1. © 2013 Vivid Ngenuity, LLC. All rights reserved. 1 Bio-Link Summer Fellows Forum 2013 Vivian Ngan-Winward, PhD, CMQ/OE

2.  Overview of a regulated environment Basics of FDA regulations How biotech companies comply Common FDA inspection observations  How to prepare students for Working in a regulated environment Making contributions toward compliance 2 © 2013 Vivid Ngenuity, LLC. All rights reserved.

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4. 4 Idea Research & Development [‘Proof of Concept’] Prototyping / Pilot Plant [Validation & Smaller Scale Production] Manufacturing [Mass / Large Scale Production]Consumer © 2013 Vivid Ngenuity, LLC. All rights reserved. Business strategy :  Develop for manufacturability  Initiate compliance efforts at the idea stage (identify market)

5.  Requires FDA approval / clearance Pre-clinical & clinical trials Submit application Include data to support : o Product claims o Product safety  Approval / clearance given by appropriate FDA center with oversight for product type 5 © 2013 Vivid Ngenuity, LLC. All rights reserved.

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7. 7 1800’s Poor meat-packing conditions → Upton Sinclair’s The Jungle Federal Food and Drug Act → first regulation of product labeling 1960 Federal Food, Drug, & Cosmetic (FD&C) Act USDA Bureau of Chemistry → Food, Drug, and Insecticide Administration (to FDA in 1930) Misbranding (e.g. labeling is false or misleading) : food, “tonics”, “elixirs of life” © 2013 Vivid Ngenuity, LLC. All rights reserved. 1906 1938 1927 Sulfanilamide elixir disaster : 107 deaths !!! 1937 Application for Kevadon denied (Frances Kelsey); thalidomide disaster in Europe (1961-1962)

8. 8 FD&C Act Medical Device Amendments GXPs GMP for Blood & Blood components – 21 CFR 606 (1975) GMP for Drugs - 21 CFR 210 & 211 (1978) GLP – 21 CFR 58 (1978) for pre-clinical studies GMP for Food – 21 CFR 110 (1986) GMP for Medical Devices [QSR] – 21 CFR 820 (1996) GMP for Dietary Supplements – 21 CFR 111 (2007) 1970’s - now © 2013 Vivid Ngenuity, LLC. All rights reserved. 1976 FD&C Act Kefauver-Harris Amendments 1962 Dalkon Shield disaster 1971

9.  Extended control to cosmetics and therapeutic devices  Required new drugs to be shown safe before marketing  Eliminated Sherley Amendment requirement (to prove intent to defraud in drug misbranding cases)  Provided for safe tolerances be set for unavoidable poisonous substances  Authorized standards of identity, quality, and fill-of- container for foods  Authorized factory inspections  Added of court injunctions to the penalties 9 © 2013 Vivid Ngenuity, LLC. All rights reserved.

10.  Required manufacturers to provide evidence that proposed drugs were both safe and effective, demonstrated by adequate and well-controlled clinical investigations conducted by qualified experts  Required FDA evaluation of new drug applications (180 days); applications would no longer become automatically effective  Required affirmative FDA decision of new drugs before marketing  Required manufacturers to maintain records of adverse drug events and to report these promptly to FDA 10 © 2013 Vivid Ngenuity, LLC. All rights reserved.

11.  Sets standards for manufacturers and expectations for their products  Protects the public: some assurance of safety and efficacy 11 © 2013 Vivid Ngenuity, LLC. All rights reserved.

12. 12  FDA : What We Do : History http://www.fda.gov/AboutFDA/WhatWe Do/History/default.htm http://www.fda.gov/AboutFDA/WhatWe Do/History/default.htm  Sinclair (1906) The Jungle © 2013 Vivid Ngenuity, LLC. All rights reserved.

13. 13  Discussion on an aspect of regulations history  Research / presentation on one of the product “disasters” Goal: orientation to the history and importance of regulations © 2013 Vivid Ngenuity, LLC. All rights reserved.

14. 14 © 2013 Vivid Ngenuity, LLC. All rights reserved.

