1. Pre-Market and the QSR Presented by: Dawn Fernandes

2. To Understand:  Why You Need a Quality System  When to Implement a Quality System  Effects of an Inadequate Quality System

3. With the exception of those Class I devices that are exempt from both premarket notification and GMPs, most devices are required to:  Be developed and manufactured according to 21 CFR 820, the Quality System Regulation  Have obtained appropriate premarket approval or clearance prior to distribution in commerce The exemption from premarket notification for certain Class I devices, does not always mean a device is exempt from the QSR requirements.

4. 21 CFR § 820.1 Scope. (a) Applicability. (1) Current good manufacturing practice (CGMP) requirements are set forth in this quality system regulation. The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. The scope is manufacturing, and everything around it – i.e. product realization

5. In addition to the fact that compliance with the QSR is required, following the principles of Design Control as laid out in 21 CFR 820.30 for design and development of a device provides an ordered context that facilitates: Planning Cross-functional communication Clarification of deliverables Identification of design deficiencies Verification that the design satisfies its identified requirements Successful transfer into production.

6. Successful Product Launch ! Higher Costs due to re-work Late Launch Requirements changing Design InPut Review Design Output Review V&V review Design Transfer Review A Poor or Non-Existent QS leads to : The FDA Phase-Gate Approach Encourages Good Project Practices Resource Headcount Months

7. Start of Project Launch to Market

8. Why do we need a Quality Management System if we aren’t even sure what our final device design will look like yet? As long as we have the Quality System in place before we’re doing commercial manufacture, we should be fine, right? Hey, we’re just doing the specification development - we’re not even manufacturing! Can’t we wait to see if our device is even approved by the FDA before we go through all of that trouble?

9. Hey, we’re just doing the specification development - we’re not even manufacturing! Per 21 CFR 820.3 Definitions.  (o) Manufacturer means any person who designs, manufactures, fabricates, assembles, or processes a finished device. Manufacturer includes but is not limited to those who perform the functions of contract sterilization, installation, relabeling, remanufacturing, repacking, or specification development, and initial distributors of foreign entities performing these functions.

10. Can’t we wait to see if our device is even approved by the FDA before we go through all of that trouble? Recall Sec. 820.1 Scope.  (a) Applicability. (1) Current good manufacturing practice (CGMP) requirements are set forth in this quality system regulation. The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. Other points to consider: Some 510(k) submission types require a declaration of conformity to 820.30; and, a PMA will usually trigger an inspection.

11. Can’t we wait to see if our device is even approved by the FDA before we go through all of that trouble? SSec. 820.30(b) Design and development planning. Each manufacturer shall establish and maintain plans that describe or reference the design and development activities and define responsibility for implementation. The plans shall identify and describe the interfaces with different groups or activities that provide, or result in, input to the design and development process. The plans shall be reviewed, updated, and approved as design and development evolves.

12. Why do we need a Quality Management System if we aren’t even sure what our final device design will look like yet?  Sec. 820.30(c) Design input. Each manufacturer shall establish and maintain procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient. ….The approval, including the date and signature of the individual(s) approving the requirements, shall be documented.

13. The answer is that once the idea for a device leaves the proverbial napkin, a QMS must be in place and followed!

14. Start with the basics:  Quality Manual  Management Responsibility  Document & Records Control procedures  Training procedure  Design Control procedures  Risk Management procedures  CAPA, Nonconformances  Change Control

15. Then, add procedures for other elements before they’re actually needed; for example:  Equipment Qualification, Operation, Calibration & Maintenance procedures  Housekeeping and Environmental Control procedures  Test Methods  Purchasing Controls and Vendor Qualification procedures  Validation procedures (VMP? But, that’s another )

16. Some procedures may be implemented later than others as the Quality System develops. The key is to ensure all required procedures are in place prior to conducting activities governed by the procedure. Once a Quality System has been established, it is important to verify its effectiveness through monitoring of key metrics, internal audits and Management Review.

17.  Withholding of regulatory approvals/clearances – rejected submissions  483s or Warning Letters  Injunction or Consent Decree  Customer Complaints  Adverse Events  Recalls  Seizure

18. 2014 – over 590 warning letters issued!!! 2015 – over 375 warning letters issued through May!!!

19.  Depending on the year referenced, the percentage of Warning Letters containing citations related to inadequate Design Controls is around 47 to 61%.  This is one of the most commonly cited subsystems, with Production and Process controls, CAPA, and Complaint file deficiencies rounding out the top categories.

20.  Review the provided Warning Letter  Determine which of the citations you feel may be evidence of a QMS that was not fully implemented prior to development activities  Discuss the implications

21. Distribute hard copy to group

22. What did you find? 3. Failure to establish and maintain adequate procedures for verifying the device design. Design verification shall confirm that the design output meets the design input requirements, as required by 21 CFR 820.30(f). For example: a.Your firm failed to validate the (b)(4) test methods implemented during the Durata design verification testing. These test methods were created in-house to verify your firm’s design inputs; however, they were not based on and did not follow a national standard. b.Your firm failed to follow its test procedure, (b)(4) Rev. D, released 05/09/2003, during design verification testing of the (b)(4). Specifically, the procedure required each lead to be tested 5 times and the mean of the 5 tests would be considered the result. However, your firm only tested each lead one time to determine the results. c.Your firm performed design verification of the Durata lead prior to establishing design inputs. Specifically, your firm performed the design verification study to ensure the (b)(4) was not excessive on June 7, 2007, prior to establishing the design input that “the (b)(4) of the (b)(4) shall be (b)(4)” on July 16, 2007.

23. What did you find? 4. Failure to establish and maintain a design history file for each type of device, as required by 21 CFR 820.30(j). For example, your firm was unable to demonstrate when key elements of a design history file for the Durata design project were conducted and approved, such as design inputs, outputs, verification, validation, and design transfer.

24. Actually, any of the citations in the Warning Letter could be taken as evidence of a QMS that has not been fully implemented, as many of the deficiencies are prefaced with ‘failure to establish and maintain procedures’ for the cited element. The take away message from this solitary example, out of so many like it, is that an effective QMS must be implemented early, must encompass the activities you’re performing, and must be reviewed to ensure effectiveness.

26. Thank you for your participation!!!!