was considered low, in part due to stringent controls placed at each step of manufacturing.ConclusionsExtensive variability in allergen potency is a critical issue during immunotherapy, particularly during OIT initial dose escalation and up-dosing, as it may result in lack of efficacy or avoidable adverse allergic reactions. Based on EU and US regulatory requirements, the production of PTAH includes manufacturing controls to ensure drug product safety, potency, and quality. For example, although PTAH contains all peanut allergens, each lot has met strict criteria ensuring consistent allergenic potency of Ara h 1, Ara h 2, and Ara h 6. The rigor of PTAH's manufacturing process ensures reliable dose consistency and stability throughout its shelf life.

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“…The U.S. Food and Drug Administration (FDA) recently approved SLIT in tablet form for use in the United States. 3 , 4 , 22 , 23 , 24 …”

Section: Allergen Immunotherapy Modalities Available In Brazilmentioning

confidence: 99%