15. 15 FDA United States Code (U.S.C.) – Title 21 US Federal Government Code of Federal Regulations (CFRs) – Title 21, Food & Drugs Promulgated in Federal Register Laws Codified © 2013 Vivid Ngenuity, LLC. All rights reserved.

16.  Chapter I: Short Title  Chapter II: Definitions  Chapter III: Prohibited Acts and Penalties  Chapter IV: Food  Chapter V: Drugs and Devices  Chapter VI: Cosmetics  Chapter VII: General Authority  Chapter VIII: Imports and Exports  Chapter IX: Miscellaneous 16 © 2013 Vivid Ngenuity, LLC. All rights reserved.

17. 17 © 2013 Vivid Ngenuity, LLC. All rights reserved. FD&C Act / U.S.C. section number cross- reference http://www.fda.gov/RegulatoryInformation /Legislation/FederalFoodDrugandCosmeti cActFDCAct/default.htm

18. PartsCovers 100 seriesFood – 110 cGMPs ; Dietary supplements – 111 cGMPs 200 & 300 seriesPharmaceuticals – 210 & 211 cGMPs 500 seriesAnimal feeds & medications 600 seriesBiological products – 606 cGMPs 700 seriesCosmetics (limited regulations) 800 seriesMedical devices – 820 cGMPs 900 seriesMammography quality requirements 1000 seriesRadiation emitting device 1200 seriesNon-FD&C Act rulings OtherGLP – 58; GCP – 50, 54, 56; Electronic Records – 11 18 © 2013 Vivid Ngenuity, LLC. All rights reserved.

19. 21 CFR Parts can be viewed at http://www.ecfr.gov 19 © 2013 Vivid Ngenuity, LLC. All rights reserved.

20. 20  Select several 21 CFR Parts and assign one to each student to summarize and present to the class  Assign students to select and report on one 21 CFR Part of interest Goal: exposure to 21 CFRs, and how to find them © 2013 Vivid Ngenuity, LLC. All rights reserved.

21. 21 © 2013 Vivid Ngenuity, LLC. All rights reserved.

22.  An agency of Department of Health and Human Services (as of 1979)  Mission: 1.“ responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation ” 22 © 2013 Vivid Ngenuity, LLC. All rights reserved.

23.  Mission (cont.) : 2.“ responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health ” 23 © 2013 Vivid Ngenuity, LLC. All rights reserved.

24. 24 From: www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/default.htm © 2013 Vivid Ngenuity, LLC. All rights reserved.

25. 25 © 2013 Vivid Ngenuity, LLC. All rights reserved. SubdivisionResponsibility Office of the CommissionerProgram administration Office of Regulatory Affairs Enforces FDA regulations, monitors industry for compliance, recalls Center for Biologics Evaluation & Research (CBER) Assorted biological products/biologics (these replicate natural human substances): allergenic extracts for shots, blood & blood components, gene therapy products, transplant-related human tissue and cellular products, vaccines FDA Subdivisions:

26. 26 © 2013 Vivid Ngenuity, LLC. All rights reserved. SubdivisionResponsibility Center for Drug Evaluation & Research (CDER) Drugs (purely chemical substances), therapeutic biological products (e.g. monoclonal Abs, cytokines, growth factors, enzymes, thrombolytics, proteins [natural or recombinant]) extracted from animals for therapeutic use, non-vaccine therapeutic immunotherapies Center for Devices & Radiological Health (CDRH) Medical devices (e.g. catheters, breast pumps, contact lenses, lab instrumentation), diagnostic test kits, GMP, compliance, postmarket tracking, radiological health screening procedures (mammography, whole body CT scanning, medical imaging) FDA Subdivisions (continued):

27. 27 © 2013 Vivid Ngenuity, LLC. All rights reserved. SubdivisionResponsibility Center for Food Safety & Applied Nutrition (CFSAN) Various food products, GMOs, cosmetics, dietary supplements, infant formula, foodborne illness, food labeling & nutrition Center for Veterinary Medicine (CVM) Food additives and drugs given to animals; animals from which human foods are derived FDA Subdivisions (continued):

