CDC Overview
FPGA与SoC芯片设计中五步法CDC跨时钟域检查方法学
Advanced Verification White Paper Five Steps to QualityCDC VerificationPing Yeung Ph.D.Mentor GraphicsCDC synchronizers are used to reduce the probability of metastable signals. Taking unpredictable metastable sig-nals and creating predictable behavior, they prevent metastable values from reaching the receiving clock domain.Metastability EffectsEven when proper CDC synchronizers are used for all clock-domain crossings and all CDC protocols are cor-rectly implemented, metastability inevitably leads to unpredictable cycle-level timing [4, 5]. Traditional RTL simulation does not model metastability, therefore, it cannot be used to find functional problems that may arise when metastability manifests in hardware. We are going to show two scenarios in which the cycle-level timing of RTL simulation differs from the cycle-level timing of the actual hardware in the presence of metastability.In Figure 3, the incoming CDC signal, cdc_d , violates the register setup time. Although it is sampled correctly in RTL simulation, the register is metastable and the output settles to 0. As a result, the hardware transition is delayed by one cycle.Figure 2: A two-register CDC synchronizer.Figure 4: Hold time violation: hardware transition is advanced by one cycle.Figure 3: Setup time violation: hardware transition isdelayed by one cycle.In Figure 4, the incoming CDC signal, cdc_d, violates the register hold time. In RTL simulation, it is not sam-pled until the next cycle. However, the register is metastable and the output settles to 1. As a result, the hardware transitions one cycle before simulation.CDC VerificationMany designers know that metastability can be controlled using synchronizers on CDC signals. The most com-mon solution is to use synchronizers made up of two D flip-flops (2-DFF), or more, in sequence to dramatically increase the mean time between failure (MTBF) of the crossings. It is important to point out that simply ensur-ing the presence of synchronizers on the appropriate signals, while necessary, is not nearly sufficient. There are three different aspects of CDC verification that must be carefully addressed:•Structural verification. Each synchronizer must have the correct structure for the type of signal being sent across clock domains. For example, a 2-DFF synchronizer is usually the best solution for single-bit signals but should not be used for multi-bit signals unless they are gray-coded to ensure that only one bit changes at a time [1, 2]. Multi-bit signals may be synchronized across domains using a separate control signal, an asynchronous FIFO, or other methods. Also, there should be no combinational logic inside or before a synchronizer.•Protocol verification. Each synchronizer must follow a set of rules, called a transfer protocol, to ensure that the CDC signal is properly transferred across clock domains. For example, even the simplest 2-DFF synchronizer requires that the transmitting signal be held stable long enough to guarantee that it is captured in the receiving domain. This may not occur if the transmitting clock is faster than the receiving clock. Synchronization structures for multi-bit signals require more complex protocol checks [2, 3]. When CDC transfer protocols are violated, an error may not occur in simulation but will eventually occur in real hardware.•Metastability verification. Problems associated with the reconvergence of CDC signals must be avoided. Reconvergence occurs when multiple signals are synchronized separately from one clock domain to another and then used by the same logic in the receiving domain (Figure 5). If that logic assumes a timing relationship between the signals, the design is not tolerant of metasta-Figure 5: Reconvergence of CDC signals.running CDC verification at the chip-level is not idealas there are too many behavioral models. For this reason, designs with the RTL representation arebest suited for CDC verification. All multiple-bit regis-ters and buses can be identified explicitly. As CDCrequirements for data and control signals are different,they can be analyzed separately. Conversely, with a gate-level representation, all buses have been synthesized intosingle-bit wires. It is impossible to distinguish data fromcontrol signals. Thus, only a subset of the CDC schemeis applicable.In addition, knowledge of the internal structure of thedesign is essential for successful CDC verification.Performing CDC analysis on third-party IP blocks orlegacy designs are not very beneficial. Without designknowledge, you may not be able to confirm the bugs orfilter violations. You need access to the original design-er; knowledge of the design is essential to understandthe results.Document CDC requirements This step is important. It has the biggest impact on the quality of the result. You need to ensure that your CDC verification will be aware of all relevant design characteristics, clock relationships, and the external environ-ment. Although a set of CDC rules have been defined already in the tool, with this additional information, extra design rules and filters will be activated. As a result, the results will be more accurate and thorough. You should define the operational modes of the design, outline the clock structures, document the domains for interface sig-nals, and determine the acceptable or unacceptable synchronization rules.•Define operational modes . Some users may be interested in verifying that all registers are driven by only the test clock when the design is in scan mode. However, in general, we want to perform CDC verification when the design is in normal operation. You should disable the non-functional modes (i.e., test, BIST, JTAG , etc.)and define the meaningful operational modes and configurations for the tool (Figure 8). In many cases, some parts of a design can be put into sleep or powered-down mode. The combinations can be countless. Hence, it is important to focus CDC verification on the important combinations.•Outline clock structures . For a multiple-clock design, the primary clocks, the clock distribution structure, and the internal clock generators, dividers, and clock gating schemes are important and should be documented. The 0-In CDC tool [7] can understand these structures and extract the clock tree information automatically. It is useful to verify the original design intent with the extracted clock structures. Only crossings between asynchronous clocks should be analyzed, and there may be clock gating conditions that need to be set up properly. As the number of CDC paths Figure 7: Blocks suitable for running CDC verification are A, C, and D.Figure 8: Define meaningful modes for CDC verification.is proportional to the number of clock domains, it is much more efficient to limit analysis to the relevant clock domains only.