qualitysystemsapproachtopharmaceuticalscGMP

1、Guidance for IndustryQuality Systems Approach to Pharmaceutical CGMP RegulationsU.S. Department of Health and Human Services Food and Drug AdministrationCenter for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM)Office of Re

2、gulatory Affairs (ORA)September 2006 Pharmaceutical CGMPsGuidance for IndustryQuality Systems Approach toPharmaceutical CGMP RegulationsAdditional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and ResearchFood and Dru

3、g Administration 5600 Fishers LaneRockville, MD 20857(Tel) 301-827-4573 HYPERLINK /cder/guidance/index.htm /cder/guidance/index.htm orOffice of Communication, Training andManufacturers Assistance, HFM-40 Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Roc

4、kville, MD 20852-1448 HYPERLINK /cber/guidelines.htm /cber/guidelines.htm.(Tel) 800-835-4709 or 301-827-1800orCommunications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration7519 Standish Place, Rockville, MD 20855(Tel) 301-827-3800 HYPERLINK /cvm/guidance/published.html /cvm

5、/guidance/published.htmlU.S. Department of Health and Human Services Food and Drug AdministrationCenter for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM)Office of Regulatory Affairs (ORA)September 2006 Pharmaceutical CGMP

6、 RegulationsContains Nonbinding RecommendationsTABLE OF CONTENTSINTRODUCTION.1BACKGROUND AND PURPOSE.1Background.1Goal of the Guidance.2Scope of the Guidance.3D.Organization of this Guidance4CGMPS AND THE CONCEPTS OF MODERN QUALITY SYSTEMS4Quality.4B.Quality by Design and Product Development4C.Quali

7、ty Risk Management5D.CAPA (Corrective and Preventive Action)5E.Change Control.5F.The Quality Unit5G.Six-system Inspection Model.6IV.THE QUALITY SYSTEMS MODEL8Management Responsibilities.8Provide Leadership.8Structure the Organization.9Build Your Quality System to Meet Requirements.9Establish Policie

8、s, Objectives, and Plans.10Review the System.10Resources.12General Arrangements.12Personnel Development.13Facilities and Equipment.13Control Outsourced Operations.14Manufacturing15Design, Develop, and Document Product and Processes.15Examine Inputs16Perform and Monitor Operations.17Address Nonconfor

9、mities.19Evaluation Activities.21Analyze Data for Trends.21Conduct Internal Audits.21Quality Risk Management.22Corrective Action.22Preventive Actions.23Promote Improvement.23V.CONCLUSION.24USEFUL REFERENCE MATERIALS.25GLOSSARY2 7Contains Nonbinding Recommendations PAGE 3Guidance for Industry1Quality

10、 Systems Approach to Pharmaceutical Current Good Manufacturing Practice RegulationsThis guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can us

11、e an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate nu

12、mber listed on the title page of this guidance.INTRODUCTIONThis guidance is intended to help manufacturers implementing modern quality systems and risk management approaches to meet the requirements of the Agencys current good manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211). The

13、 guidance describes a comprehensive quality systems (QS) modehl,ighlighting the models consistency with the CGMP regulatory requirements for manufacturing human and veterinary drugs, including biological drug products. The guidance also explains how manufacturers implementing such qualitysystems can

14、 be in full compliance with parts 210 and 211. This guidance is not intended to place new expectations on manufacturers, nor to replace the CGMP requirements.Readers are advised to always refer to parts 210 and 211 to ensure full compliance with the regulations.FDAs guidance documents, including thi

15、s guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.The use of the wordshould in Agency guidances means that

16、 something is suggested or recommended, but not required.BACKGROUND AND PURPOSEBackgroundIn August 2002, the FDA announced the Pharmaceutical CGMPs for the 2s1t Century Initiative. In that announcement, the FDA explained the Agency s intenqtutaoliitnytesgysratetemsand risk managementapproaches into

17、its existing programs with the goal of encouraging industry toadopt modern and innovative manufacturing technologies.The CGMP initiative was spurred by the fact that since 1978, when the last major revision of the CGMP regulations was published,1 This guidance was developed by the Office of Complian

18、ce in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER), the Center for Veterinary Medicine (CVM), and the Office of Regulatory Affairs (ORA).there have been many advances in manufacturing science and in our understanding o

19、f quality systems.In addition, many pharmaceutical manufacturers are already implementing comprehensive, modern quality systems and risk management approaches. This guidance is intended to help manufacturers implementing modern quality systems and risk management approaches to meet the requirements

20、of the Agencys CGMP regulations. The Agency also saw a need to harmonize the CGMPs with other non-U.S. pharmaceutical regulatory systems and with FDA s own medical device quality systems regulations.This guidance supports these goals. It also supports the objectives of the Critical Path Initiative,

