Planning for and Managing FDA Inspections. Focus: 21 CFR, Part 820

Transcription

1 Planning for and Managing FDA Inspections Focus: 21 CFR, Part 820 Information, Preventive Action and Strategy 1

2 The Authority behind Inspections The Safe Medical Devices Act of 1990 (the SMDA), enacted on November 28, 1990, amended section 520(f) of the act, providing FDA with the authority to add preproduction design controls to the CGMP regulation. This change in law was based on findings that a significant proportion of device recalls were attributed to faulty design of product. The SMDA also added new section 803 to the act (21 U.S.C. 383) which, among other things, encourages FDA to work with foreign countries toward mutual recognition of CGMP requirements. FDA undertook the revision of the CGMP regulation to add the design controls authorized by the SMDA to the CGMP regulation, as well as because the agency believed that it would be beneficial to the public and the medical device industry for the CGMP regulation to be consistent, to the extent possible, with the requirements for quality systems contained in applicable international standards. FDA published the revised CGMP requirements in the final rule entitled Quality System Regulation in the Federal Register of October 7, 1996 (61 FR 52602). This regulation became effective on June 1, 1997 and remains in effect. QSIT 2

3 Scheduling Inspections of Medical Device Manufacturers Priorities for QS Inspection District Offices will target coverage of manufacturers of Class II and Class III devices, utilizing a risk based methodology. Selection of firms will be focused using the risk based list of possibilities: Pre-Market and Pre-Clearance inspections Manufacturers of Class III devices that have never been inspected. Compliance Follow Up/For Cause Inspections 3

4 Scheduling Inspections of Medical Device Manufacturers Priorities for QS Inspection District Offices will target coverage of manufacturers of Class II and Class III devices, utilizing a risk based methodology. Selection of firms will be focused using the risk based list of possibilities: Manufacturers of high risk devices which can be identified by: Devices with a higher frequency of recalls and MDRs; Devices that are driven by software and those with rapidly evolving technological changes. Both of these types of devices are subject to rapid and potentially poorly controlled modifications that could affect their continued safety and efficacy; or, New devices that have not been manufactured and distributed for very long. Single Use Device re-processors: Hospital re-processors and Third Party re-processors. Highest priority will be given to those Class III device manufacturers that have not been previously inspected. 4

5 Class I Medical Device Manufacturers All Class I devices, including those exempted from most of the Quality System regulation requirements, must comply with record keeping requirements and complaint file requirements, as well as reporting requirements under the MDR regulation. Class I manufacturers should not be routinely scheduled for inspection but should receive lowest inspectional priority unless addressed by a special, For Cause assignment or when a health hazard is apparent. 5

6 Inspectional Strategy The QS inspectional goal is to assess the firm s quality management system for compliance with the appropriate regulations. The QS inspections should generally start with a walk through of the facility to become familiar with the firm s operations and general state of control. 6

7 Inspectional Strategy The inspection will assess the firm s systems, methods, and procedures to ensure that the firm s quality management system is effectively established (defined, documented and implemented) and effectively maintained. QS inspections should include the assessment of postmarket information on distributed. 7

8 Inspectional Strategy Due Diligence QS inspections should include the assessment of post-market information on distributed devices to include: Review of recalls Review of MDRs (Be alert to the fact that MDRs may contain information on recalls that have not been reported through the district) Review of corrections and removals Review of significant changes in device specifications or in the manufacturing specifications Follow-up on previous FDA 483 observation(s), to include the corrections, corrective actions or preventive actions for the observation(s) and the related system(s) 8

9 Inspectional Strategy Available post-market information should be reviewed as a part of the preparation for the inspection, in order to facilitate efficient time spent at the facility. Identify in the EIR post-market information reviewed during the inspection and adequately document your findings. See IOM Any problems identified as a result of the review of post-market information should be developed during the inspection. Important Note : The review of post-market information does not mean that the investigator should open the inspection with the review of complaints and complaint information. Complaints should be reviewed within the context of the Corrective and Preventive Action sub-system according to the procedures described below in this part. 9