•Document interface signals.CDC verification will not check an interface signal if it does not know which clock domain it is coming from or fanning out to. You should group signals for each functional interface and clock domain and explicitly identify any input signals that are asynchronous to all clock domains. The tool will then determine whether input signals require synchronization before use. Asynchronous and synchro-nous reset signals should be labeled separately. The synchronization schemes used for reset signals are dif-ferent from normal interface signals.•Define synchronization rules.Some companies require all CDC signals to be synchronized with a particular CDC scheme (for instance, 3-level DFFs) or with a custom synchronization cell. The 0-In CDC tool [7] rec-ognizes many CDC schemes. It is important to review those schemes first. Then you can categorize the legal or illegal synchronization schemes, turn off the unused schemes and capture the characteristics of the syn-chronization cells or modules.Some detail-oriented designers will specify the clock domain information and capture the CDC paths in the design document. This is a practice we encourage. With this information, you can pay special attention to the specified CDC paths to ensure they are well covered.Formalize known exceptionsIt is not unusual that a simple CDC error will generate a lot of violations, especially when the CDC signal fans out to a large number of asynchronous domains. Hence, we want to identify upfront all registers that can be con-sidered stable and do not require synchronization. This is especially true for configuration registers, status regis-ters, or control registers that are programmed by software before the design enters into normal operation. Usually this information is in the design specification. Often these control registers all reside within a single module or follow a common naming scheme. It is useful to leverage this information for CDC verification.In addition to registers, some of the interface or internal signals are known to be stable during normal opera-tion; for example, the internally generated reset signals, the power-down signals, the chip select, and functional enable and disable signals. These are all useful in improving the efficacy of CDC verification. Finally, in previ-ous revisions of the chip, there may be known CDC bugs and issues found using manual or gate-level method-ologies.. These are painful lessons which should be captured in the verification plan. During CDC verification, you should ensure that those CDC paths are analyzed and that all problems were fixed correctly.Define coverage goalsBased on our experience, CDC paths are poorly verified by traditional functional verification because, in a functional simulation environment, the clock periods are defined to be constants, the clock skews and relation-ships are fixed, and the clock signals are well-behaved without any buffer or propagation delay. To ensure metastability effects on CDC paths are better verified, companies use various ad-hoc approaches. Some ran-domly reduce or prolong the clock periods. Some randomly change the skews and relationships among multiple asynchronous clocks.Regardless of the technique used, when verifying CDC transfer protocols in simulation, it is important to moni-tor protocol coverage to make sure the CDC paths are adequately verified. This can be done by using a checker from an assertion library [9, 10, 11] to capture the semantics of the protocol. Checkers collect coverage infor-mation to ensure that each CDC protocol is fully exercised. Insufficient coverage means that the design may contain undiscovered bugs.CDC Handshake:- Assertion:i.multiple requests violationii.acknowledge without request violationiii.request drop violationiv.acknowledge timeout violation- Coverage:i.#request assertedii.#acknowledge assertedCDC FIFO:- Assertion:i.FIFO overflow violationii.FIFO underflow violationiii.Simultaneous push and pop violation- Coverage:i.#push assertedii.#pop assertediii.maximum FIFO entryYou start by itemizing the protocols used in the CDC paths, ordering them from most important to least, and identifying the protocols that require coverage. For each CDC protocol, you will determine the assertion and coverage items, as in the code shown above. To measure how well your simulation is verifying the metastability effects, you should also monitor the alignments of the RX and the TX clocks.Select a verification strategyYou may choose to perform exhaustive verification on each individual block or use a hierarchical approach on the entire top-level of a chip. The top-level represents the highest functional hierarchy of the design, excluding the pad ring, the test logic, the power controls, etc. You may be looking for a known bug or hunting for a prob-lem that has appeared in the lab. The strategies you choose will determine how to run your CDC analysis tools. Based on our experience, there are four common strategies•Block-level verification.During block-level design, static analysis of the CDC structures should be run before checking in the RTL code. This ensures strict compliance with CDC schemes. If issues are discov-ered, they can be identified and debugged quickly at this level. The generated CDC protocol monitors can also be used with block-level functional verification methodologies, such as formal verification [8] and simulation. These ensure that CDC protocols are followed without any data loss.•Top-level verification. During top-level integration, static analysis of the CDC structures should be re-run to check the new CDC signals created when multiple blocks are integrated together. The number of CDC signals goes up exponentially at the top-level. Hence, it is important to follow the five-step planning processdescribed above. For large and complex designs, especially ones with a lot of IP modules, a hierarchical veri-fication approach can be used. The generated CDC protocol monitors should be included in the regression for system-level functional verification.