However, multiple discussions between experts, competent authorities and policymakers have led to an increasing awareness that sustainable (sur-mesure) phage therapy is not compatible with the conventional approaches to the development and application of medicinal products [4]. Next to the classical medicinal product pathway, which should be adjusted to support the industrial production of (first line) broad-spectrum phage cocktails or phage-derived products (e.g., phage endolysins), there is a need for a specific framework (including realistic production and quality and safety requirements) that allows a timely (rapid) supplying of adapted productions of natural bacteriophages for ‘personalized therapy’. This regulatory framework could be based on the Quality by Design (QbD) concept, which is increasingly applied to the development and production of biopharmaceutical molecules [7]. The QbD approach entails designing quality into the process and the product, and this in a science- and risk-based manner. Understanding patients’ needs and determining the specific science and quality characteristics of the product that are linked to safety and efficacy are crucial components of QbD. More research is urgently needed to gather the required data with regard to the efficacy of phage therapy and to broaden our understanding of bacteria-phage coevolution in nature and in the context of human disease [8, 9]. To avoid the mistakes of the past (which lead to the current antibiotic resistance crisis), phage therapy products should not exclusively be developed and marketed as antibiotics, i.e., applying current pharmacoeconomic principles. Ideally, phage therapy should be coordinated and standardized (in a first instance) by national phage therapy centers, which operate under the supervision of relevant public health authorities and in interaction with private stakeholders.
然而，专家、主管当局和政策制定者之间的多次讨论使人们日益认识到，可持续（超常规）噬菌体疗法与传统的医药产品开发和应用方法并不兼容[4]。除了应调整传统的医药产品途径以支持（一线）广谱噬菌体鸡尾酒或噬菌体衍生产品（如噬菌体内溶素）的工业化生产之外，还需要一个特定的框架（包括现实的生产、质量和安全要求），以便及时（快速）提供适应 “个性化疗法 “的天然噬菌体产品。这种监管框架可以基于设计质量（QbD）概念，这一概念正越来越多地应用于生物制药分子的开发和生产[ 7]。QbD 方法要求以科学和风险为基础，在工艺和产品中设计质量。了解患者的需求，确定产品与安全性和有效性相关的具体科学和质量特征，是 QbD 的关键组成部分。我们迫切需要开展更多研究，以收集有关噬菌体疗法疗效的必要数据，并拓宽我们对自然界和人类疾病背景下细菌与噬菌体共同进化的认识[8, 9]。为避免重蹈覆辙（导致当前的抗生素耐药性危机），噬菌体疗法产品不应完全作为抗生素开发和销售，即应用当前的药物经济学原则。理想情况下，噬菌体疗法（首先）应由国家噬菌体疗法中心进行协调和标准化，这些中心应在相关公共卫生机构的监督下运作，并与私人利益相关者进行互动。
There are precedents for such a dedicated ‘non-medicinal product’ approach. In the European Union (EU), human tissues and cells that are not considered as ‘Advanced Therapy Medicinal Products (ATMPs)’ are procured, processed, tested and allocated by (or under the responsibility of) dedicated tissue establishments and are exclusively regulated by the EU Tissue and Cell Directives (EUTCDs). The EUTCDs consist of three Directives, the parent Directive (2004/23/EC), which provides the framework legislation, and two technical Directives (2006/17/EC and 2006/86/EC), which provide the detailed requirements of the EUTCD. The purpose of these Directives was to facilitate a safer and easier exchange of human tissues and cells between member states and to improve safety standards for European citizens. They set a benchmark for the standards that must be met when carrying out any activity involving tissues and cells for human application.
这种专门的 “非医药产品 “方法已有先例。在欧盟（EU），不被视为 “先进治疗药物产品（ATMP）”的人体组织和细胞由专门的组织机构采购、加工、测试和分配（或由其负责），并受《欧盟组织和细胞指令》（EUTCDs）的专门监管。EUTCD 包括三项指令，即提供框架立法的母指令（2004/23/EC）和提供 EUTCD 详细要求的两项技术指令（2006/17/EC 和 2006/86/EC）。这些指令旨在促进成员国之间更安全、更便捷地交换人体组织和细胞，并提高欧洲公民的安全标准。它们为开展任何涉及人体应用组织和细胞的活动时必须达到的标准设定了基准。
In view of further meetings with phage experts and representatives of the competent authorities and policymakers – coordinated by the European Commission Joint Research Centre, which acts in an advisory capacity to the Commission and its policy making directorates general –, a group of ‘phage experts’ (the authors of this paper) were asked through the intermediary of a not-for-profit organization (www.p-h-a-g-e.org) to set realistic quality and safety requirements for sustainable phage therapy products (Table I). These requirements are intended to apply to the production of phage therapy products (finished products), starting from banked characterized natural therapeutic bacteriophages (Master Seed lots), and possibly using intermediate bacteriophage products (Working Seed lots or Active Substances). They were roughly based on the EUTCD quality and safety standards for human cells and were defined by consensus among 32 phage experts (biologists, geneticists, bioengineers, quality managers, pharmacists and MDs) from 12 countries. This document enumerates all possible phage product related quality and safety risks known to the experts, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research. The exact tests used and limits applied will depend on the route of administration (e.g., topical or systemic) and the regulatory path the product is being used under. These requirements do not address efficacy aspects of phage therapy products.
在欧盟委员会联合研究中心的协调下，一组 “噬菌体专家”（本文作者）与噬菌体专家及主管当局和政策制定者的代表举行了进一步会议，并通过非营利组织（www.p-h-a-g-e.org）的中介，要求他们为可持续噬菌体治疗产品制定切实可行的质量和安全要求（表 I）。这些要求旨在适用于噬菌体治疗产品（成品）的生产，从储存的特征天然治疗噬菌体（主种子批次）开始，并可能使用中间噬菌体产品（工作种子批次或活性物质）。这些标准大致以 EUTCD 人体细胞质量和安全标准为基础，由来自 12 个国家的 32 位噬菌体专家（生物学家、遗传学家、生物工程师、质量管理人员、药剂师和医学博士）协商一致确定。本文件列举了专家们已知的与噬菌体产品相关的所有可能的质量和安全风险，以及为最大限度地降低这些风险而可以进行的检测，但仅限于保护患者、允许并推进负责任的噬菌体治疗和研究所需的程度。所使用的确切测试和限制将取决于给药途径（如局部或全身给药）和产品使用的监管途径。这些要求并不涉及噬菌体疗法产品的疗效方面。
Table I Expert Consensus Quality and Safety Requirements for Sustainable Phage Therapy Products
表 I 可持续噬菌体疗法产品的质量与安全要求专家共识
Should bacteriophages be used for a public health or medical emergency and no adequate finished products, Master Seed lots or Working Seed lots are available, then less stringent requirements could be considered, pending compliance (as quick as possible) to the quality and safety requirements.
如果噬菌体被用于公共卫生或医疗紧急情况，而又没有足够的成品、主种子批次或工作种子批次，那么在（尽快）符合质量和安全要求之前，可以考虑放宽要求。