实验室分析仪器的验证

实验室分析仪器的验证
March 2010 王旭
目的和定义
分析仪器的验证是对所有用于产生GxP数据的仪器设备的要求 － 法规 要求 这里的分析仪器定义为： “直接或间接影响用于物料、产品质量评估的数据质量和有效性的测 量、监控、称量、记录和控制设备” 分析仪器验证提供文件证明：用于GxP目的的分析仪器将持续的符合其 预定的标准和质量要求

法规要求
EUDRALEX - Volume 4 - Medicinal Products for Human and Veterinary Use : Good Manufacturing Practice Annex 15 – Qualification and Validation 21 CFR Part 211, Part 11 USP 30 NF 25 Physical tests and determinations
? 621 ? CHROMATOGRAPHY ? 851 ? SPECTROPHOTOMETRY AND LIGHT-SCATTERING ? 1058 ? Analytical Instrument Qualification – draft Jul/Aug. 2005
总的指导原则
? GAMP Good Practice Guide Validation of Laboratory Computerized Systems
? GAMP 4 GAMP Guide for Validation of Automated Systems

ANS Validation Life Cycle
Validation Plan Phase
Validation Master Plan QC007
Production
GSOPBIO_VAL_1204_30001 GSOPBIO_VAL_1205_30047
Maintenance & Change Control
Specification Phase
URS Supplier Assessment
Performance Phase
Performance Qualification
GSOPBIO_VAL_1205_30046 GSOPBIO_VAL_1204_30007
GSOPBIO_VAL_1201_30031
Installation & Operational Phases
Operational Qualification
Design Phase
System Configuration Installation Qualification
Installation Phase
System installed
ANS Validation Life Cycle

GSK Bio compliance with CAP45
ANS Validation Life Cycle

验证文件
URS ? Document describing user
specifications for equipment
URS 1 Specificity 2 Linearity 3 Precision 4 Repeatability 5 Accuracy 6 Robustess
Test Instructions.
Test Methodology
Test Annexes
Test Instructions ? Methodology to execute
the test & acceptance criteria
QA approval
Test Annexes ? Form to record test results Test Protocol / Record ? Form for manual entering
all test results
NonConformity Rec. IQ/OQ Protocol IQ/OQ Report
Test Attachments
? Any existing evidences used for entering test data (e.g. Weight print out)
Test Records ? Any automatically generated
record with test data (e.g. Chromatogram)
Test Annexes
T TES mts ch Att T TES RD O REC
Non Conformity Record ? Form for handling
identification and corrective action of any incidents
紫外分光光度计 － 标准
在特定背景溶液和波长 条件下透光率>75%

紫外分光光度计 － 性能测试标准
3.3.2
波长准确度 (高氯酸钬溶液) 药典对<241nm波长 精度没有检查要 求： ?咖啡因溶液：205 +/- 1nm ?汞：185 +/- 1nm
紫外分光光度计 － 性能测试标准
3.3.2
波长准确度 (钬玻璃) 其他替代方法： ? 铷玻璃：可见光 ? 氘灯、汞灯
吸收峰波长以供应商提供的为准

紫外分光光度计 － 性能测试标准
3.3.3
吸收值准确度 (重铬酸钾溶液) 其他替代方法： ?中密度滤光片 ?硅金片 注意清洁 ！
欧洲药典要 求测可见光
紫外分光光度计 － 性能测试标准
3.3.4
? ? ?
基线稳定性
200nm – 700nm 透射值＝ 100 +/- 2% 吸收值＝ 0 +/- 0.005

紫外分光光度计 － 性能测试标准
3.3.5
离散光
1. 1.0%碘化钠 / 0.025%重铬酸钾: 220nm、370nm 2. Schott WG295 glass filter：220nm 3. 12 g/l 氯化钾：198nm
透光率< 1.0%; 吸光率> 2.0
紫外分光光度计 － 性能测试标准
3.3.6
分辨率 （若用于鉴别）
0.020% 苯/正己烷溶液，在269 nm和266 nm 下的吸光率比值
若光谱带宽<=2nm; 比值应>=1.5 若光谱带宽>2nm; 比值应<1.5
3.3.7
吸光度可读性 （若读数通过模拟信号输出）
在0.0 – 0.7 吸光值范围内可读性小于0.005

HPLC－ 性能测试标准
流量准确性 流量重现性
梯度
进样体积 重现性 温度稳定性 柱分离率 波长准确性
SSC和校验参数 称量法：+/- 5% RT：0.50% 2％理论值偏差 峰面积偏差 峰保留时间偏差 每年腔体mapping 拖尾因子、塔板 数、分离度 每年校验
HPLC－ 性能测试标准
泵梯度混合准确性： newer equipment a more challenging gradient check：100, 90, 89, 51, 50, 6, and 5%
梯度组成 20% A, 80%B 10%A, 90%B 5% A, 接受标准（实际）～ 10％ 18.5-21.5% A ；78.5-81.5%B 8.5 – 11.5% A；88.5% - 91.5% 4.5-5.5%
波长准确度（每年）： 扫描4-5%高氯酸钬溶液：241nm、287nm、361nm 扫描25μg/mL咖啡因水溶液：205nm、273nm 标准：± 3nm