•Bug hunting and triage. This is performed to identify known or suspected CDC issues in the design. It is important to distinguish timing from CDC issues. Timing issues tend to cause the chip to fail consistently. By changing the frequencies of the clocks or of some of the signals, the problems may disappear permanently. On the other hand, as metastability is unpredictable, CDC problems will cause the chip to fail randomly. Based on our experience, it is extremely difficult to look for CDC issues at the system or chip level. There are just too many potential candidates. Hence, the first task is to narrow down the problem to the block or subsystem level.You should focus on blocks with asynchronous clock domains. Blocks with CDC reconvergence are especially suspicious. The random delays from different CDC paths may cause the data to be sampled incorrectly or cor-rupted completely. Once the candidate blocks are identified, the block-level verification strategy can be applied.•Targeting coverage.This can be an extension of the block-level or top-level verification strategy. The goal is to ensure that all CDC protocols have been fully exercised and that the metastability effects are fully verified on all CDC paths. The coverage on the CDC protocols monitors should be examined and additional tests created to fill any coverage holes. Once the bug rate of system-level regression has stabilized, metastability can be injected into simulation. Metastability effects will change the timing of the CDC paths. If the block is not designed to handle the random delays of the CDC paths, it may fail functionally. To make debugging easier, it is better to start with a representative subset of the regression.In the next two sections, we will elaborate on the two most commonly used strategies: block-level andtop-level verification.•Correctly implemented synchronizers•Missing and incorrectly implemented synchronizers•Complex synchronizers that require protocol verification•Potential reconvergence problemsAt this level, since the design description contains a lot of modules with a lot of asynchronous clock domains, most of the CDC paths fall into the complex and reconvergence categories. The GUI environment is particularly useful in this case as the CDC path may span multiple levels of hierarchy and several modules.2. Run protocol verification with simulation. With the testbench environment already available for functional veri-fication, we can run the CDC protocol monitors within the simulation environment. These monitors ensure that the CDC signal is stable when going from the TX to the RX domain; the multiple-bit CDC data is gray-coded, or it is stable when it is sampled. Any assertion failure caught by the monitors means that the CDC protocol is vio-lated and should be fixed. Functional simulation gives lengthy margins for CDC signals. They tend to be suffi-ciently stable when going through the clock domains. This approach does a poor job stressing the timing of the CDC paths. Hence, when running CDC protocol monitors with functional simulation, it is important to examine the corner case coverage of the protocol monitors. Monitors which pass should have adequate coverage when the results from the whole regression suite are merged together. In order to stress the timing of the CDC paths explic-itly, we can add some direct tests into the regression suite. With a constrained-random verification environment, we can tighten the timing of the stimulus generator.3. Run metastability verification with simulation and effect injection.If your design contains potential reconver-gence violations that cannot be easily waived after manual inspection, the 0-In CDC tool [7] can be used to iden-tify reconvergence problems by injecting metastability effects dynamically. In simulation, metastability effect injectors will change the delays through synchronizers. As a result, any logic that assumes a fixed timing rela-tionship between the outputs of the synchronizers is likely to fail. Running simulation with the effect injectors is the most cost effective way to imitate CDC metastability effects during functional verification. It enables any potential problems to be discovered quickly, before any hardware is built.Debugging CDC ViolationsIn this section, we will describe a few common CDC violations and the techniques you can use to determine whether they are real design issues or not.Missing synchronizer violationAn unsynchronized CDC signal is the most common violation reported during structural verification. For instance, in Figure 11, depending on the clock frequency, the RX register may not be able to sample its input reliability. This is a real problem. In other cases, violation are due to the following exceptions.References1. Clifford E. Cummings, “Synthesis and Scripting Techniques for Designing Multi-Asynchronous Clock Designs,” SNUG-2001. Downloadable from /papers2. Tai Ly, “The Need for an Automated Clock Domain Crossing Verification Solution,” White Paper, Downloadable from /fv3. Chris Kwok, et al, “Using Assertion-Based Verification to Verify Clock Domain Crossing Signals,” DVCon 20034. Tai Ly, et al, “Formally Verifying Clock Domain Crossing Jitter Using Assertion-Based Verification,” DVCon 20045. Tai Ly, et al, “A Methodology for Verifying Sequential Reconvergence of Clock Domain Crossing Signals,” DVCon 20056. Harry Foster, et al, “Assertion-Based Design,” Kluwer Academic Publishers, 20037. Mentor Graphics, “CDC Compiler User Guide V2.5,” Feb 20078. Mentor Graphics, “Formal Verification User Guide V2.5,” Feb 20079. Accellera, “Accellera Standard OVL Library Reference Manual,” July 200610. Mentor Graphics, “QuestaTM Verification Library Checkers Data Book V6.2f,” Jan 2007.11. Mentor Graphics, “CheckerWare Data Book Assertion Library V2.5,” Feb 2007Corporate Headquarters Mentor Graphics Corporation 8005 S.W. Boeckman RoadPacific RimMentor Graphics TaiwanRoom 1603, 16F,EuropeMentor GraphicsDeutschland GmbHSilicon ValleyMentor Graphics Corporation1001 Ridder Park DriveJapanMentor Graphics Japan Co., Ltd.Gotenyama HillsCopyright © 2007 Mentor Graphics Corporation. This document contains information that is proprietary to Mentor Graphics Corporation and may be duplicated in whole or in part by the original recipient for internal business purposed only, provided that this entire notice appears in all copies. In accepting this document, the recipient agrees to make every reasonable effort to prevent the unauthorized use of this information. 0-In and Mentor Graphics are registered trademarks of Mentor Graphics Corporation. All other trademarks are the property of their respective owners.For more information, visit /fv。
Candela__ICE_Overview (to SI)中文
ICEcap 捕获的损伤参数以一个可编辑的XML 文件在ICE中回放。
Packet dump特点捕获数据包流,在 LANforge FIRE 流量发生器中回放。 LANforge ICE 运行在 LANforge 内核或者标准的Linux 内核中。 WISER (Wireless IP Scalable EmulatoR) 子系统仿真军方无线网络，具有 terrain, propagation和radio损伤，可加入到IP 流中。是与合作伙伴Telcordia一起开发出 来的。
军方 & 航空航天公司: Lockheed Martin, Navy, SAIC, Raytheon, General Dynamics.