10 Inspectional Strategy QS inspections should generally be conducted using the Quality System Inspection Technique (QSIT). Guidance for performing an inspection is provided in the Guide to Inspections of Quality Systems, August 1999, also called the QSIT Guide. This QSIT tool can be scaled to meet the needs of each particular inspection. The table below correlates the level of inspection and the guidance on how to perform the inspections. 10

11 Inspectional Strategy Inspection Level Type of Inspection Guide to Inspections 1 Abbreviated QSIT Two subsystems; Corrective and Preventive Actions (CAPA) plus Production and Process Controls (P&PC) or Design Controls 2 Comprehensive QSIT - The four major subsystems; Management Controls, Design Controls, CAPA and P&PC 3 Compliance Follow-up - As directed by inspectional guidance and Special For Cause - elements of QSIT As directed by inspectional guidance and elements of QSIT 11

12 Inspectional Strategy Compliance Follow-up and For Cause inspections are dictated by the previous FDA 483 findings and other regulatory information and may differ from the typical QSIT approach. The inspectional guidance provided by the assignment, the district compliance branch, and/or CDRH will guide the direction of these inspections. However, elements of the QSIT Guide may also be utilized. Investigators must ensure that the EIR clearly states what was covered during the inspection due to the directed nature of these types of inspections. 12

13 Inspectional Strategy NOTE: The Quality System regulation can be grouped into seven subsystems; however, the following four subsystems are considered major subsystems and are the basic foundation of a firm s quality management system: Management Controls, Design Controls, Corrective and Preventive Actions (CAPA), and Production and Process Controls (P&PC). MDR, Corrections and Removals, and Tracking requirements (where applicable) should be covered when covering the CAPA subsystem. The three remaining subsystems (Facilities and Equipment Controls, Materials Controls and Document/Records/Change Controls) cut across a firm s quality management system and are evaluated while covering the four major subsystems. 13

14 Inspectional Strategy This process for performing subsystem inspections is based on a "topdown" approach to inspecting. The subsystem approach is designed to provide you with the key objectives that can help determine a firm's state of compliance. The process was designed to account for the time constraints placed on field investigators when performing device quality system inspections..focus the effort on key elements of a firm's quality system..efficiently and effectively evaluate that quality system. 14

15 Inspectional Strategy Instruction to Investigators: When you begin an inspection by looking at one or more instances of quality problems, such as nonconforming device reports, and work your way back through the firm's quality system, you are doing a "bottom-up" inspection. This method has been helpful in zeroing in on specific problems, and evaluating the firm's actions relating to those problems. However, with the "top-down" approach, we are looking at the firm's "systems" for addressing quality before we actually look at specific quality problems. In the "top-down" approach, we "touch bottom" in each of the subsystems by sampling records, rather than working our way from records review backwards towards procedures. 15

16 Inspectional Strategy The "top-down" approach begins each subsystem review with an evaluation of whether the firm has addressed the basic requirements in that subsystem by defining and documenting appropriate procedures. This is followed by an analysis of whether the firm has implemented the requirements of that subsystem. 16

17 Inspectional Strategy Record Review One similarity between "top-down" and "bottom-up" inspectional approaches is record review. Both approaches involve review of raw data, or individual records. In the "top-down" approach, however, we are asking you to use a sampling approach to the record review. With the "top-down" approach, you will sample records in many of the subsystems to verify whether or not the firm is in compliance. In other words, you are doing the raw data review as you did in the past, but in a more controlled manner. The FDA provides sampling tables to assist in determining how many records you need to review, and what confidence you can have in the potential prevalence of the observed conditions. 17

18 Level One Inspection This level of inspection (CAPA plus P&PC or Design Controls) may be used for routine surveillance and initial inspections of all firms, other than firms that manufacture Class III devices. However, it is recommended that initial inspections of Class II manufacturers utilize a Level 2 Comprehensive inspection whenever district resources permit. Level 1 inspections should cover the CAPA subsystem, then P&PC or Design Controls, using the QSIT Guide. The selection of CAPA plus either the P&PC or Design Controls subsystem will provide an adequate review of the compliance status of the firm. 18