系统适应性控制参数接受标准－1
系统适应性参数 公式 分离度检查 拖尾因子 0.95 – 1.05 可接受标准
分辨率
>=1.5
塔板数
系统适应性控制参数接受标准－2
系统适应性参数 公式 精确度检查 保留时间重现性 比较标样和样品的保留时间 标准重复性 +/- 2% 比较同一标准品不同制备液间的峰面积 RSD =<2.0％ 可接受标准
系统重现性
比较同一标准品制备液5次连续进样的 RSD =<1.0％ 峰面积
注：可接受标准可能不同，参见具体实验方法和药典

HPLC方法原理
外标 法：
内标法：
注：至少制备2个标样
HPLC进样方法
? ?
1-6, 12,13,19,2026,27 的RSD<=2.0% 用12,13,19,20来计算样品J-M

菌检仪Steritest－ 性能测试标准
培养基生长促进试验 无菌试验
膜完整性（泡点试验） 分离均匀性: +/-10%=
实验室自动系统验证简介

GAMP – 分类 - 1/2
GAMP Class CAP045 Class GAMPidentification Translation to GSK Biologicals laboratory environment (CAP045) Simple COTS equipment used mostly in sample preparation or otherwise indirectly used in laboratory areas. Readings from these are not used to generate GxP data. Typically firmwarebased – no data storage, run- time parameters set when used. Not connected to a computerized system. Typical examples within QC Laboratories
A
Not defined within GAMP
Stirrers, hotplates, heating, mantles, glassware washing machines, water stills, rotary evaporators, sonicators, centrifuges… (Out of scope of this procedure)
0 Logistic equipments: Non- electronic COTS devices and standards not depending on electronic logic, embedded logic or external computer systems to control instrument function. They do not store data on durable media or report information. All critical parameters are assured by a calibration program, maintenance program or similar.
B
Not defined within GAMP
Direct impact: Rulers, non- digital thermometers Indirect impact: check weights, mechanical friability testers, analog- type chart recorders, U- tube viscometers, stiring plates, simple water baths, mercury thermometer, … (Non – CRS ; Out of scope of this procedure) (Out of scope of this procedure) Windows 95, 98, NT, 2000, Me, XP (Not considered to be analytical systems; Out of scope of this procedure) Digital thermometers, digital callipers, pH meter(with printer and/or temperature compensation), balances, conductivity meters, digital viscometers, digital chronometer…
1
NA
Operating Systems
Operating systems
2
C
Firmware
Simple, non- programmable firmware- based COTS equipment that provides a measurement reading via a digital display and/ or to an attached printer. Will be calibrated periodically. Data storage will be limited to a few simple run- time parameter settings. Not connected to an external computer. Firmware based COTS systems but with additional features such as the ability to store run- time configurations as methods. Could be controlled from an external computer or system via an electronic interface. Usually will not store measurement data except where data logging is the main functionality. Calibrated periodically or at run- time. No direct programmable interface.
3
D
Standard software packages
Some autotitrators, HPLC or GC hardware components such as pumps, column ovens, autosamplers, Chessel chart recorders. Excel spreadsheets.
GAMP-分类 - 2/2
GAMP Class CAP045 Class GAMP-identification Translation to GSK Biologicals laboratory environment (CAP045) Hardware may be firmware- based or controlled by an external computer. Standard application software which will allow configuration of run- time parameters, instrument control, data acquisition and standard reporting functionality. Standard (nonprogrammable) data processing functionality, which may involve regulated records and signatures applicability. Usually standalone, not relying on CDS or similar separate controlling and post- acquisition data processing systems. Typically utilises a local level of access control. More complex systems that mostly have PC- based application software. Mostly programmable via standard method sequence lists. May utilise computer network functionality. Often these are hardware and software components used to control a variety of other standard COTS lab equipment. Likely to involve regulated records and signatures. May acquire and utilise reference data as libraries, requiring advanced statistical or pattern recognition data processing. Typically uses operating system functionality for access control. Custom (bespoke) Software Custom build or bespoke systems, prototypes. They can either be custom built analytical systems, or individual custom built software packages. Typical examples within QC Laboratories
4
E
Configurable Software Packages
Stand- alone UV/ Vis, FT- IR spectrophotometers, stand- alone HPLC system software i. e. not connected via CDS (Chromatography Data System). Spectrophotometer or HPLC with standard, dedicated application software (including custom reports, ..), …
F
Robotic workstation controllers e. g. Zymark, some NIR systems, NMRs, Mass Spectrometers, Vitek speciation systems, HPLC connected via CDS
5
NA
Electrolyte System (E-Lise) Excel spreadsheets with macro (VB)

电脑验证特别应注意的地方
DQ IQ OQ Generic Protocol 数据保护和完整性
Audit Trails Data Integrity
数据备份和恢复
Back-up and Restore Data Archiving Data Reconstruction/Reprocessing
权限控制
Physical Security Logical Security
Questions ?