其他组织机构: International banking, state & federal, foreign military, telecoms, etc.
Router A LANforge ICE Router B
eth0
eth1
Network After
Network Test and Emulation
14
LANforge ICE 应用
802.1q 中继
允许不同的网络/VLANs 来体验不同的损伤。 LANforge ICE 能够共享资源，仅使用两个物理接口。
Network Test and Emulation
17
LANforge ICE 蓝图
即将发布:
应用层 ICEcap:
支持除ICMP之外的协议为了更真实的参数。
高级损伤:
L14_IPA_项目会计合集
6
Overview（总体介绍） 如何实现？——灵活的自动会计
根据企业的核算需要，设置自动会计规则，大大降低手工劳动
事物处理
10 小时 劳动 周一, 五月 12, 1997 发生在项目 XYZ, 任务1
公司-成本中心--帐户 金额
01-100-5153
$220
10 Preliminary Design
24 Detailed Design
37 Programming and Testing
47 Integration Testing
54 System Test
59 Installation
70 Operations and Maintenance
76
14
Overview（总体介绍）
software!
21
定义你的项目
详尽的在线查询和报告
定义 条款 & 规则
收集成本
把资产投入 使用
定义项目
确认收入
生成发票
其他的 Oracle或 非Oracle 应用产品
灵活的调整能力
22
项目模板
Templates ensure consistent Best Practices 使用模板可以确保项目管理的连贯性和采用最好 的管理模式。
接受
拒绝
接受
Oracle 应付帐模块:
$100 外协 05-1月-1997
Oracle PTE:
8 小时工时 18-8月-1996
外部的成本
采集系统:
$1200 机票 04-8月-1996
Oracle 采购模块:
$100 外协 29-12月-1996
精神病人的病发率与死亡率【英文】
Target Providers, Families and Clients Focus on Prevention and Wellness
Track Morbidity and Mortality in Public Mental Health Populations Implement Established Standards of Care
32.2 31.8
Compared to the general population, persons with major mental illness typically lose more than 25 years of normal life span
Colton CW, Manderscheid RW. Prev Chronic Dis [serial online] 2006 Apr [date cited]. Available from: URL:/pcd/issues/2006/apr/05_0180.htm
Some Psychiatric Medications Contribute to Risk Established Monitoring and Treatment Guidelines to Lower Risk Are Underutilized in SMI Populations
ห้องสมุดไป่ตู้ Overview - PROPOSED SOLUTIONS
Overview- THE PROBLEM
Increased Morbidity and Mortality Associated with Serious Mental Illness (SMI) Increased Morbidity and Mortality Largely Due to Preventable Medical Conditions
MFC中滑动条的使用
滑动控件是Windows中最常用的控件之一。
一般而言它是由一个滑动条，一个滑块和可选的刻度组成，用户可以通过移动滑块在相应的控件中显示对应的值。
通常，在滑动控件附近一定有标签控件或编辑框控件，用于显示相应的值。
滑动控件在应用程序中用途级为广泛，如在桌面的属性中就可以看到。
为此，让我们一起来看一下它的实现方法。
（1）在VC++ 6.0中新建一个对话框文档的工程。
（2）打开资源管理器，在对话框中放置一个EDIT控件，然后在它旁边放上一个Slider控件。
基本的框架已经完成了。
（3）对Slider控件右击，选择“建立类向导”，对刚才的Slider控件定义一个变量m_Slider,类型为CSliderCtrl。
（4）在对话框初始化的代码BOOL CMy601Dlg::OnInitDialog()，后添加相应的属性。
以下是常用的属性设置函数：* GetRange,SetRange函数用于查询和设置滑动条的取值范围，默认为0~100。
函数定义形式如下：void GetRange(int &nMin,int &nMax) const;void SetRange(int nMin,int nMax,BOOL bRedrGETaw=FALSE);* GetPos,SetPos函数用于查询和设置滑动条的当前值。
函数定义形式如下：int GetPos() const;int SetPos(int nPos);* GetLineSize,SetLineSize函数用于查询和设置在按一下右或左箭头时滑块的移动量，默认为1个单位。
函数定义形式如下：int GetLineSize() const;int SetLineSize(int nSize);* GetPageSize,SetPageSize函数用于查询和设置函滑块和块移动量，块移动量是指当按下PgUp或PgDown时滑块的移动量。
函数定义形式如下：int GetPageSize() const;int SetPageSize(int nSize);* SetTicFreq函数用于设置滑动条刻度的频度。
疾控中心ppt总结汇报
疾控中心ppt总结汇报Title: Summary Report on the CDC PresentationIntroduction:The Centers for Disease Control and Prevention (CDC) recently delivered a comprehensive and informative presentation on various aspects of disease control and prevention. This report aims to summarize the key points discussed during the presentation, emphasizing the significance and impact of the CDC's work in safeguarding public health.I. Overview of the CDC:The presentation began with an introduction to the CDC, highlighting its role as a leading national public health agency. The CDC acts as a central body for disease surveillance, prevention, and control in the United States. It plays a pivotal role in identifying and responding to health threats, thereby ensuring public safety.II. Disease Surveillance and Outbreak Investigation:One of the primary responsibilities of the CDC is disease surveillance and outbreak investigation. Through the use of advanced epidemiological techniques, the CDC monitors the prevalence of diseases and identifies potential outbreaks. In the presentation, several examples were shared, including the recent COVID-19 pandemic, where the CDC's efforts have been central in tracking the spread of the virus and guiding response measures. III. Vaccination Programs:The CDC highlighted its crucial role in developing andimplementing vaccination programs. It emphasized the importance of vaccines in preventing the spread of communicable diseases and reducing associated morbidity and mortality. The CDC's extensive research and collaboration with healthcare professionals help ensure the availability of safe and effective vaccines for the public. IV. Emergency Response and Preparedness:The presentation showcased the CDC's expertise in emergency response and preparedness. The agency's dedicated teams work diligently to develop response plans for various public health emergencies, including natural disasters, pandemics, and bioterrorism threats. The CDC's rapid response capabilities and coordination with local, state, and international agencies enable effective management of crises and minimize their impact on public health.V. Promoting Healthy Behaviors:Another key