The Quality System Inspection Technique (QSIT) Paul R. Whitby CONSUMER SAFETY OFFICER FDA/ORA/LOS-DO

REGULATIONS code of federal regulations Food and Drugs 21 PARTS 800 to 1299 Revised as of April 1, 1998 Please do not confuse QSIT with the Quality System Regulation Quality System Regulation 21 CFR Part 820

QSIT is an Inspection Technique QSIT Guide Purpose and Importance Objectives Flow charts Narratives Sampling Plans QSIT is not the QS Regulation Preannounce QSIT step towards harmonization

The QSIT Approach What is important is: QSIT focuses on evaluating whether the Quality System and subsystems have been implemented effectively. QSIT acknowledges that nonconforming product and quality problems happen. What is important is: Did the manufacturer identify the nonconforming product or quality problem? Did the manufacturer take effective corrective and preventive action?

QSIT QSIT is a Top down approach Key quality system sub-systems are audited QSIT provides directions for sampling of records The binomial staged sampling plans outlined in the QSIT guide help to indicate what the extent of any deficiencies may be

MANAGEMENT QSIT is based an auditing seven systems Reports of Corrections and Removals Medical Device Tracking Medical Device Reporting Corrective & Preventive Actions Facility & Equipment Controls Design Controls MANAGEMENT QSIT is based an auditing seven systems The four major systems are MC, DC, CAPA and P&PC Production & Process Controls Material Controls Records/ Documents/ Change Controls Sterilization Process Controls

QSIT Focuses on Four Major Subsystems Management Controls Design Controls Corrective & Preventive Action Controls Production & Process Controls

The Three Other Subsystems Facility & equipment controls Product controls Documents, records & change controls

Satellites Sterilization Process Controls are inspected as a satellite system to the Production and Process Controls Subsystem Medical Device Reporting, Reports of Corrections and Removals, and Medical Device Tracking are satellites of CAPA

Management Controls Production & Design Controls Process Controls Corrective & Preventive Actions Equipment & Facility Controls Material Controls Records, Documents, & Change Controls Emphasis is on Management Controls Start and end the inspection with MC Controls

Management Controls - Purpose Provide adequate resources for device design, manufacturing, quality assurance, distribution, installation and servicing Assure proper function of quality system Monitor quality system Make necessary adjustments

Management Controls - Inspectional Objectives 1. Verify that a quality policy, management review and quality audit procedures, quality plan, and quality system procedures and instructions have been defined & documented. 2. Verify that a quality policy and objectives have been implemented. Underlined words are directions of activities to the investigator You can review the QSIT book and see what we are directed to verify

Management Controls - Inspectional Objectives 3. Review the firm’s established organizational structure to confirm that it includes provisions for responsibilities, authorities and necessary resources. 4. Confirm that a management representative has been appointed. Evaluate the purview of the management representative.

Management Controls - Inspectional Objectives 5. Verify that management reviews, including a review of the suitability and effectiveness of the quality system are being conducted. 6. Verify that quality audits, including re-audits of deficient matters, of the quality system are being conducted.

Design Controls-Purpose Control the design process to assure that devices meet: user needs intended uses specified requirements

Focusing the Inspection of Design Controls... 52 Objectives (Design Control Inspectional Strategy) 36 Objectives (Design Control Report and Guidance) 15 Objectives (QSIT)

Design Controls - Inspectional Objectives 1. Select a single design project. 2. For the design project selected, verify that design control procedures that address the requirements of Section 820.30 of the regulation have been defined and documented. Inspectional Objectives for review of DC

Design Controls - Inspectional Objectives 3. Review the design plan for the selected project to understand the layout of the design and development activities including assigned responsibilities and interfaces. 4. Confirm that design inputs were established.

Design Controls - Inspectional Objectives 5. Verify that the design outputs that are essential for the proper functioning of the device were identified. 6. Confirm that acceptance criteria were established prior to the performance of verification and validation activities. sampling tables are used

Design Controls - Inspectional Objectives 7. Determine if design verification confirmed that design outputs met the design input requirements. sampling tables are used 8. Confirm that design validation data show that the approved design met the predetermined user needs and intended uses.

Design Controls - Inspectional Objectives 9. Confirm that the completed design validation did not leave any unresolved discrepancies. 10. If the device contains software, confirm that the software was validated. 11. Confirm that risk analysis was performed.

Design Controls - Inspectional Objectives 12. Determine if design validation was accomplished using initial production devices or their equivalents. 13. Confirm that changes were controlled including validation or where appropriate verification.