21、which intends to make thedevelopment of innovative medical products more efficient so that safe and effective therapies can reach patients sooner.The CGMPs for the 21st Century Initiative steering committee created a Quality System Guidance Development working group (QS working group) to compare the

22、 current CGMP regulations, which call for some specific quality management elements, to other existing qualitymanagement systems.The QS working group mapped the relationship between CGMP regulations (parts 210 and 211 and the 1978 Preamble to the CGMP regulatio2n)sand various quality system models,

23、such as the Drug Manufacturing Inspections Program (i.e., systems-based inspectional program),3 the Environmental Protection Agencys Guidance for DevelopingQuality Systems for Environmental Programs, ISO Quality Standards, other quality publications, and experience from regulatory cases.The QS worki

24、ng group determined that, although the CGMP regulations do provide great flexibility, they do not incorporate explicitly all of the elements that today constitute most quality management systems.The CGMP regulations and other quality management systems differ somewhat in organization and in certain

25、constituent elements; however, they are very similar and share underlying principles. For example, the CGMP regulations stress quality control.More recently developed quality systems stress quality management, quality assurance, and the use of risk management tools, in addition to quality control.Th

26、e QS working group decided that it would be very useful to examine exactly how the CGMP regulations and the elements of a modern, comprehensive quality system fit together in todays manufacturing world. This guidance is the result of that examination.Goal of the GuidanceThis guidance describes a com

27、prehensive quality systems model, which, if implemented, will allow manufacturers to support and sustain robust, modern quality systems that are consistent with CGMP regulations.The guidance demonstrates how and where the elements of this comprehensive model can fit within the requirements of the CG

28、MP regulations.The inherent flexibility of the CGMP regulations should enable manufacturers to implement a quality system in a form that is appropriate for their specific operations.The overarching philosophy articulated in both the CGMP regulationsand in robust modern quality systems is:2 See Refer

29、ence #1.3 See Reference #2.Quality should be built into the product, andtesting alone cannot be relied on to ensure product quality.This guidance is intended to serve as a bridge between the 1978 regulations and our current understanding of quality systems. In addition to being part of the FDAs CGMP

30、 initiative, this guidance is being issued for a number of reasons:?A quality system addresses the public and private sectors mutual goal of providing a hig quality drug product to patients and prescribers. A well-built quality system should reducethe number of (or prevent) recalls, returned or salv

31、aged products, and defective products entering the marketplace.?It is important that the CGMP regulations are harmonized to the extent possible with other widely used quality management systems, including ISO 9000, non-U.S. pharmaceutical quality management requirements, and FDA s own medical device

32、 quality system regulations.This guidance serves as a first step to highlight common elements between the CGMP regulations and Quality Management Systems.With the globalization of pharmaceutical manufacturing and the increasing prevalence of drug- and biologic-device combination products, the conver

33、gence of quality management principles across different regions and among various product types is very desirable.?The FDA has concluded that modern quality systems, when coupled with manufacturing process and product knowledge and the use of effective risk management practices, can handle many type

34、s of changes to facilities, equipment, and processes without the need for prior approval regulatory submissions. Manufacturers with a robust quality system and appropriate process knowledge can implement many types of improvements.In addition, an effective quality system, by lowering the risk of man

35、ufacturing problems, may result in shorter and fewer FDAinspections.?A quality system can provide the necessary frameworkfor implementing quality by design4(building in quality from the development phase and throughout a product s life cycle) improvement, and risk management in the drug manufacturin

36、g process. A quality system adoptedby a manufacturer can be tailored to fit the specificenvironment, taking into account factors suchas scope of operations, complexity of processes, and appropriate use of finite resources.Scope of the GuidanceThis guidance applies to manufacturers of drug products (

37、finished pharmaceuticals), including products regulated by the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Veterinary Medicine (CVM).It may also be useful to manufacturers of components (including active pharmaceutical i

38、ngredients) used in the manufacture of these products.This document is not intended to create new requirements for pharmaceutical manufacturing that go beyond those established in the current regulations, nor is the guidance intended to be a guide for the conduct of FDA inspections. Rather, the docu

39、ment explains how implementing comprehensive quality systems can help manufacturers achieve compliance with 21 CFR parts4 See ICH Q8 Pharmaceutical Development.4210 and 211. Although the QS working group found that many of the quality system elements correlate with specific CGMP requirements, some d

40、o not. The Agency expects compliance with CGMP regulations, and FDA s inspection program will remain focused on compliance with those regulations.Organization of this GuidanceTo provide a reference familiar to industry, the quality systems model described in section IV ofthis guidance is organized i