aspect of the CDC's work highlighted in the presentation is its efforts to promote healthy behaviors and prevent chronic diseases. The agency focuses on educating and empowering individuals and communities to make informed choices regarding their health, emphasizing the importance of adopting healthy lifestyles, such as engaging in regular physical activity, eating a balanced diet, and avoiding harmful habits.VI. International Collaboration:The CDC underscored the significance of international collaboration in addressing global health challenges. By collaborating with international partners, the agency enhances its ability to respond to emerging infectious diseases, shareknowledge, and improve global health security. The presentation emphasized the successful partnerships and initiatives undertaken by the CDC to combat diseases globally.Conclusion:In conclusion, the CDC presentation provided a comprehensive overview of the agency's essential role in disease control and prevention. From disease surveillance and outbreak investigation to vaccination programs and emergency response, the CDC's work plays a crucial role in protecting public health both within the United States and globally. By promoting healthy behaviors and emphasizing international collaboration, the CDC serves as a central force in safeguarding public health and preventing future health crises.。
美国FDA关于注射剂和生物制品允许的体积过量及标示量指导原则(2015-6-24终稿)
Labeled Vial Fill Size in Injectable Drug and BiologicalProductsGuidance for IndustryU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)June 2015Pharmaceutical Quality/CMCLabeled Vial Fill Size in Injectable Drug and BiologicalProductsGuidance for IndustryAdditional copies are available from:Office of Communications, Division of Drug InformationCenter for Drug Evaluation and ResearchFood and Drug Administration10001 New Hampshire Ave., Hillandale Bldg., 4th FloorSilver Spring, MD 20993Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach and DevelopmentCenter for Biologics Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Bldg. 71, Room 3128Silver Spring, MD 20993Phone: 800-835-4709 or 240-402-7800Email: ocod@/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)June 2015Pharmaceutical Quality/CMCTABLE OF CONTENTSI.INTRODUCTION (1)II.BACKGROUND (2)III.OVERVIEW (2)A.Allowable Excess Volume (2)beled Vial Fill Size (3)IV.DISCUSSION AND RECOMMENDATIONS (3)Allowable Excess Volume and Labeled Vial1 Fill Size in Injectable 1Drug and Biological Products2Guidance for Industry23456This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 7this topic. It does not establish any rights for any person and is not binding on FDA or the public. You 8can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. 9To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 10title page.11121314I. INTRODUCTION151617This guidance provides the pharmaceutical industry with the Center for Drug Evaluation and18Research’s (CDER’s) and the Center for Biologics Evaluation and Research’s (CBER’s) current 19thinking on allowable excess volume and labeled vial fill size in injectable drug and biological 20products. It replaces the draft of the same name that was published on March 14, 2014 (79 FR 2114517). Specifically, the guidance clarifies the FDA regulatory requirements and22recommendations pertaining to allowable excess volume in injectable vials and describes when 23justification is needed for a proposed excess volume in these injectable drug3 products. This24guidance also discusses the importance of appropriate fill volumes for injectable drug products 25and recommends that labeled vial fill sizes be appropriate for the intended use and dosing of the 26drug product.27This guidance addresses withdrawable volume and labeled vial fill size for injectable drug2829products that are packaged in vials and ampules, including products that require reconstitution.30It does not address injectable drug products in other packaging types (e.g., prefilled syringepackage systems and intravenous infusion bags) or noninjectable products, because there may be3132unique considerations for these packaging configurations. The recommendations in this33guidance apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs), 34biologics license applications (BLAs), as well as supplements or other changes to these35applications for new packaging or other changes that may affect the fill volume.3637In general, FDA’s guidance documents do not establish legally enforceable responsibilities.38Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 39as recommendations, unless specific regulatory or statutory requirements are cited. The use of1 The term vial used throughout this guidance refers to both vial and ampule package types.2 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation andResearch in collaboration with the Center for Biologics Evaluation and Research at the Food and DrugAdministration.3 