annex_8_qualification_of_balances

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BIORAD 荧光定量PCR手册

A number of technical deficiencies can affect RT-qPCR assay performance, including improper experimental design, inadequate controls and replicates, lack of well-defined experimental conditions and sample handling techniques, poor quality of the RNA sample, suboptimal choice of primers for reverse-transcription and qPCR reactions, lack of validation of reference genes, and inappropriate methods of data analysis. In an effort to assist the scientific community in producing consistent, high quality data
In this paper we demonstrate how to apply the MIQE guidelines (/miqe) to establish a solid experimental approach.
1. Experimental Design Proper experimental design is the key to any gene expression study. Since mRNA transcription can be sensitive to external stimuli that are unrelated to the processes studied, it is important to work under tightly controlled and welldefined conditions. Taking the time to define experimental procedures, control groups, type and number of replicates, experimental conditions, and sample handling methods within each group is essential to minimize variability (Table 1). Each of these parameters should be carefully recorded prior to conducting gene expression experiments to assure good biological reproducibility for published data.

UPDATED_Annex_1_Qualification_of_HPLC_Equipment

1st July 2011
Page 2 of 14
PA/PH/OMCL (11) 04 - OMCL Guideline on qualification of HPLC equipment (Annex 1) TABLE III Level III. Periodic and motivated instrument checks Examples of requirements for HPLC instruments and detectors Instrument module Injector Autosampler Fluorescence detector Electrochemical detector RID detector CD detector Parameter to be checked Flow rate Proportioning accuracy and precision (gradient test) Proportioning ripple Volume precision Carry-over Thermostatting accuracy and precision Oven or cooling device UV/DAD detector Thermostatting accuracy Linearity Wavelength accuracy Wavelength accuracy excitation Wavelength accuracy emission Sensitivity Accuracy of the signal Stability of the signal Signal/Noise ratio Drift over time Signal/Noise ratio Sensitivity Drift over time Linearity 2 °C r2 0.999 2 nm 3 nm 3 nm see Annex I see Annex I see Annex I see Annex I 0.1 mV/min see Annex I see Annex I see Annex I r > 0.999 0,2 % RSD 1.0 % see Annex I 3 °C Typical tolerance limits 5% 2

Annex B

BS EN 1041:2008EN 1041:2008 (E)Annex B 附件B(informative)Guidance on alternative labelling for instructions for use (IFU)选择性商标使用指导指南Directives 93/42/EEC and 90/385/EEC foresee the possibility that, in the light of technicalprogress, the information laid down in Annex I, Section 13.1 of the Directive 93/42/EEC andAnnex I, Section 15 of the Directive 90/385/EEC may be provided by alternative means in thefuture. In such circumstances, approval is necessary as described in the regulatory procedurereferred to in Article 7(2a) of the Directive 93/42/EEC or Article 9 (10) of the Directive90/385/EEC.指示预见，根据技术过程，附件1的信息，指示93/42/EEC和附件1的13.1部分，指示90/385/EEC的15部分，未来可能由选择性方法提供。

在此情况下，如调整程序中涉及指示93/42/EEC条款2和指示90/385/EEC条款9中的正式批准是必要的，If alternative labelling is approved, manufacturers should consider the following:如果选择性商标获批，厂商必须考虑以下内容：The information provided with a medical device is intended to permit the device to be usedsafely and for the purposes intended by the manufacturer. This information comprises thedetails on the label and the data in the instructions for use (IFU). When appropriate for aparticular device, e.g., for professional users, the IFU can be provided by alternative means.Examples of ways of delivering alternative labelling include, but are not limited to, physicalelectronic media such as CD/DVD-ROMs packaged with the device, "help" systems providedwith the device, and information delivered over the Internet.医疗器械的信息旨在允许设备安全使用以及为了厂商的目的。

跟我一起做学习笔记之三—电子天平

跟我一起做学习笔记之三—电子天平电子天平是我们化验室日常检验必须用到的，也是非常关键的一种仪器，因为其很常见，很多人都认为它的使用很简单，但其合理应用与否可能直接影响到产品检测结果，它的操作可能在实际工作中却存在着巨大差异，这里我们来梳理一下，把握好天平的各种要求，保证称量的结果的准确性。

这次的学习笔记主要针对实验室最常用的万分之一和十万分之一天平进行的总结。

其中：万分之一天平（分析天平）常用于精密称量100mg以上的物质、炽灼残渣（坩埚）、干燥失重（称量瓶）十万分之一天平（半微量天平）常用于精密称量100mg-10mg物质，其中最小称量值要根据USP41进行确定允许误差：精密称定系指称重量应准确到所取重量的千分之一天平的法规要求GMP要求：质量管理，指明方向，但没有具体操作说明。

药典药求：药典关注天平称量结果的准确性，控制称量结果的相对误差，例如:称量区分：“精密称定”和“称定”。

USP（美国药典）USP WEIGHINGON AN ANALYTICAL BALANCE使用分析天平称量USPWEIGHTS ANDBALANCES砝码与天平USP ANALYTICALINSTRUMENT QUALIFICATION 分析仪器确认OMCL网络质量管理文件：很好的操作性。

OMCLNetwork of theCouncil of Europe QUALITY MANAGEMENT DOCUMENT：QUALIFICATION OF EQUIPMENT ANNEX 8: QUALIFICATION OF BALANCESOMCL网络质量管理文件仪器确认附件8：天平的确认注：编码为PA/PH/OMCL (12) 77 7R计量检定规程要求：关注天平本身，对天平的各项指标有具体的阐述，最后给一个检定结论：合格与否。

eg. 天平区分等级：“I级”、“II级”、“III级”、“IIII级”国标GB/T 26497-2011 《电子天平》注：适用于检定分度值不小于1mg 电子天平的设计与制造JJG 1036－2008 《电子天平》GB/T 4167-2011 《砝码》GB/T 26797-2011 《E1、E2、F1、F2、M1、M1-2、M2、M2-3、M3等级砝码》JJG 99-2006 《砝码》检定规程JJF 1139-2005 《计量器具检定周期确定原则和方法》OIML R 76-1: 2006天平的安装要求电源电压应在220V±10%之间，电源频率在50HZ±2%之间天平房间的选择：防风、防晒、温度恒定（温度的变化不应该超过5℃/小时）、湿度：（通常应在40%~60%之间）天平台：要先用防震、水平的周围应无影响校正的强电场、强磁场、气流（考虑到空调出风口的影响）天平的最小称量值由于测量的不确定度影响，当天平在低量程段称量时，绝对误差较小的情况下，相对误差会相当大，甚至超出了允许误差范围，这时为了保证天平的可靠性，必须知道天平的最小称量。