28. 28 Product TypeFDA Center Vaccine and blood product type therapeutic proteinsCBER Some therapeutic biological products (mAbs for in vivo use, therapeutic proteins, cytokines and growth factors used as immunomodulators or alterers of cell production) Transferred to CDER Combination products (e.g. drug/device, biologic/device, drug/biologic, drug/device/biologic) – combined, packaged together, packaged separately but to be used together CBER, CDER, or CDRH, depends on primary mode of action Genetic tests for disease diagnosis or disease prevention, treatment, or cure CDRH Biosimilars (generic biologic, not identical to original)CDER © 2013 Vivid Ngenuity, LLC. All rights reserved.

29. Application TypePurpose Investigational New Drug (IND) To request exemption of approved marketing application for shipping new drug across state lines for clinical trials New Drug Application (NDA) To request approval to sell and market new drug in US; submitted with supporting documentation detailing drug ingredients; how drug is manufactured, processed, and packaged; results of animal studies and clinical studies; how the drug behaves in the body Abbreviated New Drug Application (ANDA) To request approval to sell and market generic drug in US; application need not include animal and clinical studies, but must show evidence that generic is bioequivalent to innovator drug 29 © 2013 Vivid Ngenuity, LLC. All rights reserved. Drugs

30. Application TypePurpose Over-the-Counter Drug (OTC) Not an application; manufacturer can sell and market an OTC drug with FDA pre-approval if it conforms to the FDA-published OTC monograph; one monograph for each of 80 therapeutic classes of OTC drugs; monograph contains acceptable ingredients, doses, formulation, and labeling, and defines safety and effectiveness Biologic License Application (BLA) To request approval to sell and market biologic in US; like a NDA but for a biologic 30 © 2013 Vivid Ngenuity, LLC. All rights reserved. Drugs... 2

31. 31 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Devices Application TypePurpose Investigational Device Exemption (IDE) To request exemption of approved marketing application for shipping investigational device across state lines for clinical trials; clinical trials typically required to support premarket approvals, but occasionally needed to support premarket notifications Premarket Notification (PMN) / 510(k) Clearance To request clearance to sell and market in US non- exempt Class I device or Class II device that is substantially equivalent to a legally marketed (predicate) device Premarket Approval (PMA) To request approval to sell and market non-pre- amendment Class III or non-510(k) device in US

32. 32 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Devices... 2 Application TypePurpose Humanitarian Device Exemption (HDE) To request exemption of certain requirements to sell and market humanitarian use device (HUD) in US that is intended to benefit patients through treatment or diagnosis of disease or condition affecting < 4,000 individuals per year; like a PMA but exempt from proof of effectiveness requirement

33. 33 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Device Notes  Device classification: o Depends on intended use and indications for use o Over 1,700 distinct devices, grouped into 16 medical specialty panels [per 21 CFR 862-892], have been classified o 3 classes: Class I, Class II, and Class III, with regulatory control increasing from I to III – see: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ Overview/GeneralandSpecialControls/default.htm

34. 34 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Device Notes (cont.) Device Class Definition Class I Low risk Most (~74%) are exempt; non-exempt require PMN / 510(k) Exempt manufacturers must still register establishment and list generic category or classification name Exempt devices not exempt from GMP requirements; however, some are GMP exempt but not from records and complaint files Some exempt devices have limitations to exemption status Subject to general controls

35. 35 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Device Notes (cont. 2) Device Class Definition Class II Moderate risk Most are not exempt and usually require PMN / 510(k) Some are exempt, but not from GMP requirements Subject to general controls, and special controls to assure safety and effectiveness Class III High risk - pose significant risk of illness or injury (devices usually support or sustain human life); OR not substantially equivalent to Class I or Class II predicate Not exempt and require PMA unless a pre-amendment (pre May 28, 1976) device Subject to general controls with PMA

36. 36 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Device Notes (cont. 3)  Substantial equivalence: if, in comparison to predicate... o Has same intended use AND technological characteristics o Has same intended use BUT different technological characteristics that are supported by data that (1) shows device is at least as safe and effective as predicate AND (2) does not raise new safety and effectiveness questions

37.  Center–specific information for industry AND consumers  About FDA  Regulatory info & guidance documents  Science & research  News  Recalls & alerts  Approvals & clearances 37 © 2013 Vivid Ngenuity, LLC. All rights reserved.