19 Level One Inspection QSIT Guide. The selection of CAPA plus either the P&PC or Design Controls subsystem will provide an adequate review of the compliance status of the firm. The following should be considered in determining whether to select P&PC or Design Controls: CAPA findings during the inspection; Subsystems covered during the previous EI. The previous EIR(s) should be reviewed to determine which subsystems were previously covered. The selection of the P&PC or Design Controls subsystem should be alternated over time so that more subsystems within a firm s overall quality management system are assessed; Significant changes since the previous EI. Determine if there were any design changes which required a new submission or application, or if there were any major process changes; and, Post market information indicating potential design problems. The EIR must clearly state which subsystem P&PC or Design Controls was chosen and why. Note: The adequacy of the correction(s), corrective action(s) or preventive action(s) related to any FDA 483 item(s) from the previous inspection will be covered, even if the entire subsystem will not be reviewed during the current Level 1 inspection. 19

20 Level Two Inspection Level 2 inspections are Comprehensive Inspections. Level 2 inspections will cover all four major subsystems (Management Controls, Design Controls, CAPA, and P&PC) as explained in the QSIT Guide. The Level 2 inspection is considered a comprehensive review of the compliance status of the firm. Level 2 inspections will be performed: For all initial inspections of Class III device manufacturers and where possible Class II device manufacturers For foreign inspections For training When an inspection, which started out as Level 1, reveals post market information and/or objectionable conditions which cannot be adequately assessed as a Level 1 inspection. 20

21 Level Two Inspection The Level 2 QSIT approach was validated using the following inspectional sequence: Management Controls, Design Controls, CAPA and P&PC. This inspectional sequence allows the investigator to review design control issues and how the device specifications were established before reviewing the CAPA subsystem. Investigators may however start with Management Controls, followed by CAPA, Design Controls, and P&PC with appropriate linkages. Information from Design Controls and CAPA may be used to select the products and processes for inspecting production and process controls, and appropriate linkages. The subsystems may be inspected in any appropriate and justifiable sequence in order to perform a timely and effective inspection. 21

22 Level Two Inspection The Level 2 QSIT : This approach is affected by: Selection of manufacturing processes for inspectional coverage should include the following considerations: CAPA indicators of process problems Processes used to manufacture high risk products Processes that have a high risk of causing product failure Processes that require process validation Processes that are new to the manufacturer Processes that cover a variety of process technologies and profile classes Common processes used in multiple products Processes not covered during previous inspections It is important to thoroughly cover Purchasing Controls, to include outsourced processes, as a QSIT linkage under P&PC whenever P & PC is covered. The Purchasing Control coverage must be documented in the EIR especially if the manufacturer contracts a sterilization process or contracts the manufacture of significant components, subassemblies, or processes. 22

23 Level Two Inspection Manufacturing Focus Selection of manufacturing processes for inspectional coverage should include the following considerations: CAPA indicators of process problems Processes used to manufacture high risk products Processes that have a high risk of causing product failure Processes that require process validation Processes that are new to the manufacturer Processes that cover a variety of process technologies and profile classes Common processes used in multiple products Processes not covered during previous inspections 23

24 Level Two Inspection Purchasing Controls It is important to thoroughly cover Purchasing Controls, to include outsourced processes, as a QSIT linkage under P&PC whenever P & PC is covered. The Purchasing Control coverage must be documented in the EIR especially if the manufacturer contracts a sterilization process or contracts the manufacture of significant components, subassemblies, or processes. 24

25 The chart below describes the steps for the Level 3 domestic inspection after a Level 2 inspection. 25

26 For Cause Inspections For Cause inspections are carried out in response to specific information that raises questions, concerns, or problems associated with a FDA regulated firm or commodity. This information could come to the attention of FDA from any source and including but not limited to, the following: Results of a sample analysis; Observations made during prior inspections; Recall or market withdrawal; Consumer or employee complaint / Whistle Blowing Adverse reaction report; or, Suspicion of fraud. For Cause inspections are usually initiated at the request of CDRH, ORA headquarters, Regional or District directives. For Cause inspections are dictated by the source of information and may differ from the typical QSIT approach. These inspections are generally more in-depth in particular areas than typical QSIT inspections 26