WHO_TRS_937__annex8_eng

© World Health OrganizationWHO Technical Report Series, No. 937, 2006Annex 8Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms Introduction1. Background2. WHO revisions to the criteria for Biopharmaceutics Classiﬁ cation Systemclassiﬁ cation3. WHO extensions to the scope of application of the biowaiver4. WHO additional criteria for application of the biowaiver procedure5. Explanation of the tables6. Biowaiver testing procedure according to WHOIntroductionThis proposal is closely linked to the Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchange-ability (WHO Technical Report Series, No. 937, Annex 7). It aims to give national authorities sufﬁ cient background information on the various orally administered active pharmaceutical ingredients (APIs) on the WHO Model List of Essential Medicines (EML), also taking into account local usage of the API, to enable them to make an informed decision as to whether generic formulations should be subjected to in vivo bioequivalence (B E) studies or whether a biowaiver can be granted. In light of scientiﬁ c work and dis-cussion in the last decade, some of the criteria used to evaluate the API in terms of potential for a biowaiver have been revised to allow a broadened scope of application. The result is that many APIs on the EML can now be considered for the biowaiver procedure, subject to the usage and risks in the national setting.1. Background1.1Initiatives to allow biowaivers based on the BiopharmaceuticsClassiﬁ cation SystemIn 1995 the American Department of Health and Human Services, US Food and Drug Administration (HHS-FDA) instigated the B iopharmaceutics391Classiﬁ cation System (BCS), with the aim of granting so-called biowaiv-ers for scale-up and post-approval changes (SUPAC) (/cder/ guidance/cmc5.pdf). A biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (i.e. not considered necessary for product approval). Instead of conducting expensive and time-consuming in vivo studies, a dissolution test could be adopted as the surrogate basis for the decision as to whether two pharmaceutical products are equivalent. At that time the biowaiver was only considered for SUPAC to pharmaceutical products.More recently, the application of the biowaiver concept has been extended to approval of certain orally administered generic products (/ cder/guidance/3618fnl.htm).Within the context of the documents cited above, only APIs with high solu-bility and high permeability and which are formulated in solid, immediate-release (IR) oral formulations can be approved on the basis of the biowaiver procedure. A major advantage of the biowaiver procedure is the simpliﬁ ca-tion of the product approval process and the reduction of the time required, thus reducing the cost of bringing new products to market.1.2What is the Biopharmaceutics Classiﬁ cation System?The Biopharmaceutics Classiﬁ cation System (BCS) was proposed in 1995 by Amidon et al.1 It is a scientiﬁ c framework which divides APIs into four groups, according to their solubility and permeability properties.1.3 Classiﬁ cation of active pharmaceutical ingredients accordingto the Biopharmaceutics Classiﬁ cation SystemAccording to the HHS-FDA deﬁ nitions in the documents cited above, the four possible categories for an API according to the BCS are:•BCS class I: “high” solubility – “high” permeability•BCS class II: “low” solubility – “high” permeability•BCS class III: “high” solubility – “low” permeability•BCS class IV: “low” solubility – “low” permeability.Depending on the classiﬁ cation, the oral availability of the API may be expected to range from being heavily dependent on the formulation and manufacturing method (e.g. Class II APIs: poorly soluble yet highly perme-able) to being mostly dependent on the API permeability properties (e.g.Class III APIs: highly soluble yet poorly permeable).1Amidon GL, Lennemas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classiﬁ cation: the correlation of in vitro drug product dissolution and in vivo bioavailability. Phar-maceutics Research, 1995, 12:413–420.3921.4How is high or low solubility currently deﬁ ned by the Departmentof Health and Human Services, US Food and Drug Administration?The aqueous solubility of a drug substance is considered as high according to the HHS-FDA BCS criteria when:• the ratio of the highest orally administered dose (in mg) to the solubility (mg/ml) is 250 ml or lower.—This criterion is met over the pH range 1–7.5 at 37 °C.According to HHS-FDA guidances, the determination of the equilibrium solubility should be carried out with the shake-ﬂ ask method (other methods such as acid or base titration are permitted when their ability to predict the equilibrium solubility is justiﬁ ed). The experiments should be carried out at a temperature of 37 ± 1°C. Further, a sufﬁ cient number of pH conditions should be chosen to cover the pH range of 1–7.5 and each determination should be carried out at least in triplicate. The buffer solutions given in the United States Pharmacopeia (USP) are appropriate for the tests, but other buffers are also allowed for these experiments. The pH value of each buffer solution should be checked before and after each experiment. Degradation of the API due to pH or buffer composition should be reported together with other stability data.The reason for the 250-ml cut-off criterion for the dose:solubility ratio is that in pharmacokinetic bioequivalence studies, the API formulation is to be ingested with a large glass of water (8 ounces corresponds to about 250 ml). If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 1–7.5), solubility problems are not expected to hinder the uptake of the API in the small intestine.The other important parameter for the BCS is the intestinal permeability of the API.1.5How is high or low permeability currently deﬁ ned by the Departmentof Health and Human Services, US Food and Drug Administration?According to HHS-FDA a drug is considered highly permeable, when 90 % or more of the orally administered dose is absorbed in the small intestine.Permeability can be assessed by pharmacokinetic studies (for example, mass balance studies), or intestinal permeability methods, e.g. intestinal perfusion in humans, animal models, Caco 2 cell lines or other suitable, validated cell lines. In vivo or in situ animal models or in vitro models (cell lines) are only considered appropriate by HHS-FDA for passively trans-ported drugs. It should be noted that all of these measurements assess the fraction absorbed (as opposed to the bioavailability, which can be reduced substantially by ﬁ rst-pass metabolism).393HHS-FDA suggests use of two different methods for determining the per-meability classiﬁ cation if results with one method are inconclusive.1.6Which pharmaceutical formulations can currently be consideredfor a biowaiver according to the Department of Health andHuman Services, US Food and Drug Administration?To be considered bioequivalent according to the HHS-FDA biowaiver pro-cedure, a pharmaceutical product:• should contain a Class I API;• should be rapidly dissolving, meaning it should release at least 85% of its content in 30 minutes in three different media (pH 1.2, pH 4.5 and pH6.8, composition see “Multisource document”)1 in a paddle (50 rpm) orbasket (100 rpm) apparatus at 37 °C and a volume of 900 ml;• should not contain excipients which could inﬂ uence the absorption of the API;• should not contain an API with a narrow therapeutic index; and• should not be designed to be absorbed from the oral cavity.The reasoning for the above-mentioned dissolution restrictions is that whena highly soluble, highly permeable API dissolves rapidly, it behaves like asolution in the gastrointestinal tract. If this is the case, the pharmaceutical composition of the product is insigniﬁ cant, provided that excipients which inﬂ uence the uptake across the gut wall are excluded from the formulation.The API is not prone to precipitation after its dissolution due to its good solu-bility under all pH conditions likely to be found in the upper gastrointestinal tract. The high permeability ensures the complete uptake (> 90%) of the API during its passage through the small intestine. The rapid dissolution of the product guarantees that the API is available long enough for the uptake in the small intestine (the passage time in the small intestine is approximately four hours) and negates any slight differences between the formulations.Pharmaceutical products containing an API with a narrow therapeutic index should always be tested with in vivo methods, because the risk to the patient resulting from a possible incorrect bioequivalence decision using the bio-waiver procedure is considered too high with these kinds of APIs.As the BCS is only applicable to APIs which are absorbed from the small intestine; drugs absorbed from other sites (e.g. from the oral cavity) are not eligible for a biowaiver.It is clear that the HHS-FDA requirements for the classiﬁ cation of APIs and eligibility criteria for the biowaiver are very strict. During the last decade,1Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).394several publications and continuing scientiﬁ c discussions have suggested that the original HHS-FDA criteria for application of the biowaiver pro-cedure could be relaxed without substantially increasing the risk to public health or to the individual patient. On the basis of these publications and dialogue, WHO has proposed revised BCS criteria and additional consid-erations for the eligibility of a pharmaceutical product for the biowaiver procedure in the “Multisource document”.12.WHO revisions to the criteria for BCS classiﬁ cationWHO revisions to the BCS criteria are as follows:•WHO high-solubility deﬁ nitionWhen an API shows a dose:solubility ratio of 250 ml or lower at 37 °C over a pH range of 1.2–6.8, it can be classiﬁ ed as “highly soluble”. The decrease in pH from 7.5 in the FDA guidances to 6.8 reﬂ ects the need to dissolve the drug before it reaches the mid-jejunum to ensure absorption from the gastrointestinal tract.• Furthermore, the dose that is to be used for the calculation is the highestdose indicated in the Model List of Essential Medicines (EML). In some countries, products may be available at doses exceeding the highest dose on the EML. In such cases, the classiﬁ cation given in the tables at the end of this Annex may no longer be appropriate and the dose:solubil-ity ratio and the permeability will have to be reassessed at the product dose.•WHO permeability deﬁ nitionWhen an API is absorbed to an extent of 85% or more, it is considered to be “highly permeable”. The permeability criterion was relaxed from 90% in the FDA guidance to 85% in the WHO “Multisource document”.Some examples of APIs now included in BCS Class I that were previ-ously considered to be in Class III are paracetamol, acetylsalicylic acid, allopurinol, lamivudine and promethazine.Application of these revised criteria has changed the classiﬁ cation of some APIs in the list. Thus, the classiﬁ cations in the tables attached to this docu-ment supersede those in previous publications. As new APIs appear on the EML, it will be necessary to classify them according to the revised BCS;so it is therefore anticipated that the tables will be revised regularly. In addition, some APIs have not yet been sufﬁ ciently characterized to assign them a BCS classiﬁ cation. As the tables evolve, it is anticipated that more concrete information will be generated for these APIs as well.1Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).395the basket apparatus (applies to pharmaceutical products containingClass III APIs);—rapidly dissolving (release of > 85% of the labelled amount of drug in 30 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rota-tional speed of 75 rpm in the paddle apparatus or 100 rpm in the bas-ket apparatus (applies to pharmaceutical products containing Class IAPIs and/or Class II APIs which are weak acids and meet the 250 mldose:solubility requirement at pH 6.8).(4)Considerations relating to excipientsThe national authority should be aware that some excipients can inﬂ uencemotility and/or permeability in the gastrointestinal tract. Therefore, the ex-cipients used in the multisource product formulation should be scrutinized.In this regard, the national authority can draw on the experience relat-ing to formulations which have been approved on the basis of humanbioequivalence studies in their own or in other jurisdictions.If the multisource product under consideration contains excipients thathave been used before in similar amounts in other formulations of thesame API, it can be reasonably concluded that these excipients will haveno unexpected consequences for the bioavailability of the product. If,however, the formulation contains different excipients, or amounts ofthe same excipients that are very different from usual, the national au-thority may choose to declare the biowaiver procedure inapplicable.A list of usual and acceptable excipients can be found at the following website: /cder/iig/iigfaqWEB.htm; formulations of some productscan be found on the web sites of some national drug regulatory authorities.5.Explanation of the tablesThe decision of a national authority to allow a biowaiver based on the BCS should take into consideration the solubility and permeability char-acteristics as well as the therapeutic use and therapeutic index of the API, its pharmacokinetic properties, the similarity of the dissolution proﬁ les of the multisource and the comparator products in standard buffers with a pH of 1.2, pH 4.5 and pH 6.8 at 37 °C. Data related to the excipients compo-sition in the multisource product are also required. A systematic approach to the biowaiver decision has been established by the International Pharma-ceutical Federation (FIP) and published in the Journal of Pharmaceutical Sciences (/cgi-bin/jhome/68503813).The relevant documents can also be downloaded from the FIP web site at: http://www.ﬁ/. These monographs provide detailed information which should be taken into account whenever available in the biowaiver consideration.3985.1Which active pharmaceutical ingredients are included in thetables?The substances listed in the 14th WHO Model List of Essential Medicines (EML) of March 2005 have been evaluated and classiﬁ ed according to the revised criteria given above.5.2Where do the data come from?The solubility and permeability values were found in the publicly available literature, such as Martindale’s, the Merck Index and scientiﬁ c journals.Please note that the doses used for the calculation of the dose:solubility ratio are those stated in the EML.The indications given in the tables are reproduced directly from the EML. If the EML speciﬁ es the dosage form (e.g. sublingual tablet) this is indicated under “comments”.5.3“Worst case” approach to the Biopharmaceutics Classiﬁ cationSystemThe drugs listed in the EML were classiﬁ ed according to the criteria explained above. Where no clear classiﬁ cation could be made, the “worst case” was as-sumed. For example if a substance is highly soluble, but absolute bioavailability data were not available, the test conditions for BCS Class III substances have been proposed. The same procedure was adopted for ﬁ xed combinations, for example amoxicillin and clavulanic acid, the testing procedure was always ﬁ xed according to the “worst” BCS classiﬁ cation, in this example clavulanic acid (BCS Class III/1), because amoxicillin is a BCS Class I drug. This com-bination would therefore be tested according to BCS Class III requirements.The results of the revised classiﬁ cation can be found in Tables 1–3.5.4Why are there three Tables?Table 1 lists all APIs on the EML that are administered orally, with the excep-tion of the APIs listed as complementary. Table 2 summarizes the APIs listed as complementary in the EML and Table 3 lists the APIs for which no classiﬁ cation had previously been assigned, or that had been introduced with the 14th EML (March 2005), together with a more detailed explanation of their classiﬁ cation.5.5 Risk assessmentTo minimize the risks of an incorrect biowaiver decision in terms of public health and risks to individual patients, the therapeutic indications of the API, known pharmacokinetic variations, food effects, etc. should be evalu-ated based on local clinical experience, taking into account the indications399for which the API is prescribed in that country as well as speciﬁ c pharmaco-kinetic population variations (for example CYP polymorphisms). Known potential risks are listed under “potential risks” in the tables. The absence of an entry under “potential risks” should not, however, be misconstrued as meaning that there are no risks associated with the use of the medicine. 6.Biowaiver testing procedure according to WHODepending on the BCS classiﬁ cation of the API, based on solubility and permeability characteristics listed in the accompanying tables, the testing procedure is deﬁ ned in section 9.2.1 of the “Multisource document”1:6.1For pharmaceutical products containing BiopharmaceuticsClassiﬁ cation System Class I (highly soluble, highlypermeable) APIsFor rapidly dissolving (as deﬁ ned above) pharmaceutical products contain-ing BCS Class I APIs, more than 85% dissolution of the labelled amount is required within 30 minutes in standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm. The dis-solution proﬁ les of the comparator and the multisource products should be compared by an f> 50 or an equivalent statistical criterion.2If within 15 minutes more than 85% of the API are released from the compar-ator and the multisource formulation under the above-mentioned conditions the products will be considered very rapidly dissolving. In this case the prod-ucts are deemed to be equivalent and a proﬁ le comparison is not required.6.2For pharmaceutical products containing BiopharmaceuticsClassiﬁ cation System Class III (highly soluble, lowpermeability) APIsA biowaiver can be considered only if both the multisource and the com-parator product are very rapidly dissolving. Eighty-ﬁ ve per cent or more dissolution of the labelled amount of the API should be achieved within15 minutes in standard media at pH 1.2, 4.5 and 6.8 using the paddle ap-paratus at 75 rpm or the basket apparatus at 100 rpm.Generally, the risks of an inappropriate biowaiver decision should be more critically reviewed (e.g. site-speciﬁ c absorption, induction/competition at the absorption site, excipient composition and therapeutic risks) for prod-ucts containing BCS Class III APIs than for BCS Class I drugs.1Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).4006.3For pharmaceutical products containing APIs with highsolubility at pH 6.8 but not at pH 1.2 or 4.5 and with highpermeability (by deﬁ nition, BCS Class II compoundswith weak acidic properties)These are eligible for a biowaiver provided that the multisource product:• is rapidly dissolving, i.e. 85% or more dissolution of the labelled amount of the API should be achieved within 30 minutes in standard media at pH 6.8 using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and• the multisource product exhibits similar dissolution proﬁles, as deter-mined with the f2 value or equivalent statistical evaluation, to those ofthe comparator product in buffers at all three pH values (pH 1.2, 4.5 and6.8).For multisource products containing BCS Class II APIs with dose:solubility ratios of 250 ml or less, at pH 6.8, the excipients should also be critically evaluated in terms of type and amounts of surfactants in the formulation.Further details of eligibility for the biowaiver and appropriate test proce-dures can be found in sections 5 and 9 of the “Multisource document”.11Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).401405c h l o r p h e n a -m i n e h yd r o ge n m a l e a t e 4 m g h i g hB A 25-59%, ﬁ r s t p a s s 3/19.2.1.2C Y P 2D 6 p o l y -m o r p h i s m a n t i a l l e r g i ce x t e n t of ﬁ r s t -p a s s m e t a b o l i s m u n c e r t a i nc h l o r p r o m a z i n e h yd r o c h l o r i de 100 m gh i g hl o w39.2.1.2 p s y c h o t h e r a p e u -t i c m e d i c i n e c i p r o ﬂ o x a c i nh y d r o c h l o r i d e 250 m g h i g hB A 70–82%, p o s s i b l e ﬁ r s t p a s s , h i g h i nC a c o -2 c e l l s3/19.2.1.2 a n t i b a c t e r i a le x t e n t of ﬁ r s t - p a s s m e t a b o l i s m u n c e r t a i nc l o f a z i m i n e100 m gi n s u f ﬁ c i e n t l i t e r a t u r e l o w 4/3N o t e l i g i b l e f o r b i o w a i v e r a t p r e s e n t a n t i l e p r o s y m e d i c i n ec l o m i f e n e c i t r a t e50 m g h i g h i n s u f ﬁ c i e n t l i t e r a t u r e 3/19.2.1.2o v u l a t i o n i n d u c e rc l o m i p r a m i n e h yd r o c h l o r i de 25 m g h i g h66% e x c r e t e d i n t h e u r i n e , t h e r e m a i n d e r b e i n g e l i m i -n a t e d i n t h e f a e c e s 3/19.2.1.2p s y c h o t h e r a p e u -t i c m e d i c i n el a c k o f a b s o l u t e b i o a v a i l a b i l i t y d a t ac l o x a c i l l i n (a s s od i u m s a l t )1000 m g h i g hl o w 39.2.1.2a n t i b a c t e r i a lc ode i n e p h o s p h a t e 30 m g h i g h l o w39.2.1.2r i s k o f a b u s eo p i o i d a n a l g e s i c ,d i a r r h oe a i n a d u l t sd a p s o n e100 m gl o w (w e a k b a s e ) h i g h 2N o t e l i g i b l e f o r b i o w a i v e rG 6P D d e ﬁ -c i e n c ya n t i l e p r o s y m e d i c i n ed i a ze p a m 5 m g h i g hh i g h19.2.1.1p s y c h o t h e r a p e u -t i c m e d i c i n e s c o r e d t a b l e tB A , B i o a v a i l a b i l i t y ; G 6P D , g l u c o s e -6-p h o s p h a t e d e h y d r o g e n a s e .409g l y c e r y l t r i n i t r a t e 500 μgh i g hs u b l i n g u a l a p p l i c a t i o n ,p e r m e a b i l -i t y i n t h e o r a l c a v i t y m o r e i m p o r t a n t t h a n G I p e r m e a b i l i t y3/1N A hl o c a l a b s o r p t i o n a n t i a n g i n a l m e d i c i n e s u b l i n g u a l a p p l i c a t i o ng r i s e o f u l v i n 250 m gl o w (n e u t r a l ) h i g h2N o t e l i g i b l e f o r b i o w a i v e r a n t i f u n g a lh a l o p e r i d o l2 m gb o r d e r l i n e < 0.01 m g /m l 2l o w 4/3N o t e l i g i b l e f o r b i o w a i v e rp s y c h o t h e r a p e u -t i c m e d i c i n eh y d r a l a z i n e h y d r o c h l o r i d e50 m g h i g hl o w 39.2.1.2a n t i h y p e r t e n s i v e m e d i c i n eh y d r o c h l o r o -t h i a z i d e 25 m g h i g h l o w 39.2.1.2a n t i h y p e r t e n s i v e m e d i c i n e , d i u r e t i c a n d u s e d i n h e a r t f a i l u r es c o r e d t a b l e ti b u p r o f e n 400 m gl o w , w e a k a c i d (p K a 4.4,5.2)h i g h 29.2.1.3N S A I D , a n t i m i -g r a i n e m e d i c i n ei n d i n a v i r s u l f a t e 400 m g l o w l o w (?)4/2N o t e l i g i b l e f o r b i o w a i v e r C Y P 450 3A 4, f o o d e f f e c t (–)a n t i r e t r o v i r a lu n k n o w n w h e t h e r p o o r B A i s d u e t o p o o r s o l u b i l i t y o r p o o r s o l u b i l i t y a n d p o o r p e r m e a b i l i t yD :S , D o s e :s o l u b i l i t y r a t i o ; B A , b i o a v a i l a b i l i t y .426T a b l e 3C o m p o u n d s i n t r o d u c e d t o t h e W H O M o d e l L i s t o f E s s e n t i a l M e d i c i n e s s i n c e M a r c h 2005 f o r w h i c h n o c e r t a i n c l a s s i ﬁ c a t i o n h a d b e e n p r e v i o u s l y r e p o r t e d (t h e s e c o m p o u n d s a l s o a p p e a r i n T a b l e 1 a n d T a b l e 2)M e d i c i n e aH i g h e s t o r a l s t r e n g t h a c c o r d i n g t o W H O E s s e n t i a l M e d i c i n e s L i s t a S o l u b i l i t y bP e r m e a b i l i t y c B C S c l a s s dD i s s o l u t i o n t e s t (f o r b i o w a i v e r )e P o t e n t i a l r i s k s fI n d i c a t i o n (s )a c c o r d i n g t o W H O E s s e n t i a l M e d i c i n e s L i s t (E M L )aC o m m e n t s a n d s p e c i a l d o s a g e f o r m i n d i c a t i o n s aa m l o d i p i n e 5 m gs l i g h t l y s o l u b l e (1),D :S 5 m lB A a b s60–65%,e x c r e t i o n o f d r u g m e t a b o -l i t e s i n u r i n e 90–95% (2)19.2.1.1a n t i h y p e r t e n s i v e m e d i c i n eB A a b s < 85% a s c r i b e d t o ﬁ r s t -p a s s m e t a b o l i s ma m o d i a q u i n e(b a s e )200 m g45 m g /m l 2,D :S 4.4 m lB A > 75% (3)3/19.2.1.2C Y P 2C 8p o l y m o r p h i s m ,i n c r e a s e d r i s k f o r a g r a n u l o c y -t o s i s a n d h e p a -t o t o x i c i t y (4)a n t i m a l a r i a la m o x i c i l l i n + c l a v u l a n i c a c i d 500 m g + 125 m gf r e e l y s o l u b l e i n w a t e r (1),D :S 1.25 m la b s o r p t i o n > 73% (5)1 + 3/19.2.1.2a n t ib ac t e r i a lt e s t s b a s e d o n c l a v u l a n i c a c i d c l a s s i ﬁ c a t i o na r t e s u n a t e 50 m gv e r ys l i g h t l y s o l u b l e (6),D :S 500 m l ;(w e a k a c i d ,p K a ~ 6.4)B A a b s 82% (1),B A a b s 88% (7),B A a b s 61% (8)4/2N o t e l i g i b l e f o r b i o w a i v e ra n t i m a l a r i a lp e r m e a b i l i t y d e p e n d s o n s e v e r i t y o f d i s e a s eD :S , D o s e : s o l u b i l i t y ; B A , B i o a v a i l a b i l i t y .427a z i t h r o m y c i n 500 m gp r a c t i c a l l y i n s o l u b l e i n w a t e r (1)< 0.01m g /m l , D :S 50 000 m lB A a b s 16% (9);B A 37%(10, 11); 4/2N o t e l i g i b l e f o r b i o w a i v e ra n t ib ac t e r i a l u n k n o w n w h e t h e r p o o r B A i sd ue t o p o o r s o l u b i l i t y o r p o o r s o l u b i l i t y a n d p o o r p e r m e a b i l i t yc a l c i u m f o l i n a t e 15 m gs p a r i n g l y s o l u b l e i n w a t e r (P h . E u r . 5.2); v e r y s o l u b l e (U S P 28); D :S 15 m l a n d 0.015 m l , r e s p e c -t i v e l yB A a b s 92% 25 m g (12, 13);B A a b s 73.4%(15 m g ) (14);f u l l y a b s o r b e d ;A UC a n d t 1/2s i m i l a r a f t e r i.v . & p .o (15)19.2.1.1 a n t i c y t o t o x i c m e d i c i n el e v o d o p a (l ) + c a r b i d o p a (c )(l ) 250 m g + (c ) 25 m g(l ) h i g h +(c ) s o l u b l e 1 i n 500 o f w a t e r , f r e e l y s o l u b l e i n 3 M H C l (1)(l ) h i g h +(c ) B A 58% (16); B A a b s88% (d o g s ) (17)(l ) 1 +(c ) 3/19.2.1.2n a r r o w t h e r a p e u t i c i n d e xa n t i p a r k i n s o n m e d i c i n et e s t s b a s e d o n c a r b i d o p a c l a s s i ﬁ c a t i o nc e ﬁ x i m e 400 m gs l i g h t l ys o l u b l e (2),D :S 400 m l22–54% (2)4N o t e l i g i b l e f o r b i o w a i v e ra n t ib ac t e r i a lD :S , D o s e : s o l u b i l i t y ; B A : B i o a v a i l a b i l i t y ; P h .E u r ., E u r o p e a n P h a r m a c o p o e i a ; U S P , U n i t e d S t a t e s P h a r m a c o p o e i a ; A U C , a r e a u n d e r t h e c u r v e ; i.v ., i n t r a v e n o u s .。