The term drug used throughout this guidance refers to drugs, including biological drug products.40the word should in Agency guidances means that something is suggested or recommended, but 41not required.4243II. BACKGROUND4445Injectable vial misuse, including unsafe handling and injection techniques, has led to vial46contamination and an increased risk of bloodborne illness transmission between patients.4,547Inappropriate excess volume and labeled vial fill sizes are two factors that may contribute to48unsafe handling and injection practices by consumers and health care providers. FDA has been 49concerned about these issues and is publishing this guidance to clarify its regulatory50requirements and recommendations.51III. OVERVIEW525354A. Allowable Excess Volume5556The United States Pharmacopeia (USP) General Chapter <1> Injections provides that each57container of an injectable product is filled with a volume that slightly exceeds the contentindicated in the labeling.6 The excess volumes are meant to be sufficient to permit withdrawal5859and administration of the labeled volumes. FDA regulations at 21 CFR 201.51(g) provide that 60for drugs in ampules or vials that are intended for injection, the declaration of net quantity of61contents on the label is considered to express the minimum quantity of contents and further62requires that variation above the stated measure must comply with the excess volumes set forth 63in USP. USP General Chapter <1151> Pharmaceutical Dosage Forms provides excess volume 64recommendations for mobile and viscous liquids in a range of fill volumes, noting that the excess 65volumes recommended are usually sufficient to permit withdrawal and administration of the66labeled volumes. Allowable excess volume may also be referred to as “overfill,” but should not 67be confused with “overage,” which is addressed in a separate guidance.7 Generally, an applicant 68should not declare the amount of overfill on the container label.694 Perz J, Thompson N, Schaefer M, Patel P, 2010, US Outbreak Investigations Highlight the Need for Safe InjectionPractices and Basic Infection Control, Clinics in Liver Disease, 14:137-151.5 Centers for Disease Control and Prevention, Injection Safety, Safe Injection Practices to Prevent Transmission ofInfections to Patients, 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings (/injectionsafety/IP07_standardPrecaution.html).6 For a drug product for which there is an official USP drug product monograph, the product must comply with thestandards set forth therein, including the standards set forth in General Chapter <1>, unless expressly excepted in that drug product monograph. See Federal Food, Drug, and Cosmetic Act, sections 501(b) (21 U.S.C. 351(b)) and 502(g) (21 U.S.C. 352(g)); USP 37-NF 32, General Notices and Requirements 2.10. Official Text. Thus, for aninjectable drug product for which a USP monograph exists and incorporates General Chapter <1>, the provision regarding inclusion of a slight volume exceeding the labeled volume is a mandatory requirement; for injectableproducts without a USP monograph that incorporates General Chapter <1>, compliance with the slight excessvolume provision is strongly recommended. USP has proposed moving the text discussing the container content from USP General Chapter <1> Injections to USP General Chapter <697> Container Content for Injections. These proposed changes are being considered for USP 38.7Overage is an amount of a drug substance in excess of the label claim. The use of an overage to compensate for degradation during manufacture or a product’s shelf life, or to extend the shelf life is generally discouraged. The use of an overage is discussed in section 2.2.2 of the International Conference on Harmonisation (ICH), Guidance for Industry, Q8(R2) Pharmaceutical Development.FDA becomes concerned when the excess volume in a vial is greater or less than the USP7071recommended amount without appropriate justification. Such excesses and deficiencies may72result in medication errors and may lead to misuse of leftover drug product or pooling of vials to obtain a single dose.737475beled Vial Fill Size7677While dosing flexibility is necessary with injectable drug products, applicants should determine 78the appropriate vial fill sizes during product development, considering how the vials are likely to be used. For example, single-dose vials are designed for use in a single patient as a single7980injection/infusion. However, even when appropriately labeled, single-dose vials that contain81significantly8 more drug than is required for a single dose may result in the misuse of the leftover 82drug product. Similarly, the need to combine several single-dose vials for a single patient dose 83may lead to medication errors and microbial contamination.8485According to USP General Chapter <1>, multiple-dose vials have a maximum container volume 86sufficient