27 Foreign Inspections All foreign inspections should be conducted using the QSIT Guide under the Level 2 strategy, and any special instructions contained in the inspection assignment. The foreign manufacturer's compliance with registration and listing requirements should be covered during foreign inspections. The failure of foreign device manufacturers to list products exported to the US will subject medical devices to detention upon entry. 27

28 483 Statement Part of your Strategy The following statement should be included on each FDA 483: This document lists observations made by the FDA representatives during the inspection of your facility. They are inspectional observations and do not represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective actions in response to an observation, you may discuss the objection or action with FDA representatives during the inspection or submit this information to FDA. For all medical device inspections the FDA 483 should contain the following additional statement: The observations noted in this form FDA 483 are not an exhaustive listing of objectionable conditions. Under the law, your firm is responsible for conducting internal self audits to identify and correct any and all violations of the quality system requirements. 28

29 Preparing for the Inspection 29

30 A Mindset For Everyday Record Keeping Training Document and Data Controls Internal Quality Auditing CAPA The Quality Policy Process Linkages Non-Conforming Product Complaints Management Responsibility Design Linkages with the QRB Manufacturing Batch Records 30

31 FDA Inspection Procedure Arrival of the Inspector The Inspection Team The Inspection Coordinator Focus The Control Room Photograph Policy Record Keeping Responsibilities Contact Information Document, Information and Sample Requirements 31

32 Other Sites as well Liaison Inspection Room Notes person Spokes person FDA Output Runner Input Hot Line Control Room Hot Line Info Trail output 32

33 The Control Room Logistics / Materials In close proximity to the FDA inspection room...but not too close Two or three telephones, two faxes, and active address Flip charts and magic markers Controlled copies of procedures A fast copy machine File folder units for categorizing documents and records Plenty of clerical supplies Sticky notes A hot line between the FDA Inspection Room & Control Room 33

34 The Control Room Team Qualified personnel with a strong systems background - cgmp-qsr savvy - Very familiar with the paperwork flow - Know where the gaps might be - Been through FDA inspections in the past.. street smart - Not necessarily management (preferably not) - Linkages savvy - Quick thinkers with inquiring minds - Endurance (long pauses and quick starts) - Know the right people and what buttons to push - Free thinkers..creative - Without boundaries 34

35 Having an experienced auditor in the room is a plus.. Anticipate the next steps..i.e. as you would audit the next steps..your audit checklist! 35

36 GOAL: To get the information to the inspection room as quickly as possible, but no longer than ONE Day 36

37 Investigators are not entitled to review the following information: Management Review Minutes Internal Audit Results Supplier Audit Results 37

38 Process Flow thinking this way Responsibility Responsibility Task or Activity SOP Record Task or Activity SOP 38

39 Think Inputs / Outputs INPUT TASK OR ACTIVITY OUTPUT 39

40 Think Five Moves in Advance TASK OR ACTIVITY TASK OR ACTIVITY 1 TASK OR ACTIVITY 2 Etc. TASK OR ACTIVITY 3 TASK OR ACTIVITY TASK OR ACTIVITY

41 The Control Room you re only as good as your info Complaint Files Archives Document Control Operations Regulatory Affairs Control Room Dedicated Phone Line FDA Inspection Room 41

42 The Control Room presentation is one key facet Control Room Inspection Ready FDA Inspection Room 42

43 Scenarios based upon - process orientation - process logic - process anticipation 43

44 Inspector asks for Objective Evidence Inside Liaison calls the Control Room Hot Line Control Room Plots out the Scenario Start Thinking Linkages Control Room asks for Level One Information Information Arrives in the Control Room Control Room Audits the Information Tags as Needed Asks for More? Info-Aware Objective Evidence 44