IEEE standard for Terminology and Test methods for ADC Std 1241-2000

IEEE Std1241-2000 IEEE Standard for Terminology and Test Methods for Analog-to-Digital ConvertersSponsorWaveform Measurement and Analysis Technical Committeeof theof theIEEE Instrumentation and Measurement SocietyApproved7December2000IEEE-SA Standards BoardAbstract:IEEE Std1241-2000identifies analog-to-digital converter(ADC)error sources and provides test methods with which to perform the required error measurements.The information in this standard is useful both to manufacturers and to users of ADCs in that it provides a basis for evaluating and comparing existing devices,as well as providing a template for writing specifications for the procurement of new ones.In some applications,the information provided by the tests described in this standard can be used to correct ADC errors, e.g.,correction for gain and offset errors.This standard also presents terminology and definitions to aid the user in defining and testing ADCs.Keywords:ADC,A/D converter,analog-to-digital converter,digitizer,terminology,test methodsThe Institute of Electrical and Electronics Engineers,Inc.3Park Avenue,New York,NY10016-5997,USACopyrightß2001by the Institute of Electrical and Electronics Engineers,Inc.All rights reserved. Published 13 June 2001. Printed in the United States of America.Print:ISBN0-7381-2724-8SH94902PDF:ISBN0-7381-2725-6SS94902No part of this publication may be reproduced in any form,in an electronic retrieval system or otherwise,without the prior written permission of the publisher.IEEE Standards documents are developed within the IEEE Societies and the Standards Coordinating Committees of the IEEE Standards Association(IEEE-SA)Standards Board.The IEEE develops its standards through a consensus development process,approved by the American National Standards Institute,which brings together volunteers representing varied viewpoints and interests to achieve theﬁnal product.Volunteers are not necessarily members of the Institute and serve without compensation.While the IEEE administers the process and establishes rules to promote fairness in the consensus development process,the IEEE does not independently evaluate,test,or verify the accuracy of any of the information contained in its standards.Use of an IEEE Standard is wholly voluntary.The IEEE disclaims liability for any personal injury,property or other damage,of any nature whatsoever,whether special,indirect,consequential,or compensatory,directly or indirectly resulting from the publication,use of,or reliance upon this,or any other IEEE Standard document.The IEEE does not warrant or represent the accuracy or content of the material contained herein,and expressly disclaims any express or implied warranty,including any implied warranty of merchantability orﬁtness for a speciﬁc purpose,or that the use of the material contained herein is free from patent infringement.IEEE Standards documents are supplied‘‘AS IS.’’The existence of an IEEE Standard does not imply that there are no other ways to produce,test,measure,purchase, market,or provide other goods and services related to the scope of the IEEE Standard.Furthermore,the viewpoint expressed at the time a standard is approved and issued is subject to change brought about through developments in the state of the art and comments received from users of the standard.Every IEEE Standard is subjected to review at least everyﬁve years for revision or reaﬃrmation.When a document is more thanﬁve years old and has not been reaﬃrmed,it is reasonable to conclude that its contents,although still of some value,do not wholly reﬂect the present state of the art. Users are cautioned to check to determine that they have the latest edition of any IEEE Standard.In publishing and making this document available,the IEEE is not suggesting or rendering professional or other services for,or on behalf of,any person or entity.Nor is the IEEE undertaking to perform any duty owed by any other person or entity to another.Any person utilizing this,and any other IEEE Standards document,should rely upon the advice of a competent professional in determining the exercise of reasonable care in any given circumstances.Interpretations:Occasionally questions may arise regarding the meaning of portions of standards as they relate to speciﬁc applications.When the need for interpretations is brought to the attention of IEEE,the Institute will initiate action to prepare appropriate responses.Since IEEE Standards represent a consensus of concerned interests,it is important to ensure that any interpretation has also received the concurrence of a balance of interests.For this reason, IEEE and the members of its societies and Standards Coordinating Committees are not able to provide an instant response to interpretation requests except in those cases where the matter has previously received formal consideration. Comments for revision of IEEE Standards are welcome from any interested party,regardless of membership aﬃliation with IEEE.Suggestions for changes in documents should be in the form of a proposed change of text,together with appropriate supporting ments on standards and requests for interpretations should be addressed to:Secretary,IEEE-SA Standards Board445Hoes LaneP.O.Box1331Piscataway,NJ08855-1331USANote:Attention is called to the possibility that implementation of this standard may require use of subjectmatter covered by patent rights.By publication of this standard,no position is taken with respect to theexistence or validity of any patent rights in connection therewith.The IEEE shall not be responsible foridentifying patents for which a license may be required by an IEEE standard or for conducting inquiriesinto the legal validity or scope of those patents that are brought to its attention.IEEE is the sole entity that may authorize the use of certiﬁcation marks,trademarks,or other designations to indicate compliance with the materials set forth herein.Authorization to photocopy portions of any individual standard for internal or personal use is granted by the Institute of Electrical and Electronics Engineers,Inc.,provided that the appropriate fee is paid to Copyright Clearance Center. To arrange for payment of licensing fee,please contact Copyright Clearance Center,Customer Service,222Rosewood Drive,Danvers,MA01923USA;(978)750-8400.Permission to photocopy portions of any individual standard for educational classroom use can also be obtained through the Copyright Clearance Center.Introduction(This introduction is not a part of IEEE Std1241-2000,IEEE Standard for Terminology and Test Methods for Analog-to-Digital Converters.)This standard deﬁnes the terms,deﬁnitions,and test methods used to specify,characterize,and test analog-to-digital converters(ADCs).It is intended for the following:—Individuals and organizations who specify ADCs to be purchased—Individuals and organizations who purchase ADCs to be applied in their products —Individuals and organizations whose responsibility is to characterize and write reports on ADCs available for use in speciﬁc applications—Suppliers interested in providing high-quality and high-performance ADCs to acquirersThis standard is designed to help organizations and individuals—Incorporate quality considerations during the deﬁnition,evaluation,selection,and acceptance of supplier ADCs for operational use in their equipment—Determine how supplier ADCs should be evaluated,tested,and accepted for delivery to end users This standard is intended to satisfy the following objectives:—Promote consistency within organizations in acquiring third-party ADCs from component suppliers—Provide useful practices on including quality considerations during acquisition planning —Provide useful practices on evaluating and qualifying supplier capabilities to meet user requirements—Provide useful practices on evaluating and qualifying supplier ADCs—Assist individuals and organizations judging the quality and suitability of supplier ADCs for referral to end usersSeveral standards have previously been written that address the testing of analog-to-digital converters either directly or indirectly.These include—IEEE Std1057-1994a,which describes the testing of waveform recorders.This standard has been used as a guide for many of the techniques described in this standard.—IEEE Std746-1984[B16]b,which addresses the testing of analog-to-digital and digital-to-analog converters used for PCM television video signal processing.—JESD99-1[B21],which deals with the terms and deﬁnitions used to describe analog-to-digital and digital-to-analog converters.This standard does not include test methods.IEEE Std1241-2000for analog-to-digital converters is intended to focus speciﬁcally on terms and deﬁnitions as well as test methods for ADCs for a wide range of applications.a Information on references can be found in Clause2.b The numbers in brackets correspond to those in the bibliography in Annex C.As of October2000,the working group had the following membership:Steve Tilden,ChairPhilip Green,Secretary&Text EditorW.Thomas Meyer,Figures EditorPasquale Arpaia Giovanni Chiorboli Tom Linnenbrink*B.N.Suresh Babu Pasquale Daponte Solomon MaxAllan Belcher David Hansen Carlo MorandiDavid Bergman Fred Irons Bill PetersonEric Blom Dan Kien Pierre-Yves RoyDan Knierim*Chairman,TC-10CommitteeContributions were also made in prior years by:Jerry Blair John Deyst Norris NahmanWilliam Boyer Richard Kromer Otis M.SolomonSteve Broadstone Yves Langard T.Michael SoudersThe following members of the balloting committee voted on this standard:Pasquale Arpaia Pasquale Daponte W.Thomas MeyerSuresh Babu Philip Green Carlo MorandiEric Blom Fred Irons William E.PetersonSteven Broadstone Dan Knierim Pierre-Yves RoyGiovanni Chiorboli T.E.Linnenbrink Steven J.TildenSolomon MaxWhen the IEEE-SA Standards Board approved this standard on21September2000,it had the following membership:Donald N.Heirman,ChairJames T.Carlo,Vice-ChairJudith Gorman,SecretarySatish K.Aggarwal James H.Gurney James W.MooreMark D.Bowman Richard J.Holleman Robert F.MunznerGary R.Engmann Lowell G.Johnson Ronald C.PetersenHarold E.Epstein Robert J.Kennelly Gerald H.Petersonndis Floyd Joseph L.Koepfinger*John B.PoseyJay Forster*Peter H.Lips Gary S.RobinsonHoward M.Frazier L.Bruce McClung Akio TojoRuben D.Garzon Daleep C.Mohla Donald W.Zipse*Member EmeritusAlso included are the following nonvoting IEEE-SA Standards Board liaisons:Alan Cookson,NIST RepresentativeDonald R.Volzka,TAB RepresentativeDon MessinaIEEE Standards Project EditorContents1.Overview (1)1.1Scope (1)1.2Analog-to-digital converter background (2)1.3Guidance to the user (3)1.4Manufacturer-supplied information (5)2.References (7)3.Deﬁnitions and symbols (7)3.1Deﬁnitions (7)3.2Symbols and acronyms (14)4.Test methods (18)4.1General (18)4.2Analog input (41)4.3Static gain and oﬀset (43)4.4Linearity (44)4.5Noise(total) (51)4.6Step response parameters (63)4.7Frequency response parameters (66)4.8Diﬀerential gain and phase (71)4.9Aperture eﬀects (76)4.10Digital logic signals (78)4.11Pipeline delay (78)4.12Out-of-range recovery (78)4.13Word error rate (79)4.14Diﬀerential input speciﬁcations (81)4.15Comments on reference signals (82)4.16Power supply parameters (83)Annex A(informative)Comment on errors associated with word-error-rate measurement (84)Annex B(informative)Testing an ADC linearized with pseudorandom dither (86)Annex C(informative)Bibliography (90)IEEE Standard for Terminology and Test Methods for Analog-to-Digital Converters1.OverviewThis standard is divided into four clauses plus annexes.Clause1is a basic orientation.For further investigation,users of this standard can consult Clause2,which contains references to other IEEE standards on waveform measurement and relevant International Standardization Organization(ISO) documents.The deﬁnitions of technical terms and symbols used in this standard are presented in Clause3.Clause4presents a wide range of tests that measure the performance of an analog-to-digital converter.Annexes,containing the bibliography and informative comments on the tests presented in Clause4,augment the standard.1.1ScopeThe material presented in this standard is intended to provide common terminology and test methods for the testing and evaluation of analog-to-digital converters(ADCs).This standard considers only those ADCs whose output values have discrete values at discrete times,i.e., they are quantized and sampled.In general,this quantization is assumed to be nominally uniform(the input–output transfer curve is approximately a straight line)as discussed further in 1.3,and the sampling is assumed to be at a nominally uniform rate.Some but not all of the test methods in this standard can be used for ADCs that are designed for non-uniform quantization.This standard identiﬁes ADC error sources and provides test methods with which to perform the required error measurements.The information in this standard is useful both to manufacturers and to users of ADCs in that it provides a basis for evaluating and comparing existing devices,as well as providing a template for writing speciﬁcations for the procurement of new ones.In some applications, the information provided by the tests described in this standard can be used to correct ADC errors, e.g.,correction for gain and oﬀset errors.The reader should note that this standard has many similarities to IEEE Std1057-1994.Many of the tests and terms are nearly the same,since ADCs are a necessary part of digitizing waveform recorders.IEEEStd1241-2000IEEE STANDARD FOR TERMINOLOGY AND TEST METHODS 1.2Analog-to-digital converter backgroundThis standard considers only those ADCs whose output values have discrete values at discrete times, i.e.,they are quantized and sampled.Although diﬀerent methods exist for representing a continuous analog signal as a discrete sequence of binary words,an underlying model implicit in many of the tests in this standard assumes that the relationship between the input signal and the output values approximates the staircase transfer curve depicted in Figure1a.Applying this model to a voltage-input ADC,the full-scale input range(FS)at the ADC is divided into uniform intervals,known as code bins, with nominal width Q.The number of code transition levels in the discrete transfer function is equal to 2NÀ1,where N is the number of digitized bits of the ADC.Note that there are ADCs that are designed such that N is not an integer,i.e.,the number of code transition levels is not an integral power of two. Inputs below theﬁrst transition or above the last transition are represented by the most negative and positive output codes,respectively.Note,however,that two conventions exist for relating V min and V max to the nominal transition points between code levels,mid-tread and mid-riser.The dotted lines at V min,V max,and(V minþV max)/2indicate what is often called the mid-tread convention,where theﬁrst transition is Q/2above V min and the last transition is3Q/2,below V max. This convention gets its name from the fact that the midpoint of the range,(V minþV max)/2,occurs in the middle of a code,i.e.,on the tread of the staircase transfer function.The second convention,called the mid-riser convention,is indicated in theﬁgure by dashed lines at V min,V max,and(V minþV max)/2. In this convention,V min isÀQ from theﬁrst transition,V max isþQ from the last transition,and the midpoint,(V minþV max)/2,occurs on a staircase riser.The diﬀerence between the two conventions is a displacement along the voltage axis by an amount Q/2.For all tests in this standard,this displacement has no eﬀect on the results and either convention may be used.The one place where it does matter is when a device provides or expects user-provided reference signals.In this case the manufacturer must provide the necessary information relating the reference levels to the code transitions.In both conventions the number of code transitions is 2NÀ1and the full-scale range,FSR,is from V min to V max.Even in an ideal ADC,the quantization process produces errors.These errors contribute to the diﬀerence between the actual transfer curve and the ideal straight-line transfer curve,which is plotted as a function of the input signal in Figure1b.To use this standard,the user must understand how the transfer function maps its input values to output codewords,and how these output codewords are converted to the code bin numbering convention used in this standard.As shown in Figure1a,the lowest code bin is numbered0, the next is1,and so on up to the highest code bin,numbered(2NÀ1).In addition to unsigned binary(Figure1a),ADCs may use2’s complement,sign-magnitude,Gray,Binary-Coded-Decimal (BCD),or other output coding schemes.In these cases,a simple mapping of the ADC’s consecutive output codes to the unsigned binary codes can be used in applying various tests in this standard.Note that in the case of an ADC whose number of distinct output codes is not an integral power of2(e.g.,a BCD-coded ADC),the number of digitized bits N is still deﬁned,but will not be an integer.Real ADCs have other errors in addition to the nominal quantization error shown in Figure1b.All errors can be divided into the categories of static and dynamic,depending on the rate of change of the input signal at the time of digitization.A slowly varying input can be considered a static signal if its eﬀects are equivalent to those of a constant signal.Static errors,which include the quantization error, usually result from non-ideal spacing of the code transition levels.Dynamic errors occur because of additional sources of error induced by the time variation of the analog signal being sampled.Sources include harmonic distortion from the analog input stages,signal-dependent variations in the time of samples,dynamic eﬀects in internal ampliﬁer and comparator stages,and frequency-dependent variation in the spacing of the quantization levels.1.3Guidance to the user1.3.1InterfacingADCs present unique interfacing challenges,and without careful attention users can experience substandard results.As with all mixed-signal devices,ADCs perform as expected only when the analog and digital domains are brought together in a well-controlled fashion.The user should fully understand the manufacturer’s recommendations with regard to proper signal buﬀering and loading,input signal connections,transmission line matching,circuit layout patterns,power supply decoupling,and operating conditions.Edge characteristics for start-convert pulse(s)and clock(s)must be carefully chosen to ensure that input signal purity is maintained with suﬃcient margin up to the analog input pin(s).Most manufacturers now provide excellent ADC evaluation boards,which demonstrate IN P U T IN P U T(a)Figure 1—Staircase ADC transfer function,having full-scale range FSR and 2N À1levels,corresponding to N -bit quantizationIEEE FOR ANALOG-TO-DIGITAL CONVERTERS Std 1241-2000IEEEStd1241-2000IEEE STANDARD FOR TERMINOLOGY AND TEST METHODS recommended layout techniques,signal conditioning,and interfacing for their ADCs.If the characteristics of a new ADC are not well understood,then these boards should be analyzed or used before starting a new layout.1.3.2Test conditionsADC test speciﬁcations can be split into two groups:test conditions and test results.Typical examples of the former are:temperature,power supply voltages,clock frequency,and reference voltages. Examples of the latter are:power dissipation,eﬀective number of bits,spurious free dynamic range (SFDR),and integral non-linearity(INL).The test methods deﬁned in this standard describe the measurement of test results for given test conditions.ADC speciﬁcation sheets will often give allowed ranges for some test condition(e.g.,power supply ranges).This implies that the ADC will function properly and that the test results will fall within their speciﬁed ranges for all test conditions within their speciﬁed ranges.Since the test condition ranges are generally speciﬁed in continuous intervals,they describe an inﬁnite number of possible test conditions,which obviously cannot be exhaustively tested.It is up to the manufacturer or tester of an ADC to determine from design knowledge and/or testing the eﬀect of the test conditions on the test result,and from there to determine the appropriate set of test conditions needed to accurately characterize the range of test results.For example,knowledge of the design may be suﬃcient to know that the highest power dissipation(test result)will occur at the highest power supply voltage(test condition),so the power dissipation test need be run only at the high end of the supply voltage range to check that the dissipation is within the maximum of its speciﬁed range.It is very important that relevant test conditions be stated when presenting test results.1.3.3Test equipmentOne must ensure that the performance of the test equipment used for these tests signiﬁcantly exceeds the desired performance of the ADC under ers will likely need to include additional signal conditioning in the form ofﬁlters and pulse shapers.Accessories such as terminators, attenuators,delay lines,and other such devices are usually needed to match signal levels and to provide signal isolation to avoid corrupting the input stimuli.Quality testing requires following established procedures,most notably those speciﬁed in ISO9001: 2000[B18].In particular,traceability of instrumental calibration to a known standard is important. Commonly used test setups are described in4.1.1.1.3.4Test selectionWhen choosing which parameters to measure,one should follow the outline and hints in this clause to develop a procedure that logically and eﬃciently performs all needed tests on each unique setup. The standard has been designed to facilitate the development of these test procedures.In this standard the discrete Fourier transform(DFT)is used extensively for the extraction of frequency domain parameters because it provides numerous evaluation parameters from a single data record.DFT testing is the most prevalent technique used in the ADC manufacturing community,although the sine-ﬁt test, also described in the standard,provides meaningful data.Nearly every user requires that the ADC should meet or exceed a minimum signal-to-noise-and-distortion ratio(SINAD)limit for the application and that the nonlinearity of the ADC be well understood.Certainly,the extent to whichthis standard is applied will depend upon the application;hence,the procedure should be tailored for each unique characterization plan.1.4Manufacturer-supplied information1.4.1General informationManufacturers shall supply the following general information:a)Model numberb)Physical characteristics:dimensions,packaging,pinoutsc)Power requirementsd)Environmental conditions:Safe operating,non-operating,and speciﬁed performance tempera-ture range;altitude limitations;humidity limits,operating and storage;vibration tolerance;and compliance with applicable electromagnetic interference speciﬁcationse)Any special or peculiar characteristicsf)Compliance with other speciﬁcationsg)Calibration interval,if required by ISO10012-2:1997[B19]h)Control signal characteristicsi)Output signal characteristicsj)Pipeline delay(if any)k)Exceptions to the above parameters where applicable1.4.2Minimum specificationsThe manufacturer shall provide the following speciﬁcations(see Clause3for deﬁnitions):a)Number of digitized bitsb)Range of allowable sample ratesc)Analog bandwidthd)Input signal full-scale range with nominal reference signal levelse)Input impedancef)Reference signal levels to be appliedg)Supply voltagesh)Supply currents(max,typ)i)Power dissipation(max,typ)1.4.3Additional specificationsa)Gain errorb)Oﬀset errorc)Diﬀerential nonlinearityd)Harmonic distortion and spurious responsee)Integral nonlinearityf)Maximum static errorg)Signal-to-noise ratioh)Eﬀective bitsi)Random noisej)Frequency responsek)Settling timel)Transition duration of step response(rise time)m)Slew rate limitn)Overshoot and precursorso)Aperture uncertainty(short-term time-base instability)p)Crosstalkq)Monotonicityr)Hysteresiss)Out-of-range recoveryt)Word error rateu)Common-mode rejection ratiov)Maximum common-mode signal levelw)Diﬀerential input impedancex)Intermodulation distortiony)Noise power ratioz)Diﬀerential gain and phase1.4.4Critical ADC parametersTable1is presented as a guide for many of the most common ADC applications.The wide range of ADC applications makes a comprehensive listing impossible.This table is intended to be a helpful starting point for users to apply this standard to their particular applications.Table1—Critical ADC parametersTypical applications Critical ADC parameters Performance issuesAudio SINAD,THD Power consumption.Crosstalk and gain matching.Automatic control MonotonicityShort-term settling,long-term stability Transfer function. Crosstalk and gain matching. Temperature stability.Digital oscilloscope/waveform recorder SINAD,ENOBBandwidthOut-of-range recoveryWord error rateSINAD for wide bandwidthamplitude resolution.Low thermal noise for repeatability.Bit error rate.Geophysical THD,SINAD,long-term stability Millihertz response.Image processing DNL,INL,SINAD,ENOBOut-of-range recoveryFull-scale step response DNL for sharp-edge detection. High-resolution at switching rate. Recovery for blooming.Radar and sonar SINAD,IMD,ENOBSFDROut-of-range recovery SINAD and IMD for clutter cancellation and Doppler processing.Spectrum analysis SINAD,ENOBSFDR SINAD and SFDR for high linear dynamic range measurements.Spread spectrum communication SINAD,IMD,ENOBSFDR,NPRNoise-to-distortion ratioIMD for quantization of smallsignals in a strong interferenceenvironment.SFDR for spatialﬁltering.NPR for interchannel crosstalk.Telecommunication personal communications SINAD,NPR,SFDR,IMDBit error rateWord error rateWide input bandwidth channel bank.Interchannel crosstalk.Compression.Power consumption.Std1241-2000IEEE STANDARD FOR TERMINOLOGY AND TEST METHODS2.ReferencesThis standard shall be used in conjunction with the following publications.When the following speciﬁcations are superseded by an approved revision,the revision shall apply.IEC 60469-2(1987-12),Pulse measurement and analysis,general considerations.1IEEE Std 1057-1994,IEEE Standard for Digitizing Waveform Recorders.23.Definitions and symbolsFor the purposes of this standard,the following terms and deﬁnitions apply.The Authoritative Dictionary of IEEE Standards Terms [B15]should be referenced for terms not deﬁned in this clause.3.1Definitions3.1.1AC-coupled analog-to-digital converter:An analog-to-digital converter utilizing a network which passes only the varying ac portion,not the static dc portion,of the analog input signal to the quantizer.3.1.2alternation band:The range of input levels which causes the converter output to alternate between two adjacent codes.A property of some analog-to-digital converters,it is the complement of the hysteresis property.3.1.3analog-to-digital converter (ADC):A device that converts a continuous time signal into a discrete-time discrete-amplitude signal.3.1.4aperture delay:The delay from a threshold crossing of the analog-to-digital converter clock which causes a sample of the analog input to be taken to the center of the aperture for that sample.COMINT ¼communications intelligence DNL ¼diﬀerential nonlinearity ENOB ¼eﬀective number of bits ELINT ¼electronic intelligence NPR ¼noise power ratio INL ¼integral nonlinearity DG ¼diﬀerential gain errorSIGINT ¼signal intelligenceSINAD ¼signal-to-noise and distortion ratio THD ¼total harmonic distortion IMD ¼intermodulation distortion SFDR ¼spurious free dynamic range DP ¼diﬀerential phase errorTable 1—Critical ADC parameters (continued)Typical applicationsCritical ADC parametersPerformance issuesVideoDNL,SINAD,SFDR,DG,DP Diﬀerential gain and phase errors.Frequency response.Wideband digital receivers SIGINT,ELINT,COMINTSFDR,IMD SINADLinear dynamic range fordetection of low-level signals in a strong interference environment.Sampling frequency.1IEC publications are available from IEC Sales Department,Case Postale 131,3rue de Varemb,CH 1211,Gen ve 20,Switzerland/Suisse (http://www.iec.ch).IEC publications are also available in the United States from the Sales Department,American National Standards Institute,25W.43rd Street,Fourth Floor,New York,NY 10036,USA ().2IEEE publications are available from the Institute of Electrical and Electronics Engineers,445Hoes Lane,P.O.Box 1331,Piscataway,NJ 08855-1331,USA (/).。

