Liu Frank, Hutchinson Richard W
The Estée Lauder Companies, 155 Pinelawn Rd, Melville, NY, USA.
Janssen Pharmaceuticals, 1400 McKean Road, Spring House, PA, USA.
Regul Toxicol Pharmacol. 2023 Feb;138:105335. doi: 10.1016/j.yrtph.2023.105335. Epub 2023 Jan 4.
Extractable and leachables (E&Ls) associated with parenteral pharmaceutical products should be assessed for patient safety. One essential safety endpoint is local or systemic sensitization. However, there are no regulatory guidelines for quantitative sensitization safety assessment of E&Ls. A semiquantitative sensitization safety assessment workflow is developed to refine the sensitization safety assessment of E&Ls associated with parenteral pharmaceutical products. The workflow is composed of two sequential steps: local skin sensitization and systemic sensitization safety assessment. The local skin sensitization step has four tiers. The output from this step is the acceptable exposure level for local sensitization (AEL) and this safety threshold can be used for local sensitization safety assessment. From the derived AEL, the systemic sensitization safety assessment at step 2 proceeds in 2 tiers. The output from this workflow is the derivation of acceptable exposure level for systemic sensitization (AEL). When the estimated human daily exposure (HDE) is compared with the AEL, the margin of exposure is calculated to determine the sensitization safety of E&Ls following parenteral administration. The current work represents an initial effort to develop a scientifically robust process for sensitization safety assessment of E&Ls associated with parenteral pharmaceutical products.
应评估与注射用药品相关的可提取物和可浸出物（E&Ls）对患者的安全性。一个重要的安全终点是局部或全身致敏。然而，目前尚无针对E&Ls定量致敏安全性评估的监管指南。因此，开发了一种半定量致敏安全性评估工作流程，以完善与注射用药品相关的E&Ls的致敏安全性评估。该工作流程由两个连续步骤组成：局部皮肤致敏和全身致敏安全性评估。局部皮肤致敏步骤有四个层级。此步骤的输出是局部致敏的可接受暴露水平（AEL），该安全阈值可用于局部致敏安全性评估。根据得出的AEL，第二步的全身致敏安全性评估分两个层级进行。该工作流程的输出是全身致敏的可接受暴露水平（AEL）的推导值。将估计的人体每日暴露量（HDE）与AEL进行比较时，计算暴露限度以确定注射给药后E&Ls的致敏安全性。当前的工作代表了为开发一种科学稳健的流程以评估与注射用药品相关的E&Ls的致敏安全性所做的初步努力。