38. 38  Invite a local biotech company representative to speak to your class about the process required to achieve a recent product approval / clearance  Examine and discuss an application for a recently approved / cleared product Goal: exposure to FDA submissions © 2013 Vivid Ngenuity, LLC. All rights reserved.

39. 39 © 2013 Vivid Ngenuity, LLC. All rights reserved.

40. GXPs = “best” practices & FDA mandated  defines what compliance requires  does not describe exactly how to do it 40 © 2013 Vivid Ngenuity, LLC. All rights reserved.

41. PartsCovers 100 seriesFood – 110 cGMPs ; Dietary supplements – 111 cGMPs 200 & 300 seriesPharmaceuticals – 210 & 211 cGMPs 500 seriesAnimal feeds & medications 600 seriesBiological products – 606 cGMPs 700 seriesCosmetics (limited regulations) 800 seriesMedical devices – 820 cGMPs 900 seriesMammography quality requirements 1000 seriesRadiation emitting device 1200 seriesNon-FD&C Act rulings OtherGLP – 58; GCP – 50, 54, 56; Electronic Records – 11 41 © 2013 Vivid Ngenuity, LLC. All rights reserved.

42.  Good clinical practices (GCP) : Regulates clinical trials involving human subjects Protects human rights Provides assurance of safety and efficacy of developed product  Good laboratory practices (GLP) : Regulates nonclinical laboratory studies that support FDA approval applications  Good manufacturing practices (cGMP) : Regulates manufacture of products covered by FD&C Act 42 © 2013 Vivid Ngenuity, LLC. All rights reserved.

43.  Most stringently described in 21 CFR Parts  110 : for food  111 : for dietary supplements  210 & 211 : for drugs  606 : for biologics  820 : for medical devices (QSRs)  Provides detailed requirements on how to operate manufacturing business  Indirectly impacts R&D 43 © 2013 Vivid Ngenuity, LLC. All rights reserved.

44.  Design Inputs & Outputs  Design Verification : Outputs = Inputs  Design Validation  Compilation of records:  Design History File (DHF) : describes design history of finished product  Device Master Record (DMR) : contains procedures and specifications of finished device/product (“recipe”)  Device History Record (DHR) : contains production history of device/product 44 © 2013 Vivid Ngenuity, LLC. All rights reserved.

45.  Medical device cGMP up close... Medical device cGMP See also : FDA’s CDRH Learn – Quality System Regulation 21 CFR 820 Basic Introduction presentation http://www.fda.gov/MedicalDevices/ResourcesforYou /Industry/ucm126252.htm 45 © 2013 Vivid Ngenuity, LLC. All rights reserved.

46.  GLP: o 21 CFR 58 o Lab Compliance GLP tutorial http://www.labcompliance.com/tutorial/gl p/default.aspx?sm=d_a o WHO GLP Handbook (2009) http://www.who.int/tdr/publications/traini ng-guideline-publications/good-laboratory- practice-handbook-ver1/en/ 46 © 2013 Vivid Ngenuity, LLC. All rights reserved.

47.  GMP FDA guidance documents: o http://www.fda.gov/Drugs/GuidanceComplian ceRegulatoryInformation/Guidances/ucm06497 1.htm http://www.fda.gov/Drugs/GuidanceComplian ceRegulatoryInformation/Guidances/ucm06497 1.htm o http://www.fda.gov/BiologicsBloodVaccines/G uidanceComplianceRegulatoryInformation/Gui dances/General/ucm217665.htm http://www.fda.gov/BiologicsBloodVaccines/G uidanceComplianceRegulatoryInformation/Gui dances/General/ucm217665.htm o http://www.fda.gov/MedicalDevices/DeviceRe gulationandGuidance/PostmarketRequirements /QualitySystemsRegulations/MedicalDeviceQua litySystemsManual/default.htm http://www.fda.gov/MedicalDevices/DeviceRe gulationandGuidance/PostmarketRequirements /QualitySystemsRegulations/MedicalDeviceQua litySystemsManual/default.htm 47 © 2013 Vivid Ngenuity, LLC. All rights reserved.

