GUIDELINES TO ASSURE THE QUALITY, SAFETY AND EFFICACY OF RECOMBINANT HUMAN PAPILLOMAVIRUS VIRUS¬LIKE 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) 皮卷尺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空调铝箔。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微生物添加剂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环氧大豆油丙烯酸酯
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. Guidelines on manufacturing）
3.1定义 definitions
3.1.1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.
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 virus¬like particle: A non¬infectious, non¬enveloped, icosahedral capsid particle which does not contain viral DNA and which is composed 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 seed lot. The inoculum intermediate has a defined shelf¬life. 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 defined conditions (typically <−60 °C for yeast, and in liquid nitrogen fo电机接线柱r 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 condi
tions (typically <−60 °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 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 lifetime 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 microorganisms 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:n-苯基咔唑 A suspension of cells harvested at the end of the yeast fermentation stored frozen (<¬60°C).
Single antigen harvest: A cell¬suspension 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, collected into a single vessel before clarification.
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