Mathonet Serge, Mahler Hanns-Christian, Esswein Stefan T, Mazaheri Maryam, Cash Patricia W, Wuchner Klaus, Kallmeyer Georg, Das Tapan K, Finkler Christof, Lennard Andrew
Global Regulatory Affairs-Biologics CMC, Sanofi R&D, 91385 Chilly-Mazarin, France;
Drug Product Services, Lonza AG, 4002 Basel, Switzerland;
PDA J Pharm Sci Technol. 2016 Jul-Aug;70(4):392-408. doi: 10.5731/pdajpst.2015.006189. Epub 2016 Apr 18.
Regulatory monographs in Europe and the United States require drug products for parenteral administration to be "practically free" or "essentially free" of visible particles, respectively. Both terms have been used interchangeably and acknowledge the probabilistic nature of visual particle inspection. The probability of seeing a particle in a drug product container varies according to the size and nature of the particles as well as container and inspection conditions. Therefore, the term "without visible particles" can be highly misleading in the context of what is practically achievable. This may lead to differences in understanding between industry practitioners and regulatory agencies. Is this term intended to mean "zero particles", or is there any intention to distinguish between particle type such as "zero extraneous visible particles" or "zero proteinaceous particles"? Furthermore, how can "zero" particles as a criterion for release testing be reconciled with "practically free from particles" as stated in the definition and a low, justified level of proteinaceous particles after production?The purpose of this position paper is to review best practices in the industry in terms of visual inspection process and associated operator training, quality control sampling, testing, and setting acceptance criteria corresponding to "practically free of visible particles" and providing considerations when visible proteinaceous particles are deemed unavoidable. It also provides a brief overview of visible particle characterization and gives perspectives on patient safety. This position paper applies to biotechnology-derived drug products including monoclonal antibodies in late-phase development to licensed products.
In the 2011 monoclonal antibody monograph revision, European Pharmacopoeia experts acknowledged that protein products may also contain proteinaceous particles at release or that protein particles may form during storage. Indeed, industry experience has demonstrated that therapeutic proteins such as monoclonal antibodies can exhibit a propensity for self-association leading to the formation of aggregates that range in size from nanometres (oligomers) to microns (subvisible and visible particles). As a result, the requirement for drug product appearance for monoclonal antibodies was changed from "without visible particles" to "without visible particles unless otherwise authorised or justified". In our view, "practically free from particles" should be considered a suitable acceptance criterion for injectable biotechnology and small-molecule products, as long as appropriately defined. Furthermore, we argue that visual inspection is a suitable quality control release test and that "practically free from particles" is a suitable specification when adequately described.
欧洲和美国的监管专论要求注射用药品分别“几乎无”或“基本无”可见颗粒。这两个术语一直被交替使用，并且承认了目视颗粒检查的概率性质。在药品容器中看到颗粒的概率会根据颗粒的大小和性质以及容器和检查条件而有所不同。因此，“无可见颗粒”这一术语在实际可实现的情况下可能会产生很大的误导性。这可能会导致行业从业者和监管机构之间理解上的差异。这个术语是指“零颗粒”，还是有意区分颗粒类型，如“零外来可见颗粒”或“零蛋白质颗粒”呢？此外，作为放行测试标准的“零”颗粒如何与定义中所述的“几乎无颗粒”以及生产后合理的低水平蛋白质颗粒相协调呢？本立场文件的目的是回顾行业在目视检查过程及相关操作人员培训、质量控制抽样、测试以及设定与“几乎无可见颗粒”相对应的验收标准方面的最佳实践，并在认为不可避免出现可见蛋白质颗粒时提供相关考虑因素。它还简要概述了可见颗粒的特性，并就患者安全给出了观点。本立场文件适用于从处于后期开发阶段的生物技术衍生药品，包括单克隆抗体，到已获许可的产品。
在2011年单克隆抗体专论修订中，欧洲药典专家承认蛋白质产品在放行时可能也含有蛋白质颗粒，或者在储存过程中可能形成蛋白质颗粒。实际上，行业经验表明，诸如单克隆抗体之类的治疗性蛋白质可能具有自我缔合的倾向，从而导致形成大小从纳米（寡聚体）到微米（亚可见和可见颗粒）不等的聚集体。因此，单克隆抗体药品外观的要求从“无可见颗粒”改为“无可见颗粒，除非另有授权或合理说明”。我们认为，“几乎无颗粒”应被视为注射用生物技术和小分子产品的合适验收标准，只要定义得当。此外，我们认为目视检查是合适的质量控制放行测试，并且“几乎无颗粒”在充分描述时是合适的规格要求。