48. 48  GXP comparison activity: Align these 21 CFR Parts: o GLP (21 CFR 58) o drug cGMP (21 CFR 210 & 211) o biologics cGMP (21 CFR 606) o medical device cGMP (21 CFR 820) Goal: exposure to details of GXPs and how they are similar / different © 2013 Vivid Ngenuity, LLC. All rights reserved.

49. 49 © 2013 Vivid Ngenuity, LLC. All rights reserved.

50. A tight relationship exists between  the FDA [regulating body]  the Laws [US Code]  the Code of Federal Regulations (CFRs) - gov’t agency promulgated  Good Manufacturing Practices (GMPs)  Quality System Regulations (QSRs)  Standards / Certifications (e.g. ISO)  Quality Management System 50 FDA Laws (U.S.C.) Industry-Specific CFRs GMPs Quality Management System Government Industry Company Standards / Certif. (e.g. ISO) QSRs ISO Non-gov’t Org © 2013 Vivid Ngenuity, LLC. All rights reserved.

51. How ? 51 © 2013 Vivid Ngenuity, LLC. All rights reserved.

52. 52 © 2013 Vivid Ngenuity, LLC. All rights reserved. What does the sign mean to you ? How will you ensure compliance ?

53. By appropriately interpreting the regulations 53 © 2013 Vivid Ngenuity, LLC. All rights reserved.

54. A quality management system provides a structure for the company to work within and remain compliant 54 © 2013 Vivid Ngenuity, LLC. All rights reserved.

55. 55 © 2013 Vivid Ngenuity, LLC. All rights reserved.

56.  Required by the FDA (not optional !)  “Each manufacturer shall establish and maintain a quality system that is appropriate for the specific medical device(s) designed or manufactured, and that meets the requirements of this part.” – 21 CFR 820.5  Designed by each company to align its operations with the regulations 56 © 2013 Vivid Ngenuity, LLC. All rights reserved.

57.  Per 21 CFR 820.3 – “the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management”  Per Wikipedia – “a set of policies, processes, and procedures required for planning and execution of production in the core business area of an organization” 57 © 2013 Vivid Ngenuity, LLC. All rights reserved.

58.  Has a customer focus  Often designed to meet ISO 9001 standards – based on 8 principles: 1.Customer focus 2.Leadership 3.Workforce involvement 4.Continuous improvement 5.System approach to management 6.Data-based approach to decision making 7.Positive supplier communication / relationships 8.Total process approach 58 © 2013 Vivid Ngenuity, LLC. All rights reserved.

59.  Main components Management responsibility Resource management Product realization Measurement, analysis, and improvement  Process-oriented approach to managing quality  A framework that directs quality contributions from all employees 59 © 2013 Vivid Ngenuity, LLC. All rights reserved.

60. 60 Quality Management System Continual Improvement Resource Management Process / Product Realization input Product / Service Measurement, Analysis, & Improvement Management Responsibility output © 2013 Vivid Ngenuity, LLC. All rights reserved.

61. Training & qualifying personnel Controlling product design Controlling documentation & records Controlling purchasing Identifying & tracing product at all production stages Defining & controlling production & processes Defining & controlling inspection / measuring / test equipment 61 © 2013 Vivid Ngenuity, LLC. All rights reserved.

62. Validating processes Accepting product Controlling nonconforming product Instituting corrective & preventive actions Controlling labeling & packaging Servicing production equipment Using statistical techniques 62 © 2013 Vivid Ngenuity, LLC. All rights reserved.

63.  Catalogued by the FDA on an annual basis  Access through: http://www.fda.gov/ICECI/EnforcementAc tions/ucm250720.htm http://www.fda.gov/ICECI/EnforcementAc tions/ucm250720.htm  Examples from FDA inspections during fiscal year 2012 (Oct 1, 2011 to Sep 30, 2012) – actual observations reported on Form 483’s 63 © 2013 Vivid Ngenuity, LLC. All rights reserved.