41、n its major sections according to the structure of internation quality standards.Major sections of the model include the following:?Management Responsibilities?Resources?Manufacturing Operations?Evaluation ActivitiesUnder each of these sections the key elements found in modern quality systems are di

42、scussed. When an element correlates with a CGMP regulatory requirement, that correlation is noted. In some cases, a specific CGMP regulation is discussed in more detail as it relates to a quality system element. At the end of each section, a table is included listing the quality system elements of t

43、hat section and the specific CGMP regulations with which they correlate.A glossary is included at the end of the document.CGMPS AND THE CONCEPTS OF MODERN QUALITY SYSTEMSSeveral key concepts are critical for any discussion of modern quality systems.The following concepts are used throughout this gui

44、dance as they relate to the manufacture of pharmaceutical products.QualityEvery pharmaceutical product has established identity, strength, purity, and other quality characteristics designed to ensure the required levels of safety and effectiveness. For the purposes of this guidance document, the phr

45、asaechieving quality means achieving these characteristics for a product.Quality by Design and Product Development5Quality by design means designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently at

46、tains a predefined quality at the end of the manufacturing process.Quality by design, in conjunction with a quality system, provides a sound framework for the transfer of product knowledge and process understanding from drug development to the commercial manufacturing processes and for post-developm

47、ent changes and optimization. The CGMP regulations, when5 See ICH-Q8 Pharmaceutical Development. PAGE 28viewed in their entirety, incorporate the concept of quality by design. This guidance describes how these elements fit together.Quality Risk ManagementQuality risk managementis a valuable componen

48、t of an effective quality systems framework6. Quality risk management can, for example, help guide the setting of specifications and process parameters for drug manufacturing, assess and mitigate the risk of changing a process or specification, and determine the extent of discrepancy investigations

49、and corrective actions.CAPA (Corrective and Preventive Action)CAPA is a well-known CGMP regulatory concept that focuses on investigating, understanding, and correcting discrepancies while attempting to prevent their recurrence.Quality system models discuss CAPA as three separate concepts, all of whi

50、ch are used in this guidance.?Remedial corrections of an identified problem?Root cause analysis with corrective action to help understand the cause of the deviation and potentially prevent recurrence of a similar problem?Preventive action to avert recurrence of a similarpotential problemChangeContro

51、lChange control is another well-known CGMP concept that focuses on managing change to prevent unintended consequences.The CGMP regulations provide for change control primarily through the assigned responsibilities of the quality control unit. Certain major manufacturing changes (e.g., changes that a

52、lter specifications, a critical product attribute or bioavailability) require regulatory filings and prior regulatory approval (21 CFR 314.70, 514.8, and 601.12).Effective change control activities (e.g., quality planning and control of revisions to specifications, process parameters, procedures) ar

53、e key components of any quality system.In this guidance,change is discussed in terms of creating a regulatory environment that encourages change towards continual improvement. This means a manufacturer is empowered to makechanges subject to the regulations based on the variability of materials used

54、in manufacturing and process improvements resulting from knowledge gained during a product s lifecycle.The Quality UnitMany of the modern quality system concepts described here correlate very closely with the CGMP regulations (refer to the charts later in the document). Current industry practice gen

55、erally divides the responsibilities of the quality control unit (QCU), as defined in the CGMPregulations, between quality control (QC) and quality assurance (QA) functions.?QC usually involves (1) assessing the suitability of incoming components, containers, closures, labeling, in-process materials,

56、 and the finished products; (2) evaluating the6 See ICH Q9 Quality Risk Management.performance of the manufacturing process to ensure adherence to proper specifications and limits; and (3) determining the acceptability of each batch for release.?QA primarily involves (1) review and approval of all p

57、rocedures related to production and maintenance, (2) review of associated records, and (3) auditing and performing/evaluating trend analyses.This guidance uses the termquality unit 7 (QU) to reflect modern practice while remaining consistent with the CGMP definition in 210.3(b)(15). The qcuoanlcitey

58、put noift ais also consistent with modern quality systems in ensuring that the various operations associated with all systems are appropriately planned, approved, conducted, and monitored.The CGMP regulations specifically assign the QU the authority to create, monitor, and implement a quality system

59、.Such activities do not substitute for, or preclude, the daily responsibility of manufacturing personnel to build quality into the product. The QU should nottake on the responsibilities of other units of a manufacturer s organization, such as theresponsibilities handled by manufacturing personnel, e

60、ngineers, and development scientis8ts.Manufacturing personnel and the QU are both critical in fulfilling the manufacturerresponsibility to produce quality products.Other CGMP assigned responsibilities of the QU are consistent with modern quality system approaches ( 211.22):?Ensuring that controls ar