Document #文件号

成都生物制品研究所 1881E 208 PVP CV(AC)01 0

Chengdu Institute of Biological
Products Page 1 of 6

CLEANING VALIDATION
清洁验证

ESTABLISHING OF ACCEPTANCE CRITERIA FOR

VACCINE LINE BUILDING 208

208 厂房乙脑疫苗线清洁验证接受限度设立

JEV MANUFACTURING PROCESS PROJECT

乙脑疫苗生产工艺项目
BUILDING 208
208 厂房
 成都生物制品研究所 Document #文件号
1881E 208 PVP CV(AC)01 0
Chengdu Institute of Biological
Products
Page 2 of 6
Establishing of Acceptance Criteria for
Vaccine Line Building 208
208厂房乙脑疫苗线清洁验证接受限度设立

 DOCUMENT APPROVAL 文件审批

The signatures listed below indicate the colleagues responsible for the preparation，review and
approval of this document.
下面表格的签署表明该文件已经被审核和批准。

Prepared by 编制 管日建
VTI Project Validation Manager Signature 签名 Date 日期
VTI 验证项目经理

Reviewed by 审核
郭红
CDIBP Validation Engineer Signature 签名 Date 日期
成都生物制品研究所验证工程师

Reviewed by 审核
赵赟力
CDIBP Validation Manager Signature 签名 Date 日期
成都生物制品研究所验证经理

Approved by 批准
孟丽
CDIBP QA Manager Signature 签名 Date 日期
成都生物制品研究所 QA 经理

 OBJECTIVE 目的
The objective of this document is to establish science-based acceptance criteria of cleaning validation of JE
formulation/filling line in building 208.
此文件的目的是为 208 厂房的乙脑疫苗制备、分装线的清洁验证设立科学的清洁验证接受标准。

 SCOPE 范围
o The scope of this document is limited to the acceptance criteria
establishing for formulation/filling manufacturing of JE vaccine located in
building 208.
本文件的范围限于 208 厂房乙脑制备和分装的清洁验证接受标准的制定。

o Some equipment such as the rubber stopper bowl, stop hopper and
vacuum plate, Lyophilization machine, which surface is not the dug
substance directly contact parts, will not considered during calculation of
the total share equipment contact area. However, these machines and the
upstream equipment will adopt the cleaning validation limit set according
to this documents as appreciate.
部分设备（如胶塞震荡盘，胶塞仓，真空吸塞盘，冻干机）其表面不与药
物成份直接接触，在计算总的共享面积时将不考虑。但是这些设备和上游
的设备将适当采用本文件设定的清洁验证的限度。
 成都生物制品研究所 Document #文件号
1881E 208 PVP CV(AC)01 0
Chengdu Institute of Biological
Products
Page 3 of 6
Establishing of Acceptance Criteria for
Vaccine Line Building 208
208厂房乙脑疫苗线清洁验证接受限度设立

o Dilution line is risk low line. However, aseptic media simulation filling will
be performed on this line (the TSB will be considered as the worst soil to
be removed on that line). So another cleaning validation will be performed
on that line.
稀释剂线风险较低。但是考虑到需要在这条线上进行培养基模拟灌装（TSB
被认为是那条线上的最难清洗的物料），将会对这条线进行另外的清洁验
证。

 REFERENCE DOCUMENTS 参考文件

The following documents were used as references in this document.
以下是此文件的参考文件。
Table 1: Reference Documents 参考文件

Document Name 文件名 Version 版本

PDA TR No.29 Points to Consider for Cleaning Validation 2012

PDA 技术报告 29 清洁验证要点
PDA TR No.49 Points to Consider for Biotechnology Cleaning 2010
Validation
PDA 技术报告 49 生物技术产品清洁验证要点

 PRINCIPAL TO ESTABLISH THE ACCEPTANCE CRITERIA 标准设立原则

The determination of cleaning validation acceptance criteria is a crucial element of a good cleaning
validation program. A limit is one of the requirements of the acceptance criteria of a cleaning
validation protocol. Good acceptance criteria should be:
清洁验证标准的确定对于良好清洁验证计划来说至关重要。限度是清洁验证方案的有关接受标准的
一个重要要求。好的接受标准应该：

- Practical 基于实际

- Verifiable 可核实

- Achievable 可达到

- Scientifically sound 科学合理

It is very important that the cleaning limits not be selected arbitrarily but rather, that there be a
logical and scientific basis for the numerical selected. The scientific rationale which supports the
actual limit should be logical, comprehensive and easily understood. Some time the calculated limit
is too low or too high to test, and then the LOQ (Limit of Quantitation) may be a limit for the actual
cleaning validation. Some time the calculated limit is too high and the visual inspection is easily to
found, the lower limit visual determination limit is normally adopted.
清洁限度的选择不可不通过基于逻辑的科学的方法而武断的确定。支持限度的科学的方法应该符合
逻辑，易于理解。当然有时基于计算的限度太低或太高而不能测试可以使用定量限作为清洁验证限
度。

Limits for cleaning validation generally contain some measure related to the active protein (or
major component of interest), some measure related to the cleaning agent, some measure related
to the bioburden levels, some measure related to endotoxin levels, and a requirement that the
equipment be visually clean.
 成都生物制品研究所 Document #文件号
1881E 208 PVP CV(AC)01 0
Chengdu Institute of Biological
Products
Page 4 of 6
Establishing of Acceptance Criteria for
Vaccine Line Building 208
208厂房乙脑疫苗线清洁验证接受限度设立