45 ..if there is a specific product involved have the following ready before hand: 510(k) Letters to File PMA FMEA DHF DMR DHRs Validation Master Plan CAPA Log Calibration Master Plan etc. 45

46 ..if there is a specific batch involved have the following ready before hand: Batch Record(s) DHF DMR DHR Put together a batch time-line with dates, tasks, records, people, etc. be prepared Certificates Sterility Data Training Records Non-conforming Product etc. 46

47 Common Linkages..to anticipate the next steps Organizational Structure Job Descriptions Responsibility and Authority Training Records 47

48 30,000-foot process map in control room (a reference..point of order..a reminder) Supplier ships raw material Incoming receipt and testing Warehouse controls Release to Production Production & Process Controls Product and Process Disposition Release to be shipped Customer Receipt 48

49 A Simple Scenario..to anticipate the next steps Design History File The Wall Device Master Record e.g. Design Transfer.. Essential Outputs DMR Design Verification Acceptance Activities Packaging and Labeling Label Claims Purchasing Controls Approved Supplier List 49

50 A Simple Scenario..to anticipate the next steps Product Non-conformances Management Review Audit Findings Reporting C/A Trends Complaints and MDRs P/A 50

51 Scenarios from Warning Letters Failure to establish and maintain adequate procedures for the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR (i). For example, your design control procedures did not include a procedure to ensure that design changes of existing products would include verification or where appropriate validation. 51

52 Scenarios from Warning Letters Failure to establish adequate procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR For example not all areas of the quality system are being audited as prescribed by SOP Specifically. customer interfaces (including the complaint handling system) have not been audited since Control of nonconforming product and the CAPA system have not been audited since May

53 Scenarios from Warning Letters You have failed to establish and maintain procedures for the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR (i). Specifically, a change was implemented for the design of the hub on the aspirating dental injection syringe because the hubs were falling off and the needles would not stay on. However, there is no data or documentation supporting the verification, review, and approval of design change. 53

54 Scenarios from Warning Letters You have failed to establish and maintain adequate procedures to ensure that device history records for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the device master record, as required by 21 CFR Specifically, the firm's device history record for the aspirating dental injection syringes is the Job Traveler implemented in However, only 3 travelers exist for all syringe products manufactured and shipped from 12/ /

55 Scenarios from Warning Letters You have failed to appoint and document such appointment of a member of management who, irrespective of other responsibilities, ensures that quality system requirements are effectively established and effectively maintained and reports on the performance of the quality system to management with executive responsibility, as required by 21 CFR (b)(3). Specifically, during the inspection, you stated that the firm had not appointed a management representative to the firm's quality system, to ensure the quality system requirements were met. Specifically, the firm does not have procedures for management review and management has not reviewed the suitability and effectiveness of the quality system at defined intervals and with sufficient frequency. 55

56 Scenarios from Warning Letters Failure to provide adequate resources including the assignment of trained personnel, for management, performance of work, and assessment activities, including internal quality audits, as required by 21 CFR (b)(2). Specifically, the current inspection demonstrated that there is no documentation to show that personnel performing the assembly and inspection of the aspirating dental injection syringe were trained. In addition, there are no personnel trained to conduct internal quality audits. We have reviewed your responses and have concluded that they are inadequate. Your firm promised to correct the deficiencies without providing evidence of implementation of the correction, corrective action and proposed preventive action. 56

57 Scenarios from Warning Letters The documentation provided by the establishment inspection showed that your firm did not perform an evaluation of the magnitude of a component problem that resulted in a recall to see if it was endemic to other device models. Your firm had identified and verified the root cause and had implemented a correction by January 19, 2009, but as of February 27, 2009, your firm was unable to detail the impact of the problem on other devices to the investigators on site. The firm s CAPA procedure indicates that; an evaluation of the magnitude of the issue once the investigation of root cause is completed, should be performed. 57