OMCL指导文件设备的确认

General European OMCL Network (GEON) QUALITY MANAGEMENT DOCUMENTPA/PH/OMCL (08) 73 R3QUALIFICATION OF EQUIPMENTCORE DOCUMENTFull document titleand reference Qualification of Equipment – Core documentPA/PH/OMCL (08) 73 R3Document typeGuidelineLegislative basisCouncil Directive 2001/83/EC and 2001/82/EC, as amended The present document was also accepted by EA asrecommendation document to be used in the context of Quality Management System audits of OMCLs Date of first adoption1st October 1999 Date of original entry into force1st February 2000 Date of entry into force of revised document1st May 2017Previous titles/other references / last valid version This document replaces document PA/PH/OMCL (08) 73 2R Custodian Organisation The present document was elaborated by the OMCL Network / EDQM of the Council of Europe Concerned Network GEONQUALIFICATION OF EQUIPMENTCORE DOCUMENTIntroductionThe standard ISO/IEC 17025 requires an appropriate choice and qualification of equipment to be used for testing purposes. Particularly, checks and calibrations before and during use and, if needed, intermediate tests (see ISO/IEC 17025 chapter 5.5.10) are necessary.In order to guarantee a harmonized interpretation and application within the OMCL Network, the guideline « Qualification of Equipment » has been elaborated.From experience, the terms DQ, IQ, OQ and PQ (not explicitly mentioned by ISO/IEC 17025) have been used in a non-harmonized way amongst the different OMCLs. Therefore their mention has been avoided in this document. This does not exclude their use in OMCL’s quality systems where already approved and in application, or a reference to literature using this nomenclature.In order to simplify the management of the guideline, the present document contains only the general introduction and the first two levels of qualification, which are common to all type of equipment. The third and fourth levels of qualification can be found in separate instrument-related annexes. When considered appropriate, additional requirements and/or examples related to Level I and/or Level II have also been included in the annexes, which are to be used in combination with the general recommendations given in the core document.The list of annexes, included in this document, will be updated as soon as new annexes are issued. This document should be considered as a guide to OMCLs for planning, performing and documenting the equipment qualification process. It should not be taken as an exhaustive list of compulsory tests. It is left to the professional judgement and background experience of each OMCL to decide on the most relevant tests and the most appropriate tolerance limits for each of the parameters, in order to give evidence that the instrument is working properly and is appropriate for its intended use.If the qualification of equipment is done by the manufacturer itself or an external service, it is under the responsibility of the OMCL to make sure that the checks performed are in line with the minimum requirements set in this guideline.To facilitate the implementation of a documented qualification process for the various analytical instruments, specific recommendations on minimum requirements are given in the corresponding annexes.For the more technique-related aspects of equipment qualification checks, practical examples of possible approaches are also presented in the annexes.The following four levels of Equipment Qualification should be considered by the OMCLs:Level I. Selection of instruments and suppliersThe selection and purchase of new instruments shall follow a conscious decision process, based on the needs related to the intended use of the instrument.An example for setting and documenting such specifications and decisions taken is given in Table I.Level II. Installation and release for useWhen receiving an instrument, the OMCL should check that it is received in good conditions, as ordered, and should monitor and document the installation process of the instrument in the selected environment. This includes the start up checks done by the supplier, followed by a full periodic check as described in Level III.The release for use shall be documented and authorised by the person responsible for the instrument.An example for documenting the instrument installation and release for use and decisions taken is given in Table II.Level III. Periodic and motivated instrument checksWhen instruments are installed or moved into a new environment a series of checks have to be carried out to verify the key performance parameters of the instrument avoiding additional contributory effects from the analytical method. Depending on the frequency of use and the experienced stability of the instrument this shall be repeated periodically.The same verifications (or a relevant part of them) shall be carried out following events like significant repair or maintenance operations.Examples of parameters to be checked on instruments and their typical acceptance limits can be found in the Table III of the corresponding instrument-related annex.The specifications from the manufacturer of the instrument should be taken into account when setting the tolerance limits.Some examples on how these checks may be performed on each type of instrument are also provided in the corresponding Annexes.Level IV. In-use instrument checksDuring the day-to-day use of the instruments, checks are necessary to demonstrate continued evidence of satisfactory performance by the instrument itself and compliance with the system suitability criteria as defined in the applied analytical procedure for each product or group of products tested at this occasion.Examples of parameters to be checked on instruments and their typical acceptance limits can be found in the Table IV of the corresponding instrument-related annex.In the case of OMCLs performing routine testing (batch release of vaccines and blood products), the use of control charts provides supplementary information on equipment performance, which can also be used in this context.List of instrument-related annexesThe qualification levels dealt with in each annex are indicated in brackets.∙Annex 1: Qualification of HPLC equipment (Levels III and IV)∙Annex 2: Qualification of GC equipment (Levels III and IV)∙Annex 3: Qualification of UV-Visible spectrophotometers (Levels I, III and IV)∙Annex 4: Qualification of IR spectrophotometers (Levels I, III and IV)∙Annex 5: Qualification of automatic titrators (Levels III and IV)∙Annex 6: Qualification of piston pipettes (Levels III and IV)∙Annex 7: Qualification of mass spectrometers (Levels III and IV)∙Annex 8 : Qualification of balances (Levels I to IV)∙Annex 9: Calibration/qualification of pH meters (Levels I to IV)∙Annex 10: Qualification of Atomic Absorption / Atomic Emission Spectrometers (Levels III and IV)TABLE I Level I. Selection of instruments and suppliersExample of check-list (non-exhaustive)Manufacturer:Provider/Distributor:Name of instrument and type:Attribute(This list may be adapted ifnecessary) SpecificationsBenefits(Instrument/supplier)AssessmentPass FailsTechniqueCommunication and datahandlingInterface RS232Data transfer to spreadsheetsCompatible with other hard-and software such as LIMS…SafetyIrradiation Explosion protectionDocumentationManual (paper copy)HandlingUser languageService and maintenanceServices offeredWarranty SupportDelivery (duration etc.)Installation(Service / Laboratory)Training (in-house / externalcourses)TABLE I (cont.) Requirements for media and environmentCost / Benefit AnalysisComments / DecisionsDate / Signature:Date / Signature for approval:TABLE IILevel II. Installation and release for useExample of check-list (non-exhaustive)Name of instrument and type:Identification code:Conformity with order (instrument / material / documentation)Pass Fails (description of deficiencies)Check of damagesPass Fails (description of deficiencies)Check of required media supply (connections / environmental conditions)Pass Fails (description of deficiencies)Installation of instrument(s) including possible control modulesPass Fails (description of deficiencies)Performance of start-up checks and diagnosis functions 1Pass Fails (description of deficiencies)1CommentsWhen appropriate, raw data are attached to the instrument documentationDate / Signature:Release and authorisation for use: Date / Signature:Disclaimer:The present Core Document of the OMCL Guideline “Qualification of Equipment”, as well as all its Annexes, have been drafted by ad-hoc working groups of technical experts, mainly coming from Official Medicines Control Laboratories (OMCLs) and only occasionally from other public institutions. These working groups do not include any representative from any commercial organisation.This Core Document and its Annexes may contain trade names of laboratory instruments, materials and/or reagents. These are exclusively given as example in order to make these guidelines easier to understand and implement, and were found to be suitable when the guideline was being developed. These references do not imply in any way that the mentioned instruments, materials or reagents or their suppliers are especially endorsed, recommended or certified by the EDQM, the OMCL Network or the Council of Europe, in preference to others of a similar nature which are not mentioned. It is therefore acceptable to use instruments, materials and reagents from another source, provided that they fulfil the necessary criteria laid down in these documents and appropriately satisfy the needs of the concerned laboratories in the frame of their specific activities.。

ISO 188-2011 英文加速老化或耐热性试验

International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards adopted by the technical committees are circulated to the member bodies for voting. Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote.
9
Procedure ............................................................................................................................................... 6
1
Scope ...................................................................................................................................................... 1
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DIN EN 10029-2011

Contents
Page
Foreword ..............................................................................................................................................................3 1 2 3 4 4.1 4.2 4.3 5 6 6.1 6.2 6.3 7 7.1 7.2 8 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Scope ......................................................................................................................................................4 Normative references ............................................................................................................................4 Terms and definitions ...........................................................................................................................4 Information to be supplied by the purchaser .....................................................................................4 Mandatory information ..........................................................................................................................4 Options ...................................................................................................................................................5 Designation ............................................................................................................................................5 Form of supply .......................................................................................................................................6 Tolerances on dimensions ...................................................................................................................6 Thickness ...............................................................................................................................................6 Width .......................................................................................................................................................7 Length .....................................................................................................................................................7 Tolerances on shape .............................................................................................................................7 Edge camber and out-of squareness...................................................................................................7 Flatness ..................................................................................................................................................8 Measurement ..........................................................................................................................................9 General ....................................................................................................................................................9 Thickness ...............................................................................................................................................9 Width .......................................................................................................................................................9 Length .....................................................................................................................................................9 Edge camber ....................................................................................................................................... 10 Out-of squareness .............................................................................................................................. 10 Flatness ............................................................................................................................................... 11

Phenix-refinement

coordinates, B-values, occupancies minimization, simulated annealing Function based on electron density (real-space reﬁnement) Function based on structure factors (reciprocal-space reﬁnement)
Reducing Overﬁtting in Reﬁnement
• • • •
• • • • • • •
Cross-validation
Brunger, Nature 355, 472, 1992 Rice & Brunger, Proteins 19, 277, 1994 Winn et al., Acta Cryst. D 57, 122-133, 2001 Bricogne, Meth. Enzymol. 276, 361, 1997 Murshudov, Dodson,Vagin, CCP4, 1996 Pannu & Read, Acta Cryst. A 52, 659-668, 1996 Adams, Pannu, Read, Brunger, PNAS 94, 5018, 1997
E ADP
(U
i
" Uj )
2
# Ui + U j & average_power % ( $ 2 '
Constraints
• • •
• • • • • • • •
Rigid-body reﬁnement
For example, molecule consists of two domains, only reﬁne position and orientation of each domain uses only 2 * (3 rotational + 3 translation) = 12 parameters So few parameters it requires only low-resolution data Torsion angle reﬁnement All atoms have the same B one parameter All main-chain and all side-chain atoms in each residue have the same B one or two parameters per residue TLS reﬁnement 20 parameters per group A number of N NCS-related molecules/domains are assumed to be identical Reduces the number of parameters by a factor N