Design Controls - Inspectional Objectives 14. Determine if design reviews were conducted. 15. Determine if the design was correctly transferred. What the CSO is directed to do

Using QSIT- Sample Review Confirm Verify

Sampling for Confidence Using Table 1 and reviewing a population of 35 randomly selected records of one type (DHR) and finding just one deviation. The investigator can be 95% certain that less than or equal to only 15% percent of the set of records contain unrecognized non-confirming data points (test results) 15% is the Ucl (Upper confidence Level) The Binomial Sampling tables are used for endpoints that have only two outcomes e.g., the DHR is compliant or not

“Top Down”     Review Design Control Procedures Sample Design Control Records   Review Design Control Records DHF

A “Top Down” Example...     Design Verification Were Design Verification Procedures Defined? Documented?   Sample Design Control Records   Do verification activities confirm that design output meets design input requirements? Does the DHF contain the required information? Verification Records

“Vertical Probes” Design Input Design Output Design Verification Design Validation Design Change Design Review Design Transfer

Design Controls - Review Establish a method for the examination of a design to determine the adequacy of the design requirements, that the design meets those requirements, and to identify problems with the design.

Design Controls - Verification of Outputs Determines if manufacturer did what they intended to do. Verifies output meets input. Confirm by examination and provision of objective evidence that specific requirements have been met

Design Controls - Verification Requirement: Input Test/Exam Method Output

Design Controls - Validation To assure that the device conforms to defined user needs and intended uses Performed under operating conditions with initial production units or their equivalent Actual or simulated use conditions

Design Controls - Transfer To assure the product design is correctly transferred into production specifications Procedures Training Documentation Process Validation Link to Production and Process controls

Corrective and Preventative Actions CAPA often links the systems during an inspection All inspection will include an evaluation of the CAPA system usually with a sampling of some complaint or non conformance information.

CAPA - Inspectional Objectives 1. Verify that CAPA system procedure(s) that address the requirements of the quality system regulation have been defined and documented. 2. Determine if appropriate sources of product and quality problems have been identified. Confirm that data from these sources are analyzed to identify existing product and quality problems that may require corrective action.

CAPA - Inspectional Objectives 3. Determine if sources of product and quality information that may show unfavorable trends have been identified. Confirm that data from these sources are analyzed to identify potential product and quality problems that may require preventive action. 4. Challenge the quality data information system. Verify that the data received by the CAPA system are complete, accurate and timely. sampling tables are used

CAPA - Inspectional Objectives 5. Verify that appropriate statistical methods are employed (where necessary) to detect recurring quality problems. Determine if results of analyses are compared across different data sources to identify and develop the extent of product and quality problems.

CAPA - Inspectional Objectives 6. Determine if failure investigation procedures are followed. Determine if the degree to which a quality problem or nonconforming product is investigated is commensurate with the significance and risk of the nonconformity. Determine if failure investigations are conducted to determine root cause (where possible). Verify that there is control for preventing distribution of nonconforming product. sampling tables are used

CAPA - Inspectional Objectives 7. Determine if appropriate actions have been taken for significant product and quality problems identified from data sources. sampling tables are used 8. Determine if corrective and preventive actions were effective and verified or validated prior to implementation. Confirm that corrective and preventive actions do not adversely affect the finished device.

CAPA - Inspectional Objectives 9. Verify that corrective and preventive actions for product and quality problems were implemented and documented. sampling tables are used 10. Determine if information regarding nonconforming product and quality problems and corrective and preventive actions has been properly disseminated, including dissemination for management review.

CAPA satellite systems Medical Device Reporting (MDR) sampling tables are used Reports of Corrections and Removals (recalls) Medical Device Tracking

Production & Process Controls (P&PC)

P&PC-Inspectional Objectives 1. Select a process for review based on: a. CAPA indicators of process problems; b. Use of the process for manufacturing higher risk devices; c. Degree of risk of the process to cause device failures; d. The firm's lack of familiarity and experience with the process; e. Use of the process in manufacturing multiple devices; f. Variety in process technologies and Profile classes; g. Processes not covered during previous inspections; h. Any other appropriate criterion as dictated by the assignment

P&PC-Inspectional Objectives 2. Review the specific procedure(s) for the manufacturing process selected and the methods for controlling and monitoring the process. Verify that the process is controlled and monitored. sampling tables are used

P&PC-Inspectional Objectives 3. If review of the Device History Records (including process control and monitoring records, etc.) reveals that the process is outside the firm's tolerance for operating parameters and/or rejects or that product non-conformances exist: a. Determine whether any non-conformances were handled appropriately; b. Review the equipment adjustment, calibration and maintenance; and c. Evaluate the validation study in full to determine whether the process has been adequately validated.