to permit the withdrawal of not more than a total of 30 mL, unless otherwise specified in the USP drug product monograph.9,10 Setting a maximum volume in multiple-dose vials will 87minimize vial septum punctures, which will reduce the risk of compromising vial integrity and8889the potential for vial contamination.90IV. DISCUSSION AND RECOMMENDATIONS919293With respect to allowable excess volume, the applicant of drugs in ampules or vials intended for 94injection must follow the requirements in 21 CFR 201.51(g). The regulation requires an95applicant to comply with the excess volume recommendations prescribed by the USP.96Therefore, for drugs in ampules and vials intended for injection, the applicant must comply with 97the excess volume recommendations that appear in USP General Chapter <1151>.11 In the case 98of drug products requiring reconstitution, the product should be designed to meet the label claim 99and acceptable overfill, and allow for correct dosing. Deviations from the recommendations in 100USP General Chapter <1151> with regard to excess volume should be justified.12 FDA101recommends providing the justification by obtaining extractable content testing data, which is8 While it is not possible to specify a quantitative volume of remaining drug product that would generally beconsidered significant, volumes remaining that could provide a second dose, or would encourage pooling for asecond dose, would be considered excessive.9 USP has proposed moving the text discussing the maximum container volume for multiple-dose vials from USPGeneral Chapter <1> Injections to USP General Chapter <659> Packaging and Storage Requirements. Theseproposed changes are being considered for USP 38.10 For products without a USP monograph, multiple-dose vials must have a maximum fill volume sufficient topermit the withdrawal of not more than 30 mL, unless justified in the application.11 Typically, USP General Chapters titled with numbers above <1000> are considered to be recommendations andnot requirements, unless the chapter is cited in a product-specific monograph or another General Chapter titled witha number below <1000>. However, in this case, because FDA’s regulations specifically require adherence to theUSP recommendations on this topic, the recommendations in USP General Chapter <1151> are considered to berequirements.12 For example, for a drug product requiring reconstitution that is dosed based on body weight, it is important for thefinal concentration to be a whole number that allows for easy calculation and withdrawal of the appropriate dose.This consideration may be used to justify a slight deviation from the recommended overfill.102described in USP General Chapter <1> under Packaging, Determination of Volume of Injection 103in Containers, or other appropriately justified methods. A variety of approaches may be104considered acceptable for sample collection, for example:105106•For BLAs: Lot release testing and/or collection from batches representative of the commercial process, using appropriate sampling and methods.107108109•For NDAs and ANDAs: One or more batches representative of the commercial 110process as part of the product development studies using appropriate sampling 111and methods.112113The applicant should provide data related to proposed excess volume in the following sections of 114the application:13115116•The excess volume included in a drug product should be described in the common 117technical document (CTD) section 3.2.P.1, Description and Composition of the 118Drug Product.119120•The studies and justification (i.e., extractable volume testing, viscosity studies, fill 121volume variability) should be described in CTD section 3.2.P.2.2.1, Formulation 122Development and/or 3.2.P.2.3, Manufacturing Process Development.123124FDA recommends that a drug product’s vial fill size should be appropriate for the labeled use 125and dosing of the product.14 FDA may request justification when there are questions about the 126appropriateness of the proposed labeled vial fill sizes in an application. When deciding what is 127appropriate, applicants should consider the following:128129•Single-dose vials should not contain a significant15 volume beyond what would be 130considered a usual or maximum dose for the expected use of the drug product. 