WHO药品生产技术转移指南Annex7

285©World Health OrganizationWHO Technical Report Series, No. 961, 2011Annex 7WHO guidelines on transfer of technologyin pharmaceutical manufacturing1. Intr o duct i on2. Sc o pe3. Gl o ssary4. Organ i zat i on and management5. Pr o duct i on: transfer (process i ng, packag i ng and clean i ng)6. Qual i ty control: analyt i cal method transfer7. Prem i ses and equ i pment8. D o cumentat i on9. Qual i ﬁ cat i on and val i dat i on References1. IntroductionThese gu i d i ng pr i nc i ples on transfer of technology are i ntended to serve asa framework wh i ch can be appl i ed i n a ﬂ ex i ble manner rather than as str i ctr i g i d gu i dance. Focus has been placed on the qual i ty aspects, i n l i ne w i th WHO’s mandate.1.1 Transfer of processes to an alternat i ve s i te occurs at some stage i n thel i fe-cycle of most products, from development, scale-up, manufactur i ng, product i on and launch, to the post-approval phase.1.2 Transfer of technology i s deﬁ ned as “a log i cal procedure that controlsthe transfer of any process together w i th i ts documentat i on and profess i onal expert i se between development and manufacture or between manufacture s i tes”. It i s a systemat i c procedure that i s followed i n order to pass the documented knowledge and exper i ence ga i ned dur i ng development and or commerc i al i zat i on to an appropr i ate, respons i ble and author i zed party.Technology transfer embod i es both the transfer of documentat i on and the demonstrated ab i l i ty of the rece i v i ng un i t (RU) to effect i vely perform the cr i t i cal elements of the transferred technology, to the sat i sfact i on of all part i es and any appl i cable regulatory bod i es.1.3 L i terature searches revealed l i ttle i nformat i on on the sub j ect or i g i nat i ngfrom nat i onal or reg i onal regulatory b od i es. Gu i dance on i ntracompany transfers was prepared b y the Internat i onal Soc i ety for Pharmaceut i cal Eng i neer i ng (ISPE) (1).1.4 The ever chang i ng bus i ness strateg i es of pharmaceut i cal compan i esi ncreas i ngly i nvolve i ntra- and i ntercompany transfers of technology forreasons such as the need for add i t i onal capac i ty, relocat i on of operat i ons or consol i dat i ons and mergers. The WHO Expert Comm i ttee on Spec iﬁ cat i ons for Pharmaceut i cal Preparat i ons, therefore, recommended i n i ts forty-second report that WHO address th i s i ssue through preparat i on of WHO gu i del i nes on th i s matter (2).1.5Transfer of technology requ i res a documented, planned approach us i ngtra i ned and knowledgeable personnel work i ng w i th i n a qual i ty system, w i th documentat i on of data cover i ng all aspects of development, product i on and qual i ty control. Usually there i s a send i ng un i t (SU), a rece i v i ng un i t and the un i t manag i ng the process, wh i ch may or may not be a separate ent i ty. For “contract manufactur i ng” please see good manufactur i ng pract i ces (GMP) (3).1.6 For the transfer to be successful, the follow i ng general pr i nc i ples andrequ i rements should be met:•the pro j ect plan should encompass the qual i ty aspects of the pro j ect and be based upon the pr i nc i ples of qual i ty r i sk management;286•the capab i l i t i es of the SU and at the RU should b e s i m i lar, b ut not necessar i ly i dent i cal, and fac i l i t i es and equ i pment should operate accord i ng to s i m i lar operat i ng pr i nc i ples;• a comprehens i ve techn i cal gap analys i s between the SU and RU i nclud i ngtechn i cal r i sk assessment and potent i al regulatory gaps, should b e performed as needed;•adequately tra i ned staff should be ava i lable or should be tra i ned at the RU:—regulatory requ i rements i n the countr i es of the SU and the RU, andi n any countr i es where the product i s i ntended to be suppl i ed, shouldb e taken i nto account and i nterpreted cons i stently throughout anytransfer programme pro j ect; and—there should be effect i ve process and product knowledge transfer.1.7Technology transfer can be cons i dered successful i f there i s documentedev i dence that the RU can rout i nely reproduce the transferred product, process or method aga i nst a predeﬁ ned set of spec iﬁ cat i ons as agreed w i th the SU.1.8 In the event that the RU i dent iﬁ es part i cular problems w i th the processdur i ng the transfer, the RU should commun i cate them back to the SU to ensure cont i nu i ng knowledge management.1.9 Technology transfer pro j ects, part i cularly those b etween d i fferentcompan i es, have legal and econom i c i mpl i cat i ons. If such i ssues, wh i ch may i nclude i ntellectual property r i ghts, royalt i es, pr i c i ng, conﬂi ct ofi nterest and conﬁ dent i al i ty, are expected to i mpact on open commun i cat i onof techn i cal matters i n any way, they should be addressed before and dur i ng plann i ng and execut i on of the transfer.1.10 Any lack of transparency may lead to i neffect i ve transfer oftechnology.1.11 Some of the pr i nc i ples outl i ned i n th i s document may also b eappl i cab le to manufactur i ng i nvest i gat i onal pharmaceut i cal products for cl i n i cal tr i als as part of research and development, but th i s i s not the ma i n focus of th i s gu i dance and has been excluded due to the complex i ty of the processes.1.12 Some of the respons i b i l i t i es outl i ned i n th i s document for the SUmay also be cons i dered to be part of the management un i t respons i b i l i t i es.2. ScopeNote: Th i s sect i on spec iﬁ cally prov i des for transfer of qual i ty control (QC) methods where a techn i cal agreement ex i sts (SU manufacturer to RU manufacturer or SU manufacturer to RU QC laboratory). Where no such techn i cal agreements ex i st (e.g. test i ng by nat i onal laborator i es or test i ng287for procurement agenc i es) a number of the po i nts l i sted i n sect i on 2.4 may not be workable, and alternat i ve approaches may be requ i red.2.1 Th i s document g i ves gu i dance i n pr i nc i ple and prov i des generalrecommendat i ons on the act i v i t i es necessary to conduct a successful i ntra- or i nters i te transfer of technology as descr i bed i n the Introduct i on to these gu i del i nes. The i ntent i on i s to address the bas i c cons i derat i ons needed fora successful transfer i n order to sat i sfy the regulatory author i ty deﬁ ned forthe transfer process.2.2 The gu i del i nes w i ll be appl i ed to manufactur i ng act i ve pharmaceut i cali ngred i ents (APIs), manufactur i ng and packag i ng of b ulk mater i als,manufactur i ng and packag i ng of ﬁ n i shed pharmaceut i cal products (FPPs) and/or perform i ng analyt i cal test i ng.2.3 The recommendat i ons prov i ded i n these gu i del i nes apply to all dosageforms but need to be ad j usted on a case-by-case bas i s (e.g. by us i ng r i sk management pr i nc i ples). Part i cularly close control of certa i n aspects w i ll be requ i red for certa i n formulat i ons such as ster i le products, and metered-dose aerosols. WHO gu i dance on manufacture of spec iﬁ c pharmaceut i cal products(4,5) w i ll be useful i n th i s regard.2.4 The gu i del i nes address the follow i ng areas at the SU and the RU:—transfer of development and product i on (process i ng, packag i ng and clean i ng);—transfer of analyt i cal methods for qual i ty assurance and qual i ty control;—sk i lls assessment and tra i n i ng;—organ i zat i on and management of the transfer;—assessment of prem i ses and equ i pment;—documentat i on; and—qual iﬁ cat i on and val i dat i on.2.5Because each transfer pro j ect i s un i que, the prov i s i on of a comprehens i veset of gu i del i nes i s beyond the scope of th i s document.2.6 These gu i del i nes do not prov i de gu i dance on any legal, ﬁ nanc i al orcommerc i al cons i derat i ons assoc i ated w i th technology transfer pro j ects. 3. GlossaryThe deﬁ n i t i ons g i ven below apply to the terms used i n these gu i del i nes.They may have d i fferent mean i ngs i n other contexts.acceptance criteriaMeasurable terms under wh i ch a test result w i ll be cons i dered acceptable. 288active pharmaceutical ingredient (API)Any sub stance or m i xture of sub stances i ntended to b e used i n the manufacture of a pharmaceut i cal dosage form and that, when so used, b ecomes an act i ve i ngred i ent of that pharmaceut i cal dosage form. Such substances are i ntended to furn i sh pharmacolog i cal act i v i ty or other d i rect effect i n the d i agnos i s, cure, m i t i gat i on, treatment, or prevent i on of d i sease or to affect the structure and funct i on of the body.bracketingAn exper i mental des i gn to test only the extremes of, for example, dosage strength. The des i gn assumes that the extremes w i ll be representat i ve of all the samples between the extremes.change control (C/C)A formal system b y wh i ch qual iﬁ ed representat i ves of appropr i ate d i sc i pl i nes rev i ew proposed or actual changes that m i ght affect a val i dated status. The i ntent i s to determ i ne the need for act i on that would ensure that the system i s ma i nta i ned i n a val i dated state.commissioningThe sett i ng up, ad j ustment and test i ng of equ i pment or a system to ensure that i t meets all the requ i rements, as spec iﬁ ed i n the user requ i rement spec iﬁ cat i on, and capac i t i es as spec iﬁed b y the des i gner or developer. Comm i ss i on i ng i s carr i ed out before qual iﬁ cat i on and val i dat i on.control strategyA planned set of controls, der i ved from current product and process understand i ng, that assures process performance and product qual i ty. The controls can i nclude parameters and attr i b utes related tomater i als and components related to drug sub stances and drug product mater i als and components, fac i l i ty and equ i pment operat i ng cond i t i ons, i n-process controls, ﬁ n i shed product spec iﬁ cat i ons, and the assoc i ated methods and frequency of mon i tor i ng and control (6).corrective action (C/A)Any act i on to be taken when the results of mon i tor i ng at a cr i t i cal control po i nt i nd i cate a loss of control.criticalHav i ng the potent i al to i mpact on product qual i ty or performance i n a s i gn iﬁ cant way.critical control point (CCP)A step at wh i ch control can be appl i ed and i s essent i al to prevent or el i m i nate a pharmaceut i cal qual i ty hazard or to reduce i t to an acceptable level.289design qualiﬁ cation (DQ)Documented ev i dence that the prem i ses, support i ng systems, ut i l i t i es, equ i pment and processes have b een des i gned i n accordance w i th the requ i rements of good manufactur i ng pract i ces (GMP).design spaceThe mult i d i mens i onal comb i nat i on and i nteract i on of i nput var i ables (e.g.mater i al attr i butes) and process parameters that have been demonstrated to prov i de assurance of qual i ty (7).drug master ﬁ le (DMF)Deta i led i nformat i on concern i ng a spec iﬁ c fac i l i ty, process or product subm i tted to the med i c i nes regulatory author i ty, i ntended for i ncorporat i oni nto the appl i cat i on for market i ng author i zat i on.ﬁ nished pharmaceutical product (FPP)A product that has undergone all stages of product i on, i nclud i ng packag i ngi n i ts ﬁ nal conta i ner and labell i ng. An FPP may conta i n one or more APIs.gap analysisIdent iﬁ cat i on of cr i t i cal elements of a process wh i ch are ava i lable at the SU but are m i ss i ng from the RU.good manufacturing practices (GMP)That part of qual i ty assurance wh i ch ensures that pharmaceut i cal products are cons i stently produced and controlled to the qual i ty standards appropr i ate to the i r i ntended use and as requ i red by the market i ng author i zat i on (3).in-process control (IPC)Checks performed dur i ng product i on i n order to mon i tor and, i f necessary, to ad j ust the process to ensure that the product conforms to i ts spec iﬁ cat i ons.The control of the env i ronment or equ i pment may also be regarded as a part of i n-process control.installation qualiﬁ cation (IQ)The performance of tests to ensure that the i nstallat i ons (such as mach i nes, measur i ng dev i ces, ut i l i t i es and manufactur i ng areas) used i na manufactur i ng process are appropr i ately selected and correctly i nstalledand operate i n accordance w i th establ i shed spec iﬁ cat i ons.intercompany transferA transfer of technology between s i tes of d i fferent compan i es.intracompany transferA transfer of technology between s i tes of the same group of compan i es.290operational qualiﬁ cation (OQ)Documented ver iﬁ cat i on that the system or subsystem performs as i ntended over all ant i c i pated operat i ng ranges.performance qualiﬁ cation (PQ)Documented ver iﬁ cat i on that the equ i pment or system operates cons i stently and g i ves reproduc i b i l i ty w i th i n deﬁ ned spec iﬁ cat i ons and parameters for prolonged per i ods. (In the context of systems, the term “process val i dat i on”may also be used.)process validationDocumented ev i dence wh i ch prov i des a h i gh degree of assurance that a spec iﬁc process w i ll cons i stently result i n a product that meets i ts predeterm i ned spec iﬁ cat i ons and qual i ty character i st i cs.qualiﬁ cationAct i on of prov i ng and document i ng that any prem i ses, systems and equ i pment are properly i nstalled, and/or work correctly and lead to the expected results. Qual iﬁ cat i on i s often a part (the i n i t i al stage) of val i dat i on, but the i nd i v i dual qual iﬁ cat i on steps alone do not const i tute process val i dat i on.qualiﬁ cation batchesThose batches produced by the RU to demonstrate i ts ab i l i ty to reproduce the product (1).quality assurance (QA)Qual i ty assurance i s a w i de-rang i ng concept cover i ng all matters that i nd i v i dually or collect i vely i nﬂuence the qual i ty of a product.It i s the total i ty of the arrangements made w i th the ob j ect i ve of ensur i ng that pharmaceut i cal products are of the qual i ty requ i red for the i r i ntended use. quality control (QC)Qual i ty control covers all measures taken, i nclud i ng the sett i ng of spec iﬁ cat i ons, sampl i ng, test i ng and analyt i cal clearance, to ensure that start i ng mater i als, i ntermed i ates, packag i ng mater i als and ﬁ n i shed pharmaceut i cal products conform w i th establ i shed spec iﬁ cat i ons for i dent i ty, strength, pur i ty and other character i st i cs.quality planningPart of qual i ty management focused on sett i ng qual i ty ob j ect i ves and spec i fy i ng necessary operat i onal processes and related resources to fulﬁ l the qual i ty ob j ect i ves (6).quality policyOverall i ntent i ons and d i rect i on of an organ i zat i on related to qual i ty as formally expressed by sen i or management (6).291quality risk management (QRM)Qual i ty r i sk management i s a systemat i c process for the assessment, control, commun i cat i on and rev i ew of r i sks to the qual i ty of the pharmaceut i cal product throughout the product l i fe-cycle.receiving unit (RU)The i nvolved d i sc i pl i nes at an organ i zat i on where a des i gnated product, process or method i s expected to be transferred.sending unit (SU)The i nvolved d i sc i pl i nes at an organ i zat i on from where a des i gnated product, process or method i s expected to be transferred.spikingThe add i t i on of a known amount of a compound to a standard, sample or placeb o, typ i cally for the purpose of conﬁ rm i ng the performance of an analyt i cal procedure.standard operating procedure (SOP)An author i zed wr i tten procedure g i v i ng i nstruct i ons for perform i ng operat i ons not necessar i ly spec iﬁ c to a g i ven product or mater i al (e.g.equ i pment operat i on, ma i ntenance and clean i ng, val i dat i on, clean i ng of prem i ses and env i ronmental control, sampl i ng and i nspect i on). Certa i n SOPs may b e used to supplement product-spec iﬁc master and b atch product i on documentat i on.technology transfer reportA documented summary of a spec iﬁ c technology transfer pro j ect l i st i ngprocedures, acceptance cr i ter i a, results ach i eved and conclus i ons. Any dev i at i on should be d i scussed and j ust iﬁ ed.validationAct i on of prov i ng and document i ng that any process, procedure or method actually and cons i stently leads to the expected results.validation master plan (VMP)A h i gh-level document that establ i shes an umbrella val i dat i on plan for theent i re pro j ect and summar i zes the manufacturer’s overall ph i losophy and approach, to be used for establ i sh i ng performance adequacy. It prov i desi nformat i on on the manufacturer’s val i dat i on work programme anddeﬁ nes deta i ls of and t i mescales for the val i dat i on work to be performed,i nclud i ng a statement of the respons i b i l i t i es of those i mplement i ng theplan.292validation protocol (or plan) (VP)A document descr i b i ng the act i v i t i es to b e performed i n a val i dat i on,i nclud i ng the acceptance cr i ter i a for the approval of a manufactur i ngprocess — or a part thereof — for rout i ne use.validation report (VR)A document i n wh i ch the records, results and evaluat i on of a completedval i dat i on programme are assembled and summar i zed. It may also conta i n proposals for the i mprovement of processes and or equ i pment.n and management4. Organizatio4.1 Transfer compr i ses an SU and an RU. In some c i rcumstances theremay be an add i t i onal un i t wh i ch w i ll be respons i ble for d i rect i ng, manag i ng and approv i ng the transfer.4.2 There i s a formal agreement between the part i es, wh i ch spec iﬁ es therespons i b i l i t i es before, dur i ng and after transfer.4.3 Organ i zat i on and management of a successful technology transferneed to ensure that the ma i n steps have been executed and documented as descr i bed i n sect i on 1.6.4.4There should b e a pro j ect management plan wh i ch i dent iﬁ esand controls all the necessary act i v i t i es i dent iﬁed at the start of the undertak i ng.4.5 The transfer protocol should l i st the i ntended sequent i al stages of thetransfer. The protocol should i nclude:—ob j ect i ve;—scope;—key personnel and the i r respons i b i l i t i es;—a parallel compar i son of mater i als, methods and equ i pment;—the transfer stages w i th documented ev i dence that each cr i t i cal stage has been sat i sfactor i ly accompl i shed before the next commences;—i dent iﬁ cat i on of cr i t i cal control po i nts;—exper i mental des i gn and acceptance cr i ter i a for analyt i cal methods;—i nformat i on on tr i al product i on b atches, qual iﬁ cat i on b atches and process val i dat i on;—change control for any process dev i at i ons encountered;—assessment of end-product;—arrangements for keep i ng retent i on samples of act i ve i ngred i ents,i ntermed i ates and ﬁ n i shed products, and i nformat i on on referencesubstances where appl i cable; and—conclus i on, i nclud i ng s i gned-off approval by pro j ect manager.2934.6 The SU should prov i de the necessary val i dat i on documentat i on forthe process and i ts support funct i ons. Usually, an estab l i shed process i s transferred, and such documentat i on i s already ava i lable.4.7 The SU should prov i de cr i ter i a and i nformat i on on hazards andcr i t i cal steps assoc i ated w i th the product, process or method to b e transferred, to serve as a b as i s for a qual i ty r i sk management (QRM) exerc i se at the RU (7–10).4.8 The SU or th i rd party should assess the su i tab i l i ty and degree ofpreparedness of the RU before transfer, w i th regard to prem i ses, equ i pment and support serv i ces (e.g. purchas i ng and i nventory control mechan i sms, qual i ty control (QC) procedures, documentat i on, computer val i dat i on, s i te val i dat i on, equ i pment qual iﬁ cat i on, water for pharmaceut i cal product i on and waste management).4.9The SU and the RU should j o i ntly ver i fy that the follow i ng,sat i sfactor i ly completed, val i dat i on protocols are ava i lable:•i nstallat i on qual iﬁ cat i on (IQ) and operat i onal qual iﬁ cat i on (OQ) data formanufactur i ng and packag i ng equ i pment at the RU s i te and analyt i calequ i pment; and•qual iﬁ cat i on of the rooms for both manufacture and packag i ng at the RUs i te.4.10The SU and the RU should j o i ntly i mplement any tra i n i ngprogrammes that may b e requ i red spec iﬁc to the product, process or method to be transferred, e.g. on analyt i cal methods or equ i pment usage, and assess tra i n i ng outcomes.4.11 The SU and the RU should j o i ntly execute the transfer protocolaccord i ng to a checkl i st and or ﬂ ow d i agram show i ng the sequence of steps to be carr i ed out to effect an efﬁ c i ent transfer.4.12 Any changes and adaptat i ons made dur i ng the course of thetechnology transfer should be fully documented.4.13 The SU and the RU should j o i ntly document the execut i on of thetransfer protocol i n a transfer of technology summary i n a report.teamProject4.14 Any transfer pro j ect w i ll be managed by a team compr i s i ng membersw i th clearly deﬁ ned key respons i b i l i t i es. The team should be drawn from members of relevant d i sc i pl i nes from both the SU and RU s i tes.4.15 The team memb ers should have the necessary qual iﬁ cat i ons andexper i ence to manage the i r part i cular aspect of the transfer.2945.Production: transfer (processing, packagingand cleaning)5.1 The RU should b e ab le to accommodate the i ntended product i oncapac i ty. If poss i ble, i t should b e estab l i shed at the outset whether thei ntent i on i s to perform s i ngle-batch manufacture, cont i nuous product i on orcampa i gns.5.2 Cons i derat i on should be g i ven to the level and depth of deta i l to betransferred to support product i on and any further process development and opt i m i zat i on at the RU as i ntended under the transfer pro j ect plan.5.3 Cons i derat i on should b e g i ven to the techn i cal expert i se, s i tetechnology and s i te capab i l i t i es for the RU. It should be i dent iﬁ ed upfront by the SU of any process robustness i ssues so that plans may be put i n place at the RU.5.4 The SU and the RU should j o i ntly develop a protocol for the transferof relevant i nformat i on related to the process under cons i derat i on from the SU to the RU, as well as the development of a comparable process at the RU.materialsStarting5.5 The spec iﬁ cat i ons and relevant funct i onal character i st i cs of thestart i ng mater i als (APIs and exc i p i ents) (11,12) to be used at the RU should be cons i stent w i th mater i als used at the SU. Any propert i es wh i ch are l i kely to i nﬂ uence the process or product should be i dent iﬁ ed and character i zed.Active pharmaceutical ingredients (API)5.6 The SU should prov i de the RU w i th the open (appl i cant’s) partof the API master ﬁle (APIMF or drug master ﬁle (DMF) or act i ve substance master ﬁ le (ASMF)), or equ i valent i nformat i on and any relevant add i t i onal i nformat i on on the API of i mportance for the manufacture of the pharmaceut i cal product. The follow i ng are examples of the i nformat i on wh i ch may typ i cally be prov i ded; however the i nformat i on needed i n each spec iﬁ c case should be assessed us i ng the pr i nc i ples of QRM:•manufacturer and assoc i ated supply cha i n;•step of the API to be transferred;•ﬂ ow chart of synthes i s pathway, outl i n i ng the process, i nclud i ng entry po i nts for raw mater i als, cr i t i cal steps, process controls and i ntermed i ates;•where relevant, deﬁ n i t i ve phys i cal form of the API (i nclud i ngphotom i crographs and other relevant data) and any polymorph i c and solvate forms;•solub i l i ty proﬁ le;295•i f relevant, pH i n solut i on;•part i t i on coefﬁ c i ent, i nclud i ng the method of determ i nat i on;•i ntr i ns i c d i ssolut i on rate, i nclud i ng the method of determ i nat i on;•part i cle s i ze and d i str i but i on, i nclud i ng the method of determ i nat i on;•bulk phys i cal propert i es, i nclud i ng data on bulk and tap dens i ty, surfacearea and poros i ty as appropr i ate;•water content and determ i nat i on of hygroscop i c i ty, i nclud i ng water act i v i ty data and spec i al handl i ng requ i rements;•m i crob i olog i cal cons i derat i ons (i nclud i ng ster i l i ty, bacter i al endotox i nsand b i ob urden levels where the API supports m i crob i olog i cal growth)i n accordance w i th nat i onal, reg i onal or i nternat i onal pharmacopoe i alrequ i rements;•spec iﬁ cat i ons and j ust iﬁ cat i on for release and end-of-l i fe l i m i ts;•summary of stab i l i ty stud i es conducted i n conform i ty w i th current gu i del i nes, i nclud i ng conclus i ons and recommendat i ons on retest date;•l i st of potent i al and observed synthet i c i mpur i t i es, w i th data to supportproposed spec iﬁ cat i ons and typ i cally observed levels;•i nformat i on on degradants, w i th a l i st of potent i al and ob served degradat i on products and data to support proposed spec iﬁ cat i ons andtyp i cally observed levels;•potency factor, i nd i cat i ng ob served pur i ty and j ust iﬁ cat i on for any recommended ad j ustment to the i nput quant i ty of API for product manufactur i ng, prov i d i ng example calculat i ons; and•spec i al cons i derat i ons w i th i mpl i cat i ons for storage and or handl i ng,i nclud i ng b ut not l i m i ted to safety and env i ronmental factors (e.g. asspec iﬁ ed i n mater i al safety data sheets) and sens i t i v i ty to heat, l i ght ormo i sture.Excipients5.7 The exc i p i ents (11) to be used have a potent i al i mpact on the ﬁ nalproduct. The i r spec iﬁ cat i ons and relevant funct i onal character i st i cs should, therefore, b e made ava i lab le b y the SU for transfer to the RU s i te. The follow i ng are examples of the i nformat i on wh i ch may typ i cally be prov i ded;however, the i nformat i on needed i n each spec iﬁ c case should be assessed us i ng the pr i nc i ples of QRM:•manufacturer and assoc i ated supply cha i n;•descr i pt i on of funct i onal i ty, w i th j ust iﬁ cat i on for i nclus i on of any ant i ox i dant, preservat i ve or any exc i p i ent;•deﬁ n i t i ve form (part i cularly for sol i d and i nhaled dosage forms);•solub i l i ty proﬁ le (part i cularly for i nhaled and transdermal dosage forms);•part i t i on coefﬁ c i ent, i nclud i ng the method of determ i nat i on (for transdermal dosage forms);296•i ntr i ns i c d i ssolut i on rate, i nclud i ng the method of determ i nat i on (for transdermal dosage forms);•part i cle s i ze and d i str i but i on, i nclud i ng the method of determ i nat i on (for sol i d, i nhaled and transdermal dosage forms);•bulk phys i cal propert i es, i nclud i ng data on bulk and tap dens i ty, surface area and poros i ty as appropr i ate (for sol i d and i nhaled dosage forms);•compact i on propert i es (for sol i d dosage forms);•melt i ng po i nt range (for sem i-sol i d or top i cal dosage forms);•pH range (for parenteral, sem i-sol i d or top i cal, l i qu i d and transdermal dosage forms);•i on i c strength (for parenteral dosage forms);•spec iﬁ c dens i ty or grav i ty (for parenteral, sem i-sol i d or top i cal, l i qu i d and transdermal dosage forms);•v i scos i ty and or v i scoelast i c i ty (for parenteral, sem i-sol i d or top i cal, l i qu i d and transdermal dosage forms);•osmolar i ty (for parenteral dosage forms);•water content and determ i nat i on of hygroscop i c i ty, i nclud i ng water act i v i ty data and spec i al handl i ng requ i rements (for sol i d and i nhaled dosage forms);•mo i sture content range (for parenteral, sem i sol i d or top i cal, l i qu i d and transdermal dosage forms);•m i crob i olog i cal cons i derat i ons (i nclud i ng ster i l i ty, bacter i al endotox i ns and b i ob urden levels where the exc i p i ent supports m i crob i olog i cal growth) i n accordance w i th nat i onal, reg i onal or i nternat i onal pharmacopoe i al requ i rements, as appl i cable (for general and spec iﬁ c monographs);•spec iﬁ cat i ons and j ust iﬁ cat i on for release and end-of-l i fe l i m i ts;•i nformat i on on adhes i ves support i ng compl i ance w i th peel, sheer and adhes i on des i gn cr i ter i a (for transdermal dosage forms);•spec i al cons i derat i ons w i th i mpl i cat i ons for storage and or handl i ng, i nclud i ng b ut not l i m i ted to safety and env i ronmental factors (e.g. as spec iﬁ ed i n mater i al safety data sheets (MSDS)) and sens i t i v i ty to heat, l i ght or mo i sture; and•regulatory cons i derat i ons, e.g. documentat i on to support compl i ance w i th transm i ss i le an i mal spong i form encephalopathy cert iﬁ cat i on requ i rements (where appl i cable).Information on process and ﬁ nished pharmaceuticalproducts information5.8 The SU should prov i de a deta i led character i zat i on of the product,i nclud i ng i ts qual i tat i ve and quant i tat i ve compos i t i on, phys i cal descr i pt i on, method of manufacture, i n-process controls, control method and spec iﬁ cat i ons, packag i ng components and conﬁ gurat i ons, and any safety and handl i ng cons i derat i ons.297。

