国家药监局发布生物制品分段生产试点方案

10月21日，国家药监局发布《生物制品分段生产试点工作方案》（下称《方案》），允许部分地区、企业、品种在约两年的期限内，对生物制品分段生产先行先试。

试点地区：包括党中央、国务院区域协调发展战略提出探索生物制品分段生产任务的省级行政区域，以及生物医药产业聚集、确有项目需求且生物制品监管能力较强的省级行政区域。

试点企业和品种：受托生产企业应具有三年以上生物制品商业化生产经验。原则上品种应当为创新生物制品、临床急需生物制品或者国家药监局规定的其他生物制品，明确提出多联多价疫苗、抗体类生物制品、抗体偶联类生物制品、胰高血糖素样肽-1类生物制品以及胰岛素类生物制品等。

传统模式下，生物制品从原材料至制剂的全链条生产由单一企业独立完成，该企业需全面监控生产过程，并对产品质量与安全承担全部责任。分段生产模式则是对医药产业链进行更深层次的细分，通过专业化分工提升整体生产效率，同时规避重复建设导致的资源浪费问题。

然而，分段生产亦伴随风险，特别是在生产流程控制与产品质量管理方面增加了难度。例如，在实操层面，对于储存条件要求严苛的生物制剂而言，运输环节可能成为引入不稳定因素的关键点。此外，在管理层面，对于跨地域生产的生物制品，需高层政策文件明确界定不同地区间的职责划分，以防权责不清的现象发生。

在药品上市许可持有人制度实施前，国内缺乏分段生产的政策土壤。2019年，随着新版《药品管理法》的正式施行，药品上市许可与生产许可实现解绑，药品上市许可持有人既可自主生产，亦可委托生产。此前，分段生产的探索仅限于化学药领域，而本《方案》的出台，标志着生物制剂领域迎来了新机遇。

《方案》就生物制剂分段生产的审核、执行及总结等关键环节提供了详尽的指导建议。对于涉及两省生产的生物制品，委托与受托企业需分别向各自所在省级药品监管部门提出申请，由两地监管部门协同制定质量监管方案，经两地政府审核后上报国家药品监督管理局。尽管提及了境外药品注册申请人与持有人，但《方案》尚未就境外受托生产企业的审核主体及流程作出具体规定，预计相关解决方案仍在积极探索之中。

本《方案》对医药行业的发展具有显著正面效应，但亦需构建更为精细且严密的全面质量管理体系，确保生物制品的质量得到坚实保障。无论是内部还是外部生产流程，每一步均需实现可追溯性，以维护生物制品的安全与有效性。

On 21 October, the National Medical Products Administration (NMPA) released the Pilot Program for Segmented Production of Biological Products ("Program"), launching a two-year trial for segmented production of biological products. Applicable to selected regions, enterprises, and product types, the Program aims to improve manufacturing efficiency by delegating specific stages of the production line to specialised manufacture sites, while ensuring product quality and safety.

Eligibility and Focus Areas:

1. Regions: The pilot will include provincial regions characterised by high concentrations of biomedical enterprises, strong regulatory capabilities, and alignment with national development strategies.

2. Enterprises: Only enterprises with at least three years of experience in the commercial production of biological products are eligible for the pilot. 

3. Products: The pilot will focus on innovative and clinically urgent biologicals, as well as those prioritised by NMPA, such as multivalent vaccines, antibody-based products, antibody-drug conjugates (ADCs), GLP-1, and insulin.

The conventional biological manufacturing model, requiring a single enterprise to oversee the entire production chain, ensures direct quality control but can be inefficient. In contrast, the segmented model enhances efficiency by assigning tasks to specialised entities and reducing redundant construction. 

However, this decentralised approach requires stringent quality management in transportation and storage, where maintaining the integrity of biological products can be challenging. Segmented production also complicates cross-regional coordination and quality control, making clear delineation of responsibilities essential for high-stakes biological products. 

Before the Marketing Authorisation Holder (MAH) system was implemented, China lacked a policy framework for segmented production. The revised Pharmaceutical Administration Law, enforced in 2019, introduced the MAH system, decoupling marketing and production authorisations and giving MAHs the choice to either produce drugs independently or outsource production. While initial trials in segmented production focused on chemical drugs, the latest trial now extends these opportunities to biological products.

The Program outlines key protocols for the review, implementation, and assessment of segmented production in biologicals. When production spans two provinces, both the commissioning enterprise, which initiates the production, and the entrusted enterprises, responsible for manufacturing, must submit applications to their respective provincial drug regulatory bodies. These bodies will collaborate to establish quality control plans, which are then reviewed by provincial governments and submitted to NMPA. However, while the Program acknowledges overseas drug registration applicants and holders, it does not yet specify the review procedures for multinational cooperation, indicating that these frameworks are still under development. 

In summary, while the Program has the potential to improve innovation and efficiency in biological product manufacturing, a robust quality management and oversight framework that enables traceability at each step is crucial for mitigating safety and efficacy risks associated with segmented production.