58 Scenarios from Warning Letters Failure to maintain a Device Master Record as required by 21 CFR For example, you did not have a Device Master Record which included, or referred to the location of, device specifications or procedures for production and quality assurance. Failure to maintain Device History Records, which is a requirement of 21 CFR For example, you did not maintain records of device assembly or acceptance testing. Failure to establish procedures for finished device acceptance as required by 21 CFR (d). For example, you did not have written procedures for finished device testing including instructions for how to document testing. Failure to establish procedures for acceptance of incoming product, which is required by 21 CFR (b). For example, you did not have written procedures for incoming inspection including instructions for how to document testing. Failure to establish adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit as required by 21 CFR (a). For example, your Procedure No , Customer Complaint and Returns, was in draft form and had not been implemented. 58

59 Scenarios from Warning Letters Failure to review and evaluate complaints to determine whether an investigation is necessary, which is required by 21 CFR (b). For example, complaints (leaking), (problem with sterilizer), and (defective), were not reviewed, evaluated, and investigated. 59

60 Scenarios from Warning Letters Failure to establish adequate procedures to control product that does not conform to specified requirements, which is required by 21 CFR (a). For example, your Procedure No , Non Conforming Material, had not been fully implemented, and a Nonconforming Material Report was in draft form 60

61 Scenarios from Warning Letters You do not have an agreement that requires your solenoid valve supplier to provide notification of changes to specification. According to CAPA 002, you determined that XXXXX provided solenoid valves that were model number instead of after you found that the valves were noisy. You do not have an agreement with XXXXX that requires that XXXXX notify you of changes to the supplied product. Failure to include an agreement in purchasing documents that the suppliers, contractors, and consultants agree to notify the manufacturer of changes in the product or service so that manufacturers may determine whether the changes may affect the quality of a finished device, as required by 21 CFR (b) 61

62 Scenarios from Warning Letters Failure to establish and maintain procedures for implementing corrective and preventive action (CAPA), as required by 21 CFR (a). For example, your firm has not established or implemented written procedures for implementing CAPA. The only management official on site explained he was not aware of the requirements. We reviewed your response and conclude it is inadequate because the CAPA section of the XXXXX Policy and Procedures Manual", dated September 10, 2010, fails to provide the steps for verifying or validating the CAPA to ensure such action is effective and does not adversely affect the finished device. Additionally, there is no approval signature for this document. 62

63 Scenarios from Warning Letters We reviewed the "Control of Non-Conforming Material" section of the XXXXX Policy and Procedures Manual, included in your response, and note it fails to require an evaluation of the nonconformance including a determination of the need for an investigation and notification to the persons or organizations responsible for the nonconformance. Additionally, there is no evidence the XXXXX Policy and Procedures Manual, has been reviewed, approved and implemented. 63

64 Scenarios from Warning Letters We reviewed your response and conclude it is inadequate because your complaint handling procedure has not been revised to comply with the regulation requirements. Specifically, you included a copy of XXXXX, "Product Complaint Form" with your response. This form includes a space for selecting yes or no as an answer to the question of the need to generate an MDR as a result of the complaint. However, the form does not provide for documenting the evaluation of the need for MDR reporting and justification of the decision. No evidence was provided to demonstrate the corresponding "Complaint Handling" procedure was modified to include the instructions to evaluate and document the need to report the complaint as an event under 21 CFR

65 Scenarios from Warning Letters Failure to document acceptance activities, as required by 21 CFR (e). For example your firm failed to document all of the acceptance activities which are performed such as inspections, tests, and other verification activities. We reviewed your response and conclude it is inadequate because there is no evidence to demonstrate the inspections, tests and other verification activities are being documented. 65

66 Scenarios from Warning Letters You included a copy of the Section , "Device History Record", with your response. This document indicates the computerized system YYYYY is used to maintain device history records. No evidence was provided to demonstrate such system has been validated and implemented. No evidence was provided to demonstrate procedures to document acceptance activities using the computerized system have been developed and implemented. 66