PROCESS FOR THE QUANTIFICATION OF CELL POPULATIONS

专利名称：PROCESS FOR THE QUANTIFICATION OF CELL POPULATIONS OR SUBPOPULATIONSAND A REAGENT SUITABLE THEREFOR发明人：HARTMAT SCHETTERS,JOSEFENDL,WINFRIED ALBERT申请号：AU6538286申请日：19861119公开号：AU574281B2公开日：19880630专利内容由知识产权出版社提供摘要：A process for quantification of cell populations or subpopulations, by incubating a sample with labelled antibodies directed against characteristic surface antigens of the cell population to be quantified to form labelled antibody/antigen complexes. Standards with known, differing particle concentration and having comparable sedimentation behavior to the cells to be determined and further, carrying molecules which are directed against the labelled antibody or a part hereof are also incubated with the labelled antibodies. The cells of the sample solution, as well as the particles of the standard solution, are separated off from the excess labelled antibodies and the amount of the labelling is measured not only on the cells but also on the particles. By comparison of the measurement value from the sample with the measurement values from the standard solutions, there is ascertained the number of cells to be determined in the sample. The standard and a reagent kit for carrying out the process are also the subject of this application.申请人：BOEHRINGER MANNHEIM GMBH更多信息请下载全文后查看。

Annex_2_qualification_of_gc_equipment(欧盟GMP指南：GC)

