Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, Utrecht 3508 TB, the Netherlands; Pharmaceutical Product Evaluation Directorate, Drug sector, Saudi Food, and Drug Authority, Riyadh, Saudi Arabia.
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, Utrecht 3508 TB, the Netherlands; Foundation Pharmacy for Hospitals in Haarlem, Haarlem, the Netherlands; Department of Clinical Pharmacy, Spaarne Gasthuis, Haarlem/ Hoofddorp, the Netherlands.
Eur J Pharm Sci. 2022 Aug 1;175:106227. doi: 10.1016/j.ejps.2022.106227. Epub 2022 May 27.
The manufacturing of biopharmaceuticals is complex, and minor changes in the process may affect quality attributes (QAs) that may, in turn, impact clinical outcomes. Regulatory documents from the European Medicines Agency were used to characterize two aspects, nature and timing, of post-approval MCs for originators and biosimilars TNF-α inhibitors that were on the European market up to May 2021. The nature of MCs was evaluated in two ways: (1) the type of MCs related to the drug substance (DS) or drug product (DP), classified as manufacturing, quality control, composition, packaging, or stability with various subtypes; and (2) the risk level according to the potential impact of the MCs on QAs, classified as low, medium, or high. Timing was defined as the date of the regulatory decision on the MC in relation to the approval date. We identified 801 post-approval MCs implemented to originators (mean: 137, range: 112-175) and biosimilars (mean: 30, range: 0-133). Most of implemented MCs for originators and biosimilars were classified as low and medium risk (88.1%), and a small fraction were considered high-risk (11.9%). The average incidence rates were comparable for both originators and biosimilars (7.0/year for MCs, 0.8/year for high-risk MCs). In 20% of MCs introduced to biosimilars, the DP manufacturing site was involved (9% for originators). In contrast, 16% of MCs introduced to originators were related to the DS manufacturing processes (only 7% for biosimilars). In conclusion, while the overall MC incidence rate and the risk level of MCs was not substantially different between TNF-α inhibitor products, we observed some differences in a few types of MCs related to DS manufacturing process and DP manufacturing site between originators and biosimilars. As far as our data shows there is no reasons to assume that post-approval MCs will lead to differences between TNF-α-i originators and biosimilars in clinical practice.
生物制药的制造过程非常复杂，过程中的微小变化都可能影响质量属性（QA），进而影响临床结果。本研究使用欧洲药品管理局的监管文件，对截至 2021 年 5 月在欧洲市场上的原研 TNF-α 抑制剂和生物类似药的上市后变更（MA）的两个方面，即性质和时间进行了描述。MA 的性质通过两种方式进行评估：（1）与药物物质（DS）或药物产品（DP）相关的 MA 类型，分为制造、质量控制、组成、包装或稳定性，并有各种亚型；（2）根据 MA 对 QA 的潜在影响进行风险级别分类，分为低、中、高。时间定义为监管部门对 MA 的决定日期与批准日期之间的关系。我们确定了 801 项原研和生物类似药实施的上市后 MA（平均值：137，范围：112-175）。原研和生物类似药实施的大多数 MA 被归类为低风险和中风险（88.1%），一小部分被认为是高风险（11.9%）。原研和生物类似药的平均发生率相似（MA 为 7.0/年，高风险 MA 为 0.8/年）。在引入生物类似药的 20%的 MA 中，DP 制造地点涉及其中（原研药为 9%）。相比之下，在引入原研药的 16%的 MA 中，DS 制造过程相关（生物类似药仅为 7%）。总之，虽然 TNF-α 抑制剂产品的总体 MA 发生率和 MA 风险水平没有实质性差异，但我们观察到原研药和生物类似药之间在与 DS 制造工艺和 DP 制造地点相关的几种 MA 类型上存在一些差异。就我们的数据来看，没有理由认为上市后 MA 会导致 TNF-α-i 原研药和生物类似药在临床实践中的差异。