P&PC-Inspectional Objectives 4. If the results of the process reviewed cannot be fully verified, confirm that the process was validated by reviewing the validation study. 5. If the process is software controlled, confirm that the software was validated. The QSIT book contains a note in the Sterilization Process Controls section to verify that the manufacturer has assumed responsibility and assured the adequacy of the services of the contract sterilizer including software validation.

Sterilization Process Controls Inspectional Objectives 1. Confirm that the sterilization process was validated by reviewing the validation study. 2. Review the specific procedure(s) for the sterilization process selected and the methods for controlling and monitoring the process. Verify that the process is controlled and monitored. 3. If review of the Device History Records (including process control and monitoring records, acceptance activity records, etc.) reveals that the sterilization process is outside the firm's tolerance for operating or performance parameters: a. Determine whether the nonconformances were handled appropriately; and b. Review the equipment adjustment, calibration and maintenance 4. If the sterilization process is software controlled, confirm that the software was validated. 5. Verify that personnel have been appropriately qualified and trained to implement the sterilization process. I apologize for the small font size, but I wanted to show you the inspectional objectives for the auditing of the Sterilization Process Control Subsystem. This is straight out of the QSIT handbook. I have underlined the reference for

P&PC-Inspectional Objectives 6. Verify that personnel have been appropriately qualified to implement validated processes or appropriately trained to implement processes which yield results that can be fully verified. sampling tables are used

P&PC-Inspectional Objectives At the conclusion of the inspection… 7. Evaluate whether management with executive responsibility ensures that an adequate and effective quality system has been established and maintained.

Closing the Inspection Management Controls (again) Discussion With Management Participants No Surprises List of Inspectional Observations (FDA-483) Annotations (Be Prepared) Response to FDA-483 (What Where When)

FDA 483 Items From FDA Validation Study of QSIT

FDA-483 Annotation Reported corrected, not verified Corrected and verified Promised to correct Under Consideration

Preparation and FDA Transparency IOM CP 7382.845 QSIT MDR C&R 21 CFR Part 11 CFR: 800-1299 FD&C ACT Other

Facilitating the Inspection Be prepared Department of Health and Human Services Arrange for key employees to be available as the inspection proceeds through the QSIT sub-systems If feasible, correct any quality system deviations during the inspection and ask for the Investigator to verify the correction Remember, to correct the lack of an established procedure means more than just writing it. You must also implement it. The Investigator will expect to issue the FDA-483 to the most responsible person on the premises at the conclusion of the inspection Other key managers and professionals are invited to attend the exit interview when the FDA-483 is discussed Send a written response to any FDA-483 to the District Director with a copy to the Investigator Approximately 30 - 60 days after the inspection, you should receive a copy of your Establishment Inspection Report (EIR) written by the Investigator If there is a significant error in the EIR, then write to the District and ask for it to be corrected.

FDA Inspection Aspects FDA Initiatives Preannounced inspections Request for records in advance Quality Policy Quality Manual Quality Plan Management Review Procedures Annotation of FDA-483 Post Inspection letters and FMD-145

Presentation of History of Business Information Organizational Charts Who We Are and What We Make Product Catalog, Labeling, Demos Registration and Listing File 510(k) New Products, New Processes Corrections to Previous FDA-483 Observations

Present Control of Systems/QSIT Quality Policy and SOP Manual Documentation of Management Review Activities CAPA System Record Keeping and Retrieval (Electronic Access)

Communication Daily Agenda Interviews Potential Observations End of Day Recap Briefing Management Morning Recap and Lists

Adjusting the Agenda/Lists Two Copies Please Support for Copying Records Pace, Breaks and Lunch Interruptions Minimizing Surprises

FDA WEB RESOURCES Medical Device Quality Systems Manual http://www.fda.gov/cdrh/qsr/contnt.html QSIT “Guide”: http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm 18. Factory Inspections http://www.fda.gov/cdrh/qsr/18inspn.html Guidance on Medical Device Patient Labeling; Final Guidance for Industry and FDA Reviewers http://www.fda.gov/cdrh/ohip/guidance/1128.html

WWW.FDA.GOV thank you