OMCL Network of the Council of Europe QUALITY ASSURANCE DOCUMENTPA/PH/OMCL (16) 17 RQUALIFICATION OF EQUIPMENTANNEX 2: QUALIFICATION OF GC EQUIPMENTFull document titleand referenceQualification of EquipmentAnnex 2: Qualification of GC EquipmentPA/PH/OMCL (16) 17 RDocument type GuidelineLegislative basis The present document was also accepted by EA asrecommendation document to be used in the context of QualityManagement System audits of OMCLsDate of first adoption May 2006Date of original entryinto forceJune 2006Date of entry intoforce of reviseddocumentJuly 2016Previous titles/otherreferencesThis document replaces PA/PH/OMCL (06) 86 DEFCustodianOrganisationThe present document was elaborated by the OMCLNetwork/EDQM of the Council of EuropeConcerned Network GEONANNEX 2 OF THE OMCL NETWORK GUIDELINE“QUALIFICATION OF EQUIPMENT”QUALIFICATION OF GC EQUIPMENTIntroductionThe present document is the second Annex of the core document “Qualification of Equipment”, and it should be used in combination with it when planning, performing and documenting the GC equipment qualification process.The core document contains the general introduction and the Level I and II of qualification, common to all type of instruments, and the present annex contains GC instrument-related recommendations on parameters to be checked and the corresponding typical acceptance limits, as well as practical examples on the methodology that can be used to carry out these checks.The tests proposed in the Level III and IV of qualification are based on an overall approach, in which several parameters are checked at the same time in a combined test procedure, to obtain information on the overall system performance (e.g. peak area precision, retention time precision, temperature programme reproducibility, etc).Nevertheless, it should be noted that it is also acceptable to check these parameters individually by using other well-defined procedures.Level III. Periodic and motivated instrument checksExamples of requirements for GC instruments with FIDInstrumentmoduleParameter to be checked Typical tolerance limits1. Inlet system1.1 Injector leak testPressure drop ≤ 15 kPawithin 5 minutes1.2. Pressure/flow accuracy and stability Covered by overall test 1 1.3. Repeatability of GC injections (overall test 1)Peak areas:- In split mode- In split less modeRetention times:RSD ≤ 3.0%RSD ≤ 3.0%RSD ≤ 2.0%1.4. Injector temperature accuracy and stability Covered by overall test 2 1.5. Carry-over (overall test 3) ≤ 0.2%Head space injector1.6. Repeatability of Headspace injections- Peak areas:- Retention times:1.7Vial heater temperatureRSD ≤ 5.0 %RSD ≤ 2.0%± 4°C from set point2. Oven 2.1. Repeatability of oven temperature characteristics Covered by overall test 23. FID detector 3.1. Linearity (overall test 3) r2≥ 0.9993.2. Constant detector response Covered by overall test 1 or 2 3.3. Noise See Annex I3.3. Drift See Annex ILevel IV. In-use instrument checksExamples of requirements for GC instruments with FID Parameter to be checked Typical tolerance limits1. System suitability check for the method According to Ph. Eur. or MAH dossier or validated in-house method2. Peak area precision- GC injections- Headspace injections RSD ≤ 3.0% unless otherwise prescribed* RSD ≤ 5.0% unless otherwise prescribed*3. Retention time repeatability RSD ≤ 2.0%4. Sensitivity (where relevant, e.g. for related substances tests) According to Ph. Eur. or MAH dossier or validated in-house method* This is to be defined in conjunction with the target concentration of the analyteAll parameters given here should be checked when performing analyses under the working conditions for the actual sample determinations. Normally, the test and reference solutions to be prepared for this purpose are given as a part of the method.Level III. Periodic and motivated instrument checksPractical examples of tests and their associated tolerance limits for several parameters related to the performance of the different modules of a GC are presented below.These examples can be considered by the OMCLs as possible approaches to perform the Level III of the equipment qualification process: “Periodic and motivated instrument checks”. Several tests are proposed to check various parameters at the same time (overall tests). In order to run the tests in a more economical way, other suitable solutions can be used, as for example, the “Grob Test” mixture, available from different suppliers (e.g. Alltech, Sigma, Thames Restek). This commercial solution should be appropriate to the column material used. It is recommended to run the overall tests by using always the same test column, exclusively dedicated to qualification purposes, to guarantee reproducible conditions.1. INLET SYSTEMThe following tests are proposed for the periodic and motivated check of the GC Inlet System.1.1. INJECTOR LEAK TESTMethod:If not otherwise specified by the instrument manufacturer, the leak test is carried out according to the procedure laid down in the instrument manual or by the built in automatic leak check procedure of the instrument.Otherwise use the test described below:Disconnect the column from the injector and close the injector outlet with a sealed cap.Close the septum purge and the bypass.Adjust the flow and pressure controller to the maximal possible value of the pressure gauge. Adjust the flow controller to zero.Read the pressure after 1 minute and record the value.Record the pressure after 5 minutes.Limits:Pressure drop ≤ 15 kPa within 5 minutes.1.2. INLET PRESSURE/FLOW ACCURACY AND STABILITYA direct measurement of these parameters was not deemed practical or necessary, but the optimal conditions of flow/pressure can be verified by the overall test 1.Limits: refer to overall test 1.1.3. REPEATABILITY OF GC INJECTIONThe verification of this parameter is covered by the overall test 1.This test is to be performed in both split and split less mode.Limits: refer to overall test 1.1.4. INJECTOR TEMPERATURE ACCURACY AND STABILITYDue to the fact that the temperature cannot be reliably measured without opening and modifying the system and due to the difficulties of introducing a probe inside this module, the verification of this parameter is considered to be covered by the overall test 2.Limits: refer to overall test 2.1.5. INJECTOR CARRY OVERAfter having injected the solutions for the linearity test of the FID detector, in increasing order, inject the blank and measure the peaks that correspond to the major peaks (= analytes) in the linearity solutions.The verification of this parameter is covered by the overall test 3.Limits: refer to overall test 3.HEAD SPACE INJECTORS1.6. REPEATABILITY OF HEADSPACE INJECTIONSMethod:The GC-HS operating conditions below are provided as an example, adjustments may be needed depending on the equipment used.Test solution: 0.5 % ethanol in water R (V/V)GC-Settings:Column: 95% Dimethyl / 5% diphenylpoly siloxane 30 m x 0.25 µm; 0.25 mm (HP-5 was found suitable)Carrier gas: HeliumColumn Flow: 1.2 ml/minInjector temperature: 200 °CSplit ratio: 1:50Oven temperature: 40°C isothermDetector temperature: 250 °CRun time: 1.5 folds the retention time of the main peakRetention time: about 2.2 minHeadspace-Settings:Carrier pressure: 9.9 psiVial pressure: 14.2 psiShake: lowOven Temperature: 80 °CLoop Temperature: 90 °CTransfer line Temperature: 100 °CVial size: 20 mLVolume of sample solution/vial: 5 mLVial Equilibration Time: 15.0 minInject Time: 1.0 minLoop Equilibration Time: 0.1 minLoop Fill Time: 0.5 minVial Pressurization Time: 0.08 minCarry out 6 consecutive injections of the test solution and calculate the RSD of the different peak areas and retention times.Limits:Peak areas: the RSD should be ≤ 5.0%Retention time: the RSD should be ≤ 2.0%1.7 VIAL HEATER TEMPERATUREThe heater temperatures are to be set up at values which depend on the operating conditionsof the methods applied.Suitable calibrated temperature devices are to be used.Put the calibrated device in the oven of the head space compartment. Set the temperature at the required values. When equilibration is achieved, record the value displayed on the calibrated device.Limits: ± 4°C from set point2. OVEN2.1. REPEATABILITY OF THE OVEN TEMPERATURE CHARACTERISTICSDue to the fact that the temperature cannot be reliably measured without opening and modifying the system conditions and that even when introducing a probe inside the oven, its location would not reflect the real temperature conditions at all points, the verification of this parameter is covered by the overall tests 2A and 2B.Limits: refer to overall test 2.3. FID DETECTORThe following tests are proposed for the periodic and motivated check of the GC FID detector.3.1. FID DETECTOR LINEARITYIncreasing amounts of analyte are injected and a linear response should be obtained.The verification of this parameter is covered by the overall test 3.Limits: refer to overall test 3.3.2. CONSTANT FID DETECTOR RESPONSEThe proper and reproducible functioning of the FID can be demonstrated by checking the peak areas obtained from a pre-defined standard solution.The verification of this parameter is covered by the overall test 1 or 2.Limits: refer to overall test 1 or 2.3.3. FID DETECTOR NOISE AND DRIFTIf the instrument has a built-in automatic system for the verification of the noise and drift, follow the manufacturer’s instructions and apply the defined acceptance criteria. Otherwise, use the test described below:Settings:Column installedSuitable flow, depending on column length/diameterNo injectionOven temperature: 40°CDetector on and heated at working temperature (270-300°C)Method:After stabilisation of the system, record the signal for 15 minutes.Noise: evaluate 10 periods of 1 minute and calculate the mean value.Drift: evaluate the slope of the baseline over the 15 minutes.Limits:The acceptance criteria for these parameters have to be chosen in accordance with the instrument vendor’s instructions and the intended use of the instrument. If no instructions are given, the user has to pre-define these acceptance criteria by taking into account the previous experience and the intended use of the instrument.No fixed values can be pre-defined in this guideline due to the high variety of integration systems used and consequently the acceptance criteria may be expressed in different units (voltage, current, arbitrary units per time).OVERALL TEST 1The overall test 1 covers the following parameters:-Pressure/flow accuracy and stability in the inlet system: Retention time repeatability -Repeatability of injection: peak area precision-In split mode-In split less modeThe test may be combined with overall test 3.Split mode:Test solution:1-octanol in n-hexane 1% (V/V).Settings:Column: 100% Dimethylpolysiloxane 30m x 0.32mm ID x 0.25µm film (SPB-1 was found suitable)Carrier gas: HeliumVelocity: 25cm/secSplit: 1:100Injection: 1µlInjector temperature: 220°COven temperature: 100°C isothermDetector temperature: 300°CRun time: 1.5 folds the retention time of the main peakRetention time of 1-octanol: about 5 minSplit less mode:Stock solution: 1-octanol in n-hexane 1% (V/V)Test solution: Dilute 10 ml of the stock solution with n-hexane to 100 ml (corresponds to 1µl/ml of 1-octanol in n-hexane)Settings:Column: 100% Dimethylpolysiloxane 30m, 0.32mm ID, 0.25µm film (SPB-1 was found suitable)Carrier: HeliumVelocity: 30cm/secSplit less injection: purge valve closed during 2 minInjection: 0.2µl of the test solutionInjector Temperature: 220°COven Temperature: Initial 60°C for 4 min, 15°C/min. up to 135°C, final time 1minDetector temperature: 300°CRuntime: 1.5 folds the retention time of the main peakRetention time of 1-octanol: about 8 minMethod:Carry out 6 consecutive injections of the test solution and calculate the RSD of the different peak areas and retention times.Limits:Retention time repeatability: the RSD of the retention times should be ≤ 2.0%Peak area precision (split and split-less mode): the RSD of the peak areas should be ≤3.0%OVERALL TEST 2The overall test 2 covers the following parameters:-Injector, oven and detector temperature accuracy and stability: retention timerepeatabilityTwo alternative tests are proposed:Overall test 2ATest solution:0.035 ml 1-octanol0.035 ml 2-octanone0.035 ml 2,6-dimethylanilin0.035 ml n-tridecane0.035 ml n-tetradecane35 mg n-eicosanedissolved in 50 ml DichloromethaneSettings:Column: 100% Dimethylpolysiloxane 30m x 0.32mm ID x 0.25µm film (SPB-1 was foundsuitable)Carrier gas: HeliumVelocity: 25 cm/sSplit: 1:100Injection volume: 1 µlInjector temperature: 220°CDetector: FIDDetector temperature: 300°CGradient programme: 60°C (4 min), 5°C/min, 270°C (3 min)Method:Inject the solution twice and calculate the relative retention (RR) times in relation to n-eicosane (RR = 1)The following table shows the approximately expected relative retention times.Analyte 1-octanol 2-octanone 2,6-dimethylaniline n-tridecane n-tetradecaneRRT 0.30 0.22 0.37 0.52 0.60Limits:The RSD of each RR from two consecutive injections should be ≤1.0%Overall test 2BTest Solution:1.0% (m/m) n-Nonane and Hexadecane in Tetradecane.Settings:Column: 100% Dimethylpolysiloxane 25m x 0.32mm ID x 0.52µm film (Ultra-1 was found suitable)Injection volume: 1 μlSolvent: TetradecaneOven temperature: 110°CGradient programme: 110°C, 20°C/min, 180°C (final time: 3.5 min)Detector temperature: 250°CInjector temperature: 200°CDetector: FIDFlow rates: as defined by the instrument manufacturerSplit ratio: 1:15Split vent: 30 ± 3.0 ml/minSeptum purge: 3-5 ml/minMethod:Allow the system to equilibrate.Injection sequence:1)blank (Tetradecane)2) 6 replicates of the test solution. Calculate the mean of the retention times and peakareas and the relative standard deviation of n-Nonane and n-Hexadecane.Limits:Retention time repeatability: RSD of the peak retention times of the 6 replicates ≤ 2.0% Retention time (Rt) accuracy: for this example, the retention time ranges shown in the table below are proposed. Nevertheless, individual ranges should be predefined by the laboratory depending on the column used (e.g. Rt ± 0.2 min).(min)Compound Rtn-Nonane (C9) 1.3 – 1.7Tetradecane (C14) 4.0 – 4.7Hexadecane (C16) 5.1 – 6.0OVERALL TEST 3This test is a modified version of the overall test 1 to be used for the verification of: -Detector linearity: linearity of the areas recorded-Injector carry-over: area recorded in the blank runIt is described for both split and split less mode and may be combined with overall test 1.Split mode:Test solution: 1-octanol in n-hexane 1% (V/V)Prepare further reference solutions by diluting the test solution as described below. Settings: see overall test 1Injection sequence:5.0 ml of the test solution diluted to 25.0 ml with n-hexane (2 µl/ml): 2 injections10.0 ml of the test solution diluted to 25.0 ml with n-hexane (4 µl/ml): 2 injections15.0 ml of the test solution diluted to 25.0 ml with n-hexane (6 µl/ml): 2 injections20.0 ml of the test solution diluted to 25.0 ml with n-hexane (8 µl/ml): 2 injectionsi f combined with overall test 1 for repeatability: test solution (10 µl/ml): 6 injectionsn-hexane as blank (carry over)Split-less mode:Stock solution: 1-octanol in n-hexane 1% (V/V)Test solution: Dilute 10 ml of the stock solution with n-hexane to 100 ml (corresponds to 1µl/ml of 1-octanol in n-hexane).Prepare further reference solutions by diluting the test solution with n-hexane.Settings: see overall test 1Injection sequence:5.0 ml of the test solution diluted to 25.0 ml with n-hexane (0.2 µl/ml): 2 injections10.0 ml of the test solution diluted to 25.0 ml with n-hexane (0.4 µl/ml): 2 injections15.0 ml of the test solution diluted to 25.0 ml with n-hexane (0.6 µl/ml): 2 injections20.0 ml of the test solution diluted to 25.0 ml with n-hexane (0.8 µl/ml): 2 injectionsif combined with overall test 1 for repeatability: test solution (1 µl/ml): 6 injectionsn-hexane as blank (carry over)Limits:Linearity: coefficient of correlation of the calibration line obtained with the reference solutions and the test solution: r2≥ 0.999.Carry-over: the percentage of the peak area corresponding to the analyte in the blank solution should be ≤0.2% of the peak area of this analyte in the chromatogram obtained with the solution with the highest concentration within the sequence.。

Annex 2(QC) 世界卫生组织药品微生物实验室管理规范

© World Health Organization 世界卫生组织WHO Technical Report Series, No. 961, 2011世界卫生组织技术报告系列，编号961，2011年Annex 2 附录2WHO good practices for pharmaceutical microbiology laboratories世界卫生组织药品微生物实验室管理规范目录Background 背景 (2)Introduction and scope of document 文件介绍和范围 (2)Glossary 术语表 (3)1. Personnel 人员 (5)2. Environment 环境 (6)2.1 Premises 房屋 (6)2.3 Cleaning, disinfection and hygiene 清洁、消毒和卫生 (8)2.4 Sterility test facilities 无菌试验设施 (8)3. Validation of test methods 检验方法的验证 (10)4. Equipment 设备 (10)4.1 Maintenance of equipment 设备维护 (11)4.2 Qualiﬁcation 验证 (11)4.3 Calibration, performance veriﬁcation and monitoring of use 校准、性能确认和使用的监控 (11)4.3.3 Temperature measurement devices 温度测量装置 (11)4.3.4 Incubators, water-baths and ovens 培养箱、水浴和烘箱 (11)4.3.5 Autoclaves, including media preparators 高压灭菌锅，包括培养基制备器 (12)4.3.6 Weights and balances 砝码和天平 (13)4.3.7 Volumetric equipment 测定体积的设备 (13)4.3.8 Other equipment 其他设备 (13)5. Reagents and culture media 试剂和培养基 (14)5.1 Reagents 试剂 (14)5.2 Media 培养基 (14)5.3 Labelling 贴签 (16)5.4 Organism resuscitation 微生物复苏 (16)6. Reference materials and reference cultures 标准物质和标准菌株 (16)6.1 International standards and pharmacopoeial reference substances 国际标准和药典标准品 (16)6.2 Reference cultures 标准菌株 (17)7. Sampling取样 (18)8. Sample handling and identification 样品处理和鉴定 (18)9. Disposal of contaminated waste污染废物的处理 (19)10. Quality assurance of results and quality control of performance结果的质量保证和性能的质量控制 (19)10.1 Internal quality control内部质量控制 (19)11. Testing procedures检验程序 (20)12. Test reports检验报告 (20)References参考文件 (20)Further reading 补充书目 (21)Appendix 1 附件1 (22)Examples of zones in which operations could be carried out可进行操作的区域的例子 (22)Appendix 2 附件2 (23)Examples of maintenance of equipment设备维护的例子 (23)Appendix 3 附件3 (24)Examples of calibration checks and intervals for different laboratory equipment不同实验室设备校准检查和间隔的例子 (24)Appendix 4 附件4 (25)Examples of equipment qualification and monitoring设备验证和监控的例子 (25)Appendix 5 附件5 (27)General use of reference cultures 标准菌株的一般用途 (27)Background 背景The WHO Expert Committee on Speciﬁcations for Pharmaceutical Preparations adopted in 2009 a revised version of the Good practices for pharmaceutical quality control laboratories (1).世界卫生组织制剂产品的质量标准专家委员会在2009年通过了药品质量控制实验室管理规范的修订版本(1)。

牛奶和奶粉中八种镇定剂残留量的测定(三)

牛奶和奶粉中八种镇定剂残留量的测定（三）7.3.3.1定性测定根据液相色谱-串联质谱测定条件举行样品溶液测定。

假如检出的色谱峰的保留时光与基质标准中物质相全都，并且所挑选的离子均浮现，挑选1个母离子和2个以上子离子，样品谱图中定性离子的相对丰度与浓度临近的基质标准溶液谱图中对应的定性离子的相对丰度举行比较，偏差不超过表3规定要的范围，则可判定为样品中存在对应的待测物。

表3 定性确证时相对离子丰度的最大允许偏差7.3.3.2 定量测定用混合标准溶液(4.21)分离进样，以峰面积为纵坐标，工作溶液浓度为横坐标，绘制标准工作曲线，用标准工作曲线对样品举行定量，样品溶液中镇定剂及其代谢产物和R-阻断剂的响应值均应在仪器测定的线性范围内。

在上述的色谱条件和质谱条件下，八种镇定剂的参考保留时光见表4。

表4 八种镇定剂参考保留时光 7.4 平行实验根据以上步骤，对同一试样举行平行实验。

7.5 回收率实验除不称取试样外，均按上述步骤举行。

8 结果计算试样中每种镇定剂及其代谢物和β-阻断剂残留量利用数据处理系统计算或按式(1)计算：式中： X—试样中被测组分残留量，单位为微克每千克(ug/kg) ; c —从标准曲线上得到被测组分溶液的浓度，单位为纳克每毫升(ng/mL) ; V—样品溶液定容体积，单位为毫升(mL); m—样品溶液所代表试样的质量，单位为克(g)。