清洁验证的限度一般包括活性蛋白质（或其主要组成部分）的相关测试，清洁剂相关测试，微生物
限度相关测试，内毒素水平相关测试以及设备目视清洁等。

The possible process soil of the JE vaccine includes: culture media, buffer solutions during the cell
culture stage; aqueous salt solution, formulation components such as excipients and stabilizer
during formulation/fill stage; cleaning agent e.g. alkali/acid solution. Because of the degradation of
protein during cleaning process, the TOC is select to measure the organic residue (and the carbon
percent is supposed as 50%). The conductivity is selected to measure the residue of the ions.
乙脑疫苗的可能的工艺污染物包括：细胞培养阶段培养基，缓冲液等，配制/灌装阶段的保护剂等辅
料，酸碱清洁剂等。由于在清洗过程中蛋白质会降解，因此选用总有机碳来测试有机物的残留（假
定含碳率 50%）。选用电导率测试离子的残留。

In the following limit establishment, issues for limits are considered based on the nature of the
residue and on the stage of the manufacturing (e.g. bulk active vs formulation/fill). However, the
upstream 15L bottle and related silicone tubes used for the JE virus culture incubation, single
harvest and pool piping system will still be considered during the calculation.
在接受限度建立时，将考虑残留物的性质以及处于生产中的那个阶段（如在生产活性组分阶段还是
在配制/分装阶段）。然而，用于乙脑病毒的孵化的上游的 15L 玻璃瓶、单一收获物和收集导引管等
与活性蛋白质接触的表面将在计算标准时加以考虑。

For vaccines in which the active ingredient can not be measured at very lower level or where there
is no human dosage information/toxicological data available, for example, for antigens, it is
recommended that the dose calculation is not performed at all and the default limit (10ppm) for the
residue acceptable level calculations is used.
对于疫苗来说，如其活性组分在很低水平时不能测量或缺乏剂量或毒性数据，如抗原，可不进行日
剂量相关的计算而采用缺省值(10ppm)来进行接受标准的计算。

All of the product contact equipment will be cleaned and sterilized prior to use. So based on the
sterilization capability, purified water limit (100CFU/mL) is considered adequate. And set
10CFU/mL as the yeast and mold count. For objectionable organisms will not be tested during
cleaning validation as evaluated by CDIBP team.
所有的产品接触表面在清洁后使用前都要经过灭菌。因此相对于灭菌能力来讲，纯化水的标准
(100CFU/mL) 是足够的。霉菌标准设定为 10CFU/mL。经 CDIBP 评估，清洁验证中致病菌不进行检
测。

The limit should be reviewed when the change made to the batch size, equipment, process,
product dose, sampling area, dilution volume, rinsing sample solvent volume, introduce new
product. Modify as applicable.
当影响标准设立的因素如批量，设备，工艺，产品剂量，取样面积，稀释体积，淋洗溶剂体积，引
入新产品是应回顾接受标准。需要时进行修订。

 ACCEPTANCE CRITERIA ESTABLISHING 接受标准设立

o Visual Inspection 目视检查

No solvent or cleaning agent residue can be visually seen on product contact surface.
产品接触表面上目视没有残留溶剂或清洁剂

o Bioburden 微生物检查

TAMC (total aerobic microbial count): ≤100CFU/mL

细菌总数
 成都生物制品研究所 Document #文件号
1881E 208 PVP CV(AC)01 0
Chengdu Institute of Biological
Products
Page 5 of 6
Establishing of Acceptance Criteria for
Vaccine Line Building 208
208厂房乙脑疫苗线清洁验证接受限度设立

TYMC (total yeast and mold count): ≤10CFU/mL

霉菌总数

o Endotoxin Limit in rinsing sample 淋洗水内毒素

≤0.25 EU/mL.

o Conductivity in rinsing sample 淋洗水电导率

≤1.3 µS/cm.

o TOC 总有机碳

Maximum Residue Limit (MRL)单位设备表面 TOC 允许最大残留：≤2.09 µg/cm2

Swab Method 擦拭取样法:

Sampling area (SA), dilution volume(DV) and sampling recovery rate(SRR) of different
contact material will be considered and calculated then compare to this limit to determine
pass or fail. Formula as below:
取样面积，稀释体积和不同材质的取样回收率需要考虑，进行计算后与本标准比较确定是否
合格。公式如下：

QCresults sampe  QCresults negative (ug / mL)  DV (mL)

Actual Re sult (ug / cm 2 ) 
SRR  SA(cm 2 )

Rinse Method 淋洗取样法：

Rinsed area (RA), rinse solvent volume(RV) and sampling recovery rate(SRR) of different
contact material will be considered and calculated then compare to the above acceptance
criteria to determine pass or fail. Formula as below:
淋洗面积(RA)，淋洗溶剂体积(RV)和不同材质的取样回收率(SRR)需要考虑，进行计算后与
本标准比较确定是否合格。公式如下：

(QCresults sample  QCresults negative )(ug / mL )  RV ( mL)

Actual Re sults(ug / cm 2 ) 
SRR  RA(cm 2 )
 成都生物制品研究所 Document #文件号
1881E 208 PVP CV(AC)01 0
Chengdu Institute of Biological
Products
Page 6 of 6
Establishing of Acceptance Criteria for
Vaccine Line Building 208
208厂房乙脑疫苗线清洁验证接受限度设立

Appendix 1: TOC Residue Acceptance Criteria Calculation Sheet

(JE vaccine line in Building 208)
附录 1：208 厂房乙脑疫苗线 TOC 残留接受标准