131132•Consumers and/or health care providers should not be routinely required to use 133more than one vial to administer a typical single dose of the drug product.134135•Multiple-dose vials should contain no more than 30 mL of drug product except under specific circumstances.16136137138For all application types, the applicant should communicate with FDA early in the drug139development process about the vial fill size and unique excess volume concerns. For example,13 Guidance for Industry, M4: The CTD – Quality Questions and Answers/Location Issues/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073285.pdf.14 An ANDA that references a currently approved reference listed drug (RLD) is generally expected to have thesame labeled vial fill size as the RLD. In the event of a suitability petition permitting a change in vial fill size, the basic principles of this guidance would be applied to the petitioned ANDA.15 See footnote 8 for information on significant volumes.16 Exceeding the 30mL multiple-dose vial limit may be justified if the usual dose of the drug product packaged in amultiple-dose vial is large, making the 30 mL limit impractical.140applicants should consider such communications during the end of phase II meetings or other 141communications for investigational new drug applications (INDs).142143We recommend communicating with FDA as outlined in existing recommendations related to 144communication with applicants, including the Guidance for Review Staff and Industry Good 145Review Management Principles and Practices for PDUFA Products.1717 See/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079748.pdf.We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and the CBER Web page./BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.。
CDC类详解
CDC类详解CDCCObject└CDCCDC类定义得就是设备上下⽂对象得类。
CDC对象提供处理显⽰器或打印机等设备上下⽂得成员函数,以及处理与窗⼝客户区对应得显⽰上下⽂得成员。
通过CDC对象得成员函数进⾏所有得绘图。
类对设备上下⽂操作提供了成员函数,处理绘图⼯具。
安全型图形设备接⼝(GDI)对象收集,以及处理颜⾊与调⾊板。
它还为获取与设置绘图属性、映射,处理视点、窗⼝扩展、转换坐标,处理区域、剪贴、绘制直线及绘制简单椭圆与多边形等形状提供了成员函数。
另外还为绘制⽂本、处理字体,使⽤打印机跳转,滚动与播放元⽂件提供成员函数。
使⽤CDC对象时要构造它,然后调⽤与它平等得、使⽤设备上下⽂得Windows函数得成员函数。
注意:Windows 95下所有屏幕坐标限制在16位以内。
因此向CDC成员函数传递得int必须在-32768⾄32767之间。
CDC包含m_hDC与m_hAttribDC两个设备上下⽂,它们在CDC对象创建时参考同⼀个设备。
CDC指导所有对m_hDC得输出GDI调⽤以及对m_hAttribDC得⼤部分属性GDI调⽤(GetTextColor就是属性调⽤得例⼦,⽽SetTextColor就是⼀个输出调⽤)。
例如框架使⽤这两个设备上下⽂实现CMetaFileDC对象,在从物理设备读取属性期间向元⽂件发送输出。
打印预览以相同风格在框架中实现。
还可以以相似⽅法在特殊应⽤代码中使⽤这两个设备上下⽂。
可能多次需要来⾃m_hDC与m_hAttribDC设备上下⽂得⽂本度量信息。
以下⼏对函数提供了这项功能:jwZwNFY。
l8SuPrF。
NGAzWSc。
CDC类成员安全型选择帮助器简单绘图函数元⽂件函数* CClientDC⼦类1、 CClientDC类只能在客户区绘图;2、所谓客户区指窗⼝区域中去掉边框、标题栏、菜单栏、⼯具栏、状态栏等之外得部分,它就是⽤户可以操作得区域;3、在使⽤CClientDC进⾏绘图时,⼀般要调⽤GetClientRect()函数来获取客户区域得⼤⼩;4、 CClientDC类在构造函数中调⽤Windows API函数GetDC(),在析构时响应ReleaseDC();5、 CClientDC类得窗⼝句柄保存在成员变量m_hWnd,为构造CClientDC,需将CWnd作为参数传递给构造函数。
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
2
IBM Software Group | Infosphere Change Data Capture
CDC基于日志的架构图
基于Java的 的 基于 控制台
目标
Audit Database ODS/DW Database
源
Backup Database
IBM Software Group | Lotus software
TCP/IP
IBM Information Server
WebSphere DataStage Message Queue
Journal Log Redo/Archive Logs
Publisher Engine And Metadata
Subscriber Engine And Metadata
Web Services Business Process
图形化设计， 图形化设计，快速实现数据同步
IBM Software Group | Lotus software
9
IBM Software Group | Infosphere Change Data Capture
断点续传功能， 断点续传功能，实现高可用性
IBM Software Group | Lotus software
对异构平台的支持
SOURCE Databases
DB2 z/OS DB2 LUW DB2 i IMS
TARGET Databases
DB2 z/OS DB2 LUW DB2 i VSAM* Informix
Message Queues
MQ Series JMS TIBCO WebMethods BEA
10
IBM Software Group | Infosphere Change Data Capture
定时复制， 定时复制，实现复制调度
IBM Software Group | Lotus software
up | Infosphere Change Data Capture
捕获
推送
应用
确认
3
IBM Software Group | Infosphere Change Data Capture
不同的复制模式
3 种复制模式 种复制模式:
– 连续复制 • 将数据更改实时应用于目标
– 定期复制
IBM Software Group | Lotus software
• 按预定的时间间隔应用累积变化
– 刷新 • 应用一个数据的快照版本
4
IBM Software Group | Infosphere Change Data Capture
灵活多变的实施方式
IBM Software Group | Lotus software
5
IBM Software Group | Infosphere Change Data Capture
差异化数据复制， 差异化数据复制，实现书数据校验
IBM Software Group | Lotus software
12
– 业务活动监控 – 商业智能BI – 客户关系系统CRM – 数据分布 – 灾难恢复 - 电子商务 - 大型机整合 - 法规遵从 - 供应链管理
software
1
IBM Software Group | Infosphere Change Data Capture
IBM CDC功能
数据复制 实时 跨平台 多种复制模式 IBM 双向复制 关联 列级别过滤 行级别过滤 数据转换 统一管理 Software Group | Lotus software 容错机制 ...
Operating Systems
z/OS AIX IBM i OS Red Hat, SUSE Linux for System Z Red Hat, SUSE Linux HP-UX Solaris MS Windows
Hardware
IBM System z IBM System p IBM i Series Intel / AMD HP PA-RISC HP Itanium Sun SPARC
VSAM Informix SolidDB
IBM Software Group | Lotus software
Information Server Cognos Now! SolidDB
Oracle Oracle MS SQL Server Teradata Sybase MS SQL Server ADABAS Sybase IDMS Netezza, MySQL, Greenplum** * VSAM target only valid with VSAM source ** Customized solution, limited requirements 7
IBM Software Group | Infosphere Change Data Capture
IBM InfoSphere CDC概述
高效、端到端、多平台的数据复制和整合方案 实时地在异构平台和数据库之间进行数据捕获、数据转换和数 据分发
•
在关键业务应用之间构建实时的数据流
IBM Software Group | Lotus – 动态数据仓库 - 企业应用整合EAI
IBM Software Group | Infosphere Change Data Capture
CDC的特点
对源操作系统性能的影响最小化 – 基于本地数据库日志的数据复制对生产系统的影响几乎可以忽略不计 – 不需要批处理的时间窗口 对现有应用架构不产生任何影响 – 不需要时间戳来侦测数据变化
IBM Software Group – 不需要改变现有的应用或模式
对IT基础架构不产生任何影响 – 不需要额外的硬件系统
| Lotus software
– 只复制数据变化，对网络带宽的需求非常小 最小延迟的实时数据交付 – 变化数据在事务产生的同时被转换并发送给目标端 高性能和高扩展性
8
IBM Software Group | Infosphere Change Data Capture
简单易用
基于Java的配置，管理和监控界面 – 在一个界面上管理所有数据整合的流程 – 自动映射、鼠标拖拽方式来进行数据转换 – 提供事件日志、警告信息以及各种形式的报告
IBM Software Group | Lotus software
6
IBM Software Group | Infosphere Change Data Capture