计算结果应扣除空白值。

9 精密度9.1 普通规定本标准的精密度数据是根据GB/T 6379.1和GB/T 6379.2的规定确定的，其重复性限和再现性限的值是以95％的可信度来计算。

9.2 重复性在重复性条件下，获得的两次自立测试结果的肯定差值不超过重复性限r，牛奶和奶粉中六种镇定剂及其代谢物的添加浓度范围及重复性方程见表5。

表5 牛奶和奶粉中八种镇定剂的添加浓度范围及重复性限和再现性限方程假如差值超过重复性限r，应舍弃实验结果并重新完成两次单个实验的测定。

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OMCL Network of the Council of Europe QUALITY MANAGEMENT DOCUMENTPA/PH/OMCL (12) 77 7RQUALIFICATION OF EQUIPMENTANNEX 8: QUALIFICATION OF BALANCESFull document title and reference Qualification of BalancesAnnex 8 to the OMCL Network Guideline “Qualification of Equipment” PA/PH/OMCL (12) 77 7RDocument type GuidelineLegislative basisDate of first adoption August 2013Date of original entry intoforceDecember 2013Date of entry into force ofrevised documentn/aPrevious titles/otherreferences / last validversionn/aCustodian Organisation The present document was elaborated by the OMCL Network / EDQMof the Council of EuropeConcerned Network GEONPA/PH/OMCL (12) 77 7R 2/11ANNEX 8 OF THE OMCL NETWORK GUIDELINE“QUALIFICATION OF EQUIPMENT”QUALIFICATION OF BALANCES1.INTRODUCTIONThis document is the 8th Annex to the core document “Qualification of Equipment”, which together should be used when planning, performing and documenting the qualification process of balances.The core document contains the introduction and general forms for Level I and II of qualification, which are common to all types of instruments.Annex 8 contains instrument-related recommendations on parameters to be checked at Level III and IV of qualification and the corresponding typical acceptance limits, as well as practical examples on the methodology that can be used to carry out these checks.2.AIM AND SCOPE OF THE GUIDELINEThis guideline describes the requirements for balances (electronic - digital) used in chemical and biological tests in OMCLs.The following types of balances are considered in this guideline (Table 1):Table 1Type Ordinary name Number of digits afterdecimal position (g) Accuracy Class1.Ultra Micro Balances 7 I2.Micro Balances 6 I3.Semi-micro Balances 5 I4.Analytical Balances 4 I5.Precision Balances 1 to 3 II6.Technical Balances 0 to 1 IIIThe classifications are based on the OIML R 76-1 International Recommendation document (see Table 2).3/11 OMCL (12) 77 7R Table 2: The verification scale interval, number of verification scale intervals and minimum capacity in relation to the accuracy class of an instrument.Accuracy class Verificationscale interval (e)Number of verificationscale intervals(n = Max/e)Minimumcapacity(Min)(Lowerlimit) minimummaximumSpecialI 0.001 g <e (*) 50000 (**)- 100 eHigh II 0.001 g <e< 0.05 g0.1 g <e1005 000100 000100 00020 e50 eMediumIII 0.1 g <e< 2 g5 g <e10050010 00010 00020 e20 eOrdinaryIIII 5g<e 100 1 000 10 e* It is not normally feasible to test and verify an instrument to e < 1 mg due to the uncertainty of the test loads.** For an instrument of class I with d < 0.1 mg, n may be less than 50000. The minimum capacity is reduced to 5 e for grading instruments, i.e. instruments that determine a transport tariff or toll (e.g. postal scales and instruments weighing waste material).On multiple range instruments, the verification scale intervals are e1, e2, …, e r with e1 < e2 < … < e r. Similar sub-scripts are also used with the terms Min, n and Max.On multiple range instruments, each range is treated as if it were an instrument with one range.For special applications that are clearly marked on the instrument, an instrument may have weighing ranges in classes I and II, or in classes II and III. The instrument as a whole shall then comply with the more severe requirements of 3.9 Variations due to influence quantities and time applicable to either of the two classes (see OIML R76-1 International Recommendation document)Max = Maximum capacity of the balancee = verification scale intervale1, e i, e r = verification scale interval, rules for indices3.CONSIDERATIONS FOR LEVEL I AND II OF EQUIPMENTQUALIFICATIONAt Level I of the qualification of balances (selection of instruments and suppliers), it is recommended to select a manufacturer of balances that can satisfy the needs of the laboratory and works under ISO 9001 certification.At Level II of the qualification of balances (installation and release for use), it is recommended to check all the requirements set during the selection of the instrument and calibration should be performed before putting into service by an accredited external service supplier, or internally by appropriately qualified personnel, using certified reference weights according to an approved procedure.PA/PH/OMCL (12) 77 7R 4/114.REQUIREMENTS FOR BALANCE USELocation of the BalanceThe accuracy and precision of weighing results are closely associated with the location of the balance. OMCLs should ensure that the balance can work under optimal conditions (weighing room/laboratory, weighing bench, temperature, light, air, etc.).It is recommended that balances of types 1 to 6 (see Table 1 above) are located in a specially designed weighing room that is vibration-proof, dust-free and has an anti-static floor. For substances that are sensible to static electricity it is also possible to use an ionising unit.If a balance of type 1 to 6 is located in a laboratory outside of the weighing room, then the weighing bench on which it is placed should be in a separate part of the laboratory that is vibration-proof and dust-free. For balances of types 1 to 4, a stable bench should be used.It should be ensured that the weighing bench is stable, no matter from what material it is made. The weighing bench should not deform when work is carried out on it and it must be vibration-proof or the transfer of vibrations must not influence the weighing process. If there is a risk of instability, the balance should be equipped with a stability indicator so that the weight is only registered or printed after stabilisation of the balance.The weighing bench should be non-magnetic (i.e. no steel plates) and protected against electrostatic charges (no plastic or glass).TemperatureAs weighing results are influenced by temperature, OMCLs should ensure a constant temperature is maintained in weighing rooms/laboratories. The typical drift of balances of types 1 and 2 is 1-2 ppm/°C. The deviation should not exceed more than 5 °C per hour. Atmospheric humidityThe optimum relative humidity (% RH) during a weighing process is between 40 % to 60 % for balances of class I and II (see Table 1). The relative humidity may be expanded to 20 % to 80 % in cases where the accuracy and linearity of measurements are not affected.LightBalances should be protected from direct sunlight (heat).AirOMCLs should not place balances in the airflow of air conditioners or devices with ventilators (such as computers or large laboratory equipment), next to doorways or in areas of high traffic. This is because in addition to the potential temperature drift, strong air currents can interfere with the functioning of balances. If a balance is placed in a laminar flow workstation, e. g. for weighing of toxic material, the cabinet should be suitable for the intended use.Weighing vesselOMCLs must ensure that:-the smallest possible weighing vessels are used.-if the materials that the weighing vessel is made of have a high degree of electrical insulation (such as glass and plastic), they are not electrostatically charged.-the weighing vessel and the sample it contains should have the same temperature as their surroundings.5/11 OMCL (12) 77 7R -if the weighing vessel has been removed from a drying oven or dishwasher, it should be cooled to room temperature prior to being placed on the balance.-depending on the type of balance, it is recommended to use cotton gloves.-no magnets should be placed on the balance or into the weighing vessel.5. REQUIREMENTS FOR WEIGHTS USED IN THE QUALIFICATION Weights used for qualification should:-be clean and, if necessary, wiped with ethanol. In the latter case a waiting time must be taken into account before the weight is used-be stored in a dust-free environment.-be handled with care; the use of cotton gloves or forceps/tweezers is especially recommended.-have a suitable accuracy, depending on the type of balance.-be calibrated by an accredited external service provider.-be re-calibrated periodically.-be clearly marked after each calibration.-not be made of magnetisable material.-the verification (in use control, see Table 3) may be done with non-calibrated weights.6. FREQUENCY OF QUALIFICATIONOMCLs must ensure that qualification/calibration of balances is done on receipt (i.e. immediately after delivery) or prior to their first use and after any repair or move.The frequency of qualification/calibration depends on the extent of use of the balances and is at the discretion of individual OMCLs.Qualification/calibration must be performed in accordance with a pre-determined protocol in which acceptance criteria are defined. An external calibration should be performed by organisations accredited as calibrating laboratories according to ISO/IEC 17025 or, if performed internally, the laboratory should satisfy the same requirements in terms of measurement standards, calibration procedure, use of certified weights and qualification of personnel.Table 3 prescribes the parameters, typical frequencies and tolerance limits for the qualification of balances for periodic and motivated instrument checks (Level III) and in-use instrument checks (Level IV)PA/PH/OMCL (12) 77 7R 6/11Table 3Parameter to be checked Frequency Typical tolerance limit Levelling every day beforeweighing beginsAcceptance limits of the balanceInternal calibration (adjustment) (automatic or manual) every day beforeweighing beginsAutomatic acceptance limits of thebalanceVerification (in use control) At least once a week OMCLs shall define their ownacceptance criteriaAccuracy Frequency to be definedby OMCL, typically oncea year OMCLs shall define their own acceptance criteriaLinearity Frequency to be definedby OMCL, typically oncea year OMCLs shall define their own acceptance criteria(k = 1±0.0001)Precision Frequency to be definedby OMCL, typically oncea year OMCLs shall define their own acceptance criteria(SD = maximum 5*d)Eccentricity Frequency to be definedby OMCL, typically oncea year OMCLs shall define their own acceptance criteria(RSD = 0.05%)k = correlation coefficientSD = standard deviationRSD = relative standard deviationThe following qualification tests may also be performed in addition to those described in Table 3 (recommended, not obligatory):Parameter to be checked Frequency (recommended)Typical tolerance limitLinearity error once every six months OMCLs shall define their ownacceptance criteria(≤ accuracy of the balances)Drift test once every six months OMCLs shall define their ownacceptance criteria(RSD = 0.05%)Minimum weight once a year OMCLs shall define their ownacceptance criteria depending onthe type of the balance Measurement uncertainty once a year OMCLs shall define their ownacceptance criteria depending onthe type of the balance7/11 OMCL (12) 77 7R7.QUALIFICATION PROCEDUREVerificationVerification of the balance is performed by placing a suitable weight (depending on the type of balance) in the centre of the weighing pan once and comparing the result with pre-defined acceptance criteria. The same weight should always be used in these verifications.The acceptance criteria shall be defined by each individual OMCL.AccuracyThe accuracy of the balance is checked by weighing at least three different certified weights that cover the usual weighing range of the balance. It is recommended that the weights have approximately 5%, 50% and 100% of the maximum capacity of the balance (or of the maximum weight used on the balance), depending on the type of balance. It is recommended that the weighing is repeated at least 5 times for every weight, particularly, when the results shall also be used in the test for precision.The acceptance criteria shall be defined by each individual OMCL.LinearityThe results obtained from a series of accuracy checks can be used to calculate the correlation coefficient and to check for linearity. The correlation coefficient is calculated by comparing the nominal and measured masses of the weights.The acceptance criteria for the correlation coefficient shall be defined by each individual OMCL.(Proposed criterion: k = 1±0.0001).PrecisionThe precision of the balance should be verified by weighing at least 5 times a weight that is equivalent to approximately 50% of the maximum capacity of the balance. It is recommended to repeat the test with a weight that is equivalent to approximately 5% of the maximum capacity of the balance, if the balance is used at the lower range.The acceptance criteria shall be defined by each individual OMCL.(Proposed criterion: SD = max 5*d, where d = (actual) scale interval (e.g. d=0.1 mg)). EccentricityThe eccentricity test should be carried out using a weight equivalent to at least 30% of the maximum capacity of the balance (or of the maximum weight used on the balance). The weight should be placed between halfway to ¾ of the distance from the centre of the pan to its edge and be measured at each location in the following sequence: centre, front left, back left, back right, front right, and (optional) again centre.The acceptance criteria shall be defined by each individual OMCL.(Proposed criterion: RSD not more than 0.05%, calculated from all weighings at different locations on the pan).PA/PH/OMCL (12) 77 7R 8/11Linearity errorLinearity error is tested at least 3 times using four weights of defined masses whose aggregate total mass is approximately equal to half of the maximum capacity, depending on the type of balance.First, the combined mass of all four weights is weighed and recorded. Then, two sub-sets of weights are made and their masses are recorded.The linearity error of the balance is an absolute value calculated by the difference between the combined mass of all four weights and the sum of the masses from the two sub-sets of weights, divided by 2.The acceptance criteria shall be defined by each individual OMCL.(Proposed criterion: linearity error ≤ accuracy of the balances).Drift testA drift test is only performed on 5, 6 or 7 decimal scale balances. It is carried out by repeated measurements (every 5 minutes for 30 minutes) of a control weight (depending on the type of balance) in the morning and afternoon.The mean measurement, standard deviation and relative standard deviation can be calculated from the resulting data. The drift can also be extracted from the trend analysis of the verification test (Table 3).The acceptance criteria shall be defined by each individual OMCL.(Proposed criterion: RSD = 0.05%).Minimum weightThe minimum weight value depends on the type of balance. It is determined from technical data and the external calibration certificate.The acceptance criteria shall be defined by each individual OMCL.(Proposed criterion: tolerance 0.5%, k=3 for class I balances and 1%, k=3 for class II and III balances).Measurement uncertaintyThe measurement uncertainty can be calculated according to GUM or other relevant documents or can be determined from the external calibration certificate.A simplified procedure is proposed as follows:A weight of approximately 50% of the maximum capacity of the balance (depending on the type of balance) is weighed at least 10 times and the mean measurement, standard deviation and relative standard deviation are calculated.The acceptance criteria shall be defined by each individual OMCL.Proposed criterion: measurement uncertainty is satisfactory if three times the standard deviation of not less than ten replicate weight measurements, divided by the amount weighed (approximately 50 % of the maximum capacity of the balance), does not exceed 0.001. Alternatively to the above described qualification procedures the OMCL may use the guide OIML R76-1 from the International Organisation of Legal Metrology (current edition, see point 10. References).9/11 OMCL (12) 77 7R 8. QUALIFICATION REPORTAfter the qualification procedure, OMCLs should appropriately record the results.The following minimum information should be included:-Title of the report-Identification of the report-Version number of the master copy.-Entity that performed the qualification.-Page numbering.-Date.-Unique identification of the weights used and their qualifications (unless specified in another quality document). Traceability to certificates must be provided.-Unique identification of the balances.-Qualification results and acceptance criteria.-Conclusion (e.g. PASS/FAIL).-Name and signature of the operator who performed the qualification.-Name and signature of the person responsible for the release for use of the balances (preferably a different person from the operator who performed the qualification). Note:If an OMCL requests qualification/calibration from an external company, it must be ensured that this minimal information is contained in the external calibration report/certificate. The responsible person in the OMCL should evaluate and approve this report/certificate as a release for use of the balances.9. GLOSSARYTerms and definitions:AccuracyAccuracy is the degree of closeness of a measurement to the true value of the quantity being measured.CalibrationCalibration is a demonstration that an instrument or a device produces results within specified limits when compared to those produced by a standard (or a reference standard that is traceable to a national or international standard) over an appropriate range of measurements. Calibration is a determination of the deviation between measurements and the true value under specified measuring conditions.Drift (Sensitivity Drift )Drift is a progressive (continuously upward or continuously downward) change in the display of the digital readouts of balances, which means that weight readings are not stable. Environmental factors affect instrument stability (drift): e. g. temperature, static electricity, air flow and vibrations.EccentricityEccentricity is an error relating to variations in the positioning of weights on the weighing pan.PA/PH/OMCL (12) 77 7R 10/11LevellingLevelling is a procedure to ensure the balance is in the horizontal position.LinearityLinearity refers to the ability to deliver identical sensitivity throughout the weighing capacity of a balance.Linearity errorLinearity error is the difference between the digital display for a weight that weighs 50% of the full weighing capacity of the instrument and its true mass.Measurement uncertaintyMeasurement uncertainty is a parameter, associated with the result of a measurement, that characterises the dispersion of the values that could reasonably be attributed to the measurement variable (VIM 3.9).Measurement uncertainty is generally expressed by the standard uncertainty u or the expanded measurement uncertainty U (confidence interval). There are several ways of calculating the measurement uncertainty, one of them is given in the GUM.PrecisionPrecision is a measure of the reproducibility of results from independent measurements. QualificationSee OMCL Guideline “Qualification of equipment – Core document”, PA/PH/OMCL (08) 73 2R.WeightsWeights are objects, regulated in regard to their physical and metrological characteristics such as shape, dimensions, material, surface quality, nominal value, density, magnetic properties and maximum permissible error.11/11 OMCL (12) 77 7R 10. REFERENCESOIML R 111-1(E), current edition (E), (OIML = International Organisation of Legal Metrology).OIML R 76-1(E), current edition.METTLER TOLEDO guidelines∙Proper Weighing with Laboratory Balances∙Good Weighing Practice™ILAC G24 2007 (OIML D10 2007) GUIDELINES FOR THE DETERMINATION OF CALIBRATION INTERVALS OF MEASURING INSTRUMENTSINTERNATIONAL VOCABULARY OF METROLOGY – BASIC AND GENERAL CONCEPTS AND ASSOCIATES TERMS (VIM), JCGM 100: 2008EVALUATION OF MEASUREMENT DATA – GUIDE TO THE EXPRESSION OF UNCERTAINTY IN MEASUREMENT (GUM), JCGM 200: 2008ILAC P10: 2013, ILAC POLICY ON THE TRACEABILITY OF MEASUREMENT RESULTSISO 9001EURAMET cg-18, Version 3.0, 2011US Pharmacopoeia <41 >Internet pages:/sites/all/files/training-manuals/tg25-december2-2010.pdf/2008/08/sop-calibration-of-balances.html。