64. ObservationFreqReg Ref The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. Specifically, *** 169 21 CFR 211.22(d) There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed. Specifically, *** 119 21 CFR 211.192 There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Specifically, *** 116 21 CFR 211.100(a)

65. © 2013 Vivid Ngenuity, LLC. All rights reserved. ObservationFreqReg Ref Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity. Specifically, *** 115 21 CFR 211.160(b) Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Specifically, *** 89 21 CFR 211.110(a)

66. © 2013 Vivid Ngenuity, LLC. All rights reserved. ObservationFreqReg Ref Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, *** 73 21 CFR 211.67(b) Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance. Specifically, *** 69 21 CFR 211.68(a) Employees are not given training in [the particular operations they perform as part of their function] [current good manufacturing practices] [written procedures required by current good manufacturing practice regulations]. Specifically, *** 65 21 CFR 211.25(a)

67. © 2013 Vivid Ngenuity, LLC. All rights reserved. ObservationFreqReg Ref Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, *** 65 21 CFR 211.67(a) Written production and process control procedures are not [followed in the execution of production and process control functions] [documented at the time of performance]. Specifically, *** 64 21 CFR 211.100(b)

68. © 2013 Vivid Ngenuity, LLC. All rights reserved. ObservationFreqReg Ref Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the [final specifications] [identity and strength of each active ingredient] prior to release. Specifically, *** 62 21 CFR 211.165(a)

69. © 2013 Vivid Ngenuity, LLC. All rights reserved. ObservationFreqReg Ref Procedures for corrective and preventive action have not been [adequately] established. Specifically, *** 372 21 CFR 820.100(a) Procedures for receiving, reviewing, and evaluating complaints by a formally designated unit have not been [adequately] established. Specifically,*** 259 21 CFR 820.198(a) Written MDR procedures have not been [developed] [maintained] [implemented]. Specifically, *** 140 21 CFR 803.17 Procedures to ensure that all purchased or otherwise received product and services conform to specified requirements have not been [adequately] established. Specifically, *** 126 21 CFR 820.50

70. © 2013 Vivid Ngenuity, LLC. All rights reserved. ObservationFreqReg Ref Corrective and preventive action activities and/or results have not been [adequately] documented. Specifically, *** 115 21 CFR 820.100(b) Procedures have not been [adequately] established to control product that does not conform to specified requirements. Specifically, *** 110 21 CFR 820.90(a) A process whose results cannot be fully verified by subsequent inspection and test has not been [adequately] validated according to established procedures. Specifically, *** 102 21 CFR 820.75(a) Procedures for design change have not been [adequately] established. Specifically,*** 101 21 CFR 820.30(i)

71. © 2013 Vivid Ngenuity, LLC. All rights reserved. ObservationFreqReg Ref Complaints involving the possible failure of [a device] [labeling] [packaging] to meet any of its specifications were not [reviewed] [evaluated] [investigated] where necessary. Specifically, *** 96 21 CFR 820.198(c) Procedures for quality audits have not been [adequately] established. Specifically, *** 91 21 CFR 820.22 A device master record has not been [adequately] maintained. Specifically, *** 91 21 CFR 820.181

72.  Procedures for XXX not [adequately] established / followed © 2013 Vivid Ngenuity, LLC. All rights reserved.

73. 73  Review and discuss these common observations with students  Case studies – select Form 483’s for class review and discussion (RE: local companies have more relevance) http://www.fda.gov/AboutFDA/CentersOffices/Offi ceofGlobalRegulatoryOperationsandPolicy/ORA/ORA ElectronicReadingRoom/default.htm Goal: understand common mistakes to better contribute toward compliance © 2013 Vivid Ngenuity, LLC. All rights reserved.

74. 74 Vivian Ngan-Winward vivian.ngan-winward@slcc.edu 801-957-6210 © 2013 Vivid Ngenuity, LLC. All rights reserved.