Leonard Stephanie A, Ogawa Yasushi, Jedrzejewski Paul T, Maleki Soheila J, Chapman Martin D, Tilles Stephen A, Du Toit George, Mustafa S Shahzad, Vickery Brian P
Division of Pediatric Allergy / Immunology, University of California San Diego, Rady Children's Hospital, San Diego, CA, United States.
Medical Affairs, Aimmune Therapeutics, a Nestlé Health Science company, Brisbane, CA, United States.
Front Allergy. 2022 Oct 11;3:1004056. doi: 10.3389/falgy.2022.1004056. eCollection 2022.
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 () allergen powder-dnfp (PTAH; Palforzia®), a drug used in oral immunotherapy (OIT) for the treatment of peanut allergy.
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 (ie, aflatoxin) were measured by UPLC.
Roasting 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.
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's manufacturing process ensures reliable dose consistency and stability throughout its shelf life.
药物安全性、有效性和可接受性的重要组成部分涉及原料药和制剂的生产与测试。花生粉的采购/加工以及生产工艺可能会影响最终制剂的过敏原效力和污染水平，进而可能影响药物的安全性、质量和有效性。我们描述了用于花生过敏口服免疫疗法（OIT）的药物花生（）过敏原粉末 - dnfp（PTAH；Palforzia®）生产过程中的关键步骤。
生产PTAH制剂必须满足既定的原料标准。用亨特色度计测定烘焙程度。用燃烧分析仪、过敏原特异性蛋白质印迹法（免疫印迹法）、酶联免疫吸附测定（ELISA）和高效液相色谱法（HPLC）评估每批PTAH原料药的蛋白质/过敏原含量、特性、效力、安全性和质量。通过超高效液相色谱法（UPLC）测定污染物（即黄曲霉毒素）。
超过“轻度烘焙”的烘焙程度与不同程度的蛋白质过敏原降解或潜在聚集有关。相对效力和蛋白质过敏原含量存在变异性，部分原因是季节性/生产变异性。近年来，未达到黄曲霉毒素限量的批次比例有所增加。高达60%的花生粉原料未达到进入原料药测试的筛选选择验收标准，主要是因为未达到效力验收标准。其他批次因安全性（即黄曲霉毒素）和质量问题被拒收。在试验中观察到，在规格参数范围内，效力变化对安全性/耐受性的影响被认为较低，部分原因是在生产的每个步骤都进行了严格控制。
过敏原效力的广泛变异性是免疫疗法中的一个关键问题，尤其是在OIT初始剂量递增和加量期间，因为这可能导致疗效不佳或不可避免的过敏性不良反应。根据欧盟和美国的监管要求，PTAH的生产包括生产控制，以确保制剂的安全性、效力和质量。例如，虽然PTAH包含所有花生过敏原，但每批产品都符合严格标准，确保了Ara h 1、Ara h 2和Ara h 6的致敏效力一致。PTAH生产工艺的严格性确保了在其整个保质期内剂量的可靠一致性和稳定性。