67 Scenarios from Warning Letters Failure to establish and maintain procedures to ensure all purchased or otherwise received product and services conform to specified requirements, as required by 21 CFR For example, your firm failed to establish purchasing control procedures and to define and implement adequate quality controls which must be met by suppliers and contractors. The only management official on site explained he was not aware of the written purchasing control procedures were required. We reviewed your response and concluded it is inadequate because no evidence was provided to demonstrate procedures have been established to ensure all purchased or otherwise received product and services conform to specified requirements. You included a copy of a certificate of conformance for one material vendor; however, a copy of an approved purchasing control procedure was not provided. 67

68 Scenarios from Warning Letters Failure of management with executive responsibility to review the suitability of the quality system at defined intervals and with sufficient frequency according to established procedures to ensure the quality system satisfies the requirements of this part, as required by 21 CFR (c). For example, your firm failed to establish and implement written management review procedures. The only management official on site explained he was not aware of the requirements. 68

69 Scenarios from Warning Letters Failure to report to the FDA no later than 30 calendar days after the day that your firm received or otherwise became aware of information. from any source. that reasonably suggests that your marketed device malfunctioned and that this device or a similar device, marketed, would be likely to cause or contribute to a death or serious injury if the malfunction were to reoccur as required by 21 CFR (a)(2). 69

70 Scenarios from Warning Letters Failures to develop, maintain, and implement a written MDR procedure, as required by 21 C.F.R For example: Section 5-9 of your MDR procedure, document no. XXXXX, defines the term "becomes aware." This definition, however, is not consistent with the language in 21 C.F.R Your MDR procedure lacks clarity about the roles and responsibilities for your MDR reporting decision-making and record-keeping, See 21 C.F.R Your MDR procedure does not adequately address who makes the final determination of whether an event must be reported as an MDR to FDA and when or how MDR events are detected. Your MDR procedure lacks information about the requirements for establishing and maintaining MDR files or records. See 21 C.F.R

71 Scenarios from Warning Letters You introduced the XXXXX single use applicator in You used the same testing criteria that had been established for the reusable applicator. You determined that there were differences in the properties of the single use and re-usable applicators, this resulted in the issuance of CAPA in The CAPA identified the plastic sheath thickness as a contributor to process variability but no corrective action was initiated for this potential root cause identified. You continue to have nonconformance rejects for not meeting the test criteria. The device history showed that 11 of the batches reviewed included some non-conformances. Data analysis for these non-conformances has not been performed and there has been no additional evaluation as to whether this data should initiate a new CAPA to address the existing nonconformances. A review of the statistical process control sheets for the test for three of the batches showed that the process is not operating in a state of control. The control charts for Lot showed that the process regularly exceeded the control limits and the limit is not met at times. Data analysis for these non-conformances has not been performed and there has been no additional evaluation as to whether this data should initiate a new CAPA to address the existing non-conformances. 71

72 Scenarios from Warning Letters Failure to establish and maintain adequate procedures for verifying the device design outputs meets the design input requirements, as required by 21 CFR (f). For example, the Device History File (DHF) for the surface applicator study for the XXXXX product did not include documentation that acceptance criteria were established. We have reviewed your response dated July 23, 2010, and have concluded that is inadequate because you promised to re-examine the concerns related to the device history file for the surface applicator and forward the results to the FDA. However, you have not yet forwarded the results to the FDA. 72

73 Scenarios from Warning Letters Failure to establish and maintain adequate procedures for validating the device design to ensure that devices conform to defined user needs and intended uses to include risk analysis, where appropriate, as required by 21 CFR (g). For example, the design plan for the Surface Applicator indicates that validation was completed on June 13, 2010; however, there was no documentation that the pre-determined user needs and intended uses were validated. A review of the risk analysis report and assessment stated that the hazard of thermal penetration beyond the target tissue would be mitigated by user training. There was no evidence of validation of the design for user needs and intended uses and no evidence that this risk was indeed mitigated. We have reviewed your response dated July 23, 2009, and have concluded that it is inadequate because you promised to develop a protocol and conduct a clinical evaluation of the Applicator (Attachment 5-User Needs Document in order to validate the design. You promised to forward the final report to the FDA upon completion and did not. 73

74 Final Words Be Prepared! Get Organized! Set the Tone! John Gagliardi 74