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1、GUIDELINES TO ASSURE THE QUALITY, SAFETY AND EFFICACY OF RECOMBINANT HUMAN PAPILLOMAVIRUS VIRUSLIKE PARTICLE VACCINES HPV二、Special consideration section: 在生产、非临床及临床中过程中的考虑因素：1、 生产方面：VLP是复杂的生物产物，必须在不同水平下对其进行检测分析。因而在其生产过程及质量控制上必须考虑以下几个因素：1) 新的表达体系如杆状病毒（GSK），新的特殊要求。但我们用的毕赤酵母，相对比较常见。2) 新佐剂（略）3) 天然的L1蛋白是
2、没有被糖基化修饰，目前的两种表达体系，在糖基化修饰上不存大问题,但要对糖基化及其位点进行分析。4) L1衣壳蛋白亚单位的解聚与再聚，可能有利于纯化，并得到更稳定的VLP。目前，我们的路线可能是不经解聚，直接纯化获得VLP。个人感觉，到后期可以兵分两路，一路直接获得VLP，而另一路则将VLP解聚后，再进行纯化与重组。5) 纯化后的L1 VLP要进行生化及免疫上的鉴定，并测定L1的浓度、纯度及组聚情况。6) 如加入了防腐剂，应对其免疫性进行验证，并确认不会有负作用2、 非临床方面：关键就是要证明其免疫原性，并能否产生免疫中和抗体。3、 临床方面：（略）三、生产指导（Part A. Guidelin
3、es on manufacturing）3.1定义 definitions3.1.1国际名称和专有名称国际名称：重组人乳头瘤类病毒颗粒疫苗（基因型16 L1蛋白）3.1.2定义描述重组HPV VLP疫苗为无菌的液态疫苗，里面含纯化后由一种或多种HPV基因型重组的主要的衣壳蛋白，并与相应佐剂混合。3.1.3国际标准品在此指导原则编写时，市场上暂无国际标准品提供。但有相应试剂在实验室水平上，在进行注射后进行生物效价方面的评价如抗体滴度和病毒DNA检测。3.2术语Terminology The definitions given below apply to this document only.
4、HPV L1 protein: The major structural protein of human papillomavirus, of which 360 molecules are found in the native virion associated in 72 pentameric capsomers. L1 viruslike particle: A noninfectious, nonenveloped, icosahedral capsid particle which does not contain viral DNA and which is composed
5、of regular arrays of L1 pentameric capsomers. Parental yeast cell: Yeast host cell to be manipulated for the expression of protein(s) to give rise to a recombinant yeast production strain. Inoculum intermediate: A quantity of recombinant baculovirus of uniform composition, derived from the working s
6、eed lot. The inoculum intermediate has a defined shelflife. It is intended to be used to initiate the production of recombinant L1 proteins. Cell bank: A collection of ampoules containing aliquots of a suspension of cells from a single pool of cells of uniform composition, stored frozen under define
7、d conditions (typically 60 C for yeast, and in liquid nitrogen for insect or mammalian cell lines). Master cell bank (MCB): A collection of containers containing aliquots of a suspension of cells from a single pool of cells of uniform composition, stored frozen under defined conditions (typically 60
8、 C for yeast, and in liquid nitrogen for insect or mammalian cell lines). The MCB is used to derive all working cell banks for the anticipated lifetime of the vaccine product. Working cell bank (WCB): A collection of containers containing aliquots of a suspension of cells from a single pool of cells
9、 of uniform composition, derived from the MCB, stored frozen under defined conditions (typically 60 C for yeast, and in liquid nitrogen for insect or mammalian cell lines). One or more aliquots of the WCB are used for routine production of the vaccine. Multiple WCBs are made and used during the life
10、time of vaccine product Production cell culture: A cell culture derived from one or more containers of the WCB used for the production of vaccines. End of production cells: A cell suspension containing the cells harvested at the end of culture/fermentation. Adventitious agents: Contaminating microor
11、ganisms of the virus, or cell substrate or materials used in their cultures, that may include bacteria, fungi, mycoplasmas, and endogenous and exogenous viruses that have been unintentionally introduced. Fermentation cell paste: A suspension of cells harvested at the end of the yeast fermentation st
12、ored frozen (60C). Single antigen harvest: A cellsuspension containing the intended HPV antigens of one virus type harvested from cell cultures prepared from a single production run Single harvest pool: A homogenous pool of multiple single harvests of the intended HPV antigens of one virus type, col
13、lected into a single vessel before clarification. Purified monovalent antigen bulk: A batch of purified antigen of the same HPV type. Different batches of purified monovalent antigen bulks may be pooled before collection into a single vessel. Adsorbed monovalent antigen bulk: A batch of purified mon
14、ovalent antigen bulk adsorbed on an aluminium containing adjuvant. Different batches of adsorbed monovalent antigen bulks may be pooled before collection into a single vessel. Adjuvant: A vaccine adjuvant is a component that potentiates the immune response to an antigen and/or modulates it towards t
15、he desired immune responses. Final vaccine bulk: The formulated bulk present in the container from which the final containers are filled. The final bulk may be prepared from one or more adsorbed monovalent antigen bulks and may contain VLP antigens from one or multiple HPV virus types. Filling lot (
16、final vaccine lot): A collection of sealed final containers of vaccine that is homogeneous with respect to the risk of contamination during the filling process. A filling lot must therefore have been filled or prepared in one working session.3.3生产建议生产必须符合GMP要求，生物安全上要求无菌。不同类型HPV L1 VLP应分别生产，同时，还要有充分的清洁验证。抗原生产过程，须验证以证明生产的稳定性，至少要连续三批。但如两种蛋白的纯化步骤一样，可只用验证一种。生产一致性评估应包括关键质量参数评估及它们相应的特征，如宿主DNA与HCP
