In the eyes of the agency, transferring the design to manufacturing, the ultimate placement of product into commerce, subsequent design changes (if warranted), and sustaining the DHF are all salient requirements. A medical device manufacturer may find it difficult to recover from the dégringolade (look it up if you have to) that can ensue after a forced market recall because a design was not properly transferred, changes to the device were not validated, FDA was not notified of changes for a Pre-Market Approval (PMA) device; or the DHF was not adequately compiled or sustained. That said, please remember Dr. D’s mantra; “compliance to regulations is mandatory.”

Warning letter violation
In this week’s FDA warning letter extraction, the offending medical device manufacturer received five observations against their design control process. The FDA cited issues with validations (subsection g), design changes (subsection i), design output (subsection d), design review (subsection e), and maintaining the DHF (subsection j). Overall, FDA was extremely displeased with this organization’s commitment to design control and compliance with the QSR; and rewarded the organization accordingly, for their general lack of compliance.

Warning letter (December 2009): 1. Failure to adequately establish and maintain procedures for validating the device design, as required by 21 CFR 820.30(g). For example: 

a. Protocol (b)(4), “Stability Testing – Drugs of Abuse Products,” issued 11/20/2000 states that during a (b)(4) Stress Stability Study testing should continue at (b)(4) However, Form (b)(4) “Stability Study Testing Schedule,” dated 02/07/2003 shows that the (b)(4) testing for the Fastect II device (cat # (b)(4) was only performed at start, week (b)(4) and week (b)(4). The study was finished and approved at week (b)(4) without observing (b)(4).

b. Protocol (b)(4) “Stability Testing – Drugs of Abuse Products,” issued 11/20/2000 states that (b)(4) lots of a device must pass (b)(4) and (b)(4) storage stability studies to validate and/or change the shelf life claim. The oven stress testing (b)(4) should continue (b)(4). However, Form (b)(4), rev C, “Stability Study Testing Schedule,” completed on 08/18/2003 shows that the (b)(4) testing for the Fastect II device (cat#(b)(4))was performed using only one lot and only performed at start, weeks (b)(4) and (b)(4). The study was finished and approved at week (b)(4) without observing (b)(4).

c. When requested, no accelerated or real time stability studies were provided to support the QuickTox Multi Drug Dipcard’s expiration date.

d. Protocol (b)(4), rev. C, “Stability Testing – Urine Drugs of Abuse Products,” issued 01/16/2004 states that during a (b)(4) Temperature Stability Study testing should continue at monthly intervals until the (b)(4) for (b)(4) consecutive months or until product (b)(4) months storage. The procedure only requires that the test be read at (b)(4) minutes. However, the device’s instructions for use indicate that the test can be read up to 60 minutes.

e. Document (b)(4), Rev. A, “MET-500 Shelf-Life Stability Study,” dated 4/01/2000 and Document (b)(4),Rev. A, “MTD: Shelf-Life Stability Study,” dated 4/01/2000 indicate that the product should be tested at monthly intervals (b)(4) However, test results show that the studies were stopped at (b)(4) and (b)(4) weeks respectively (b)(4).

f. The firm’s Fastect II, Fastect II CLIA Waived, and QuickTox device package inserts include claims for accuracy and precision, and read-time. When requested, no raw data, protocols, or final reports were provided to support these claims.

g. The real time stability study to extend the shelf-life of the Fastect II device from (b)(4) months to (b)(4) months is dated 5/9/2008. However, the raw data is dated 6/24/2008 and 2/12/2009.

2. Failure to adequately 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 820.30(i). For example:

a. The firm submitted a Special 510(k) submission on July 15, 2009, to (b)(4) the Monitect Single Drug Screen Dipstick Test into the QuickTox Multiple Drug Dipcard and to (b)(4) the test strips.
When requested, the firm did not provide any verification or validation protocols or data to support these changes.

b. The firm notified FDA on February 25, 2005, of a modification to the QuickTox Multi Drug Dipcard. The new device, the Fastect II Drug Screen Dipstick Test, was a change from a dipcard to a (b)(4). When requested, the firm did not provide any verification or validation protocols or data to support this change. 

c. “Project 004 (Fastect II – CLIA. Waive)” includes a change in the (b)(4) of the Fastect II strips and holder from (b)(4) to (b)(4). When requested, the firm did not provide any verification or validation protocols or data to support this change.

d. The firm notified FDA on October 16, 2002, of (b)(4) to the QuickTox Multi Drug Dipcard. Changes to the device included (b)(4) for (b)(4) and (b)(4) from (b)(4) to (b)(4) and (b)(4) to (b)(4) respectively. When requested, the firm did not provide any verification or validation protocols or data to support this change.

3. Failure to adequately establish and maintain procedures for defining and documented design output including documenting, reviewing, and approving design outputs before release, as required by 21 CFR 820.30(d). For example, Form (b)(4),Rev. A, “Product Technical Specifications (PTS),” dated 4/09/2004 for the CLIA Waive Fastect II device does not document any design outputs. When questioned, the firm stated that they did not establish any final design outputs.

4. Failure to adequately establish and maintain procedures to ensure that formal documented reviews for the design results are planned and conducted at appropriate stages of the device’s design development, as required by 21 CFR 820.30(e). For example, the design history file for “Project 004 (Fastect II – CLIA Waive)” does not contain documented design reviews for Phase IV Pre-Production, Phase V Design Verification, or Phase VI Design Validation.

5. Failure to establish and maintain a design history file for each type of device, as required by 21 CFR 820.30(j). For example, when requested, the firm indicated that they did not establish a design history file for the QuickTox Multi Drug Dipcard.

Quality system regulation – 21 CFR, Part 820 Subpart C Sec. 820.30 Design controls

Section	Device
868.6810	Catheter, Tracheobronchial Suction
878.4460	Glove, Surgeon’s
880.6760	Restraint, Protective
892.5650	System, Applicator, Radionuclide, Manual
892.5740	Source, Radionuclide Teletherapy

(a) General. 
(1) Each manufacturer of any class III or class II device, and the class I devices listed in paragraph (a)(2) of this section, shall establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met.
(2) The following class I devices are subject to design controls:
(i) Devices automated with computer software; and
(ii) The devices listed in the chart.

(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.

(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 procedures shall include a mechanism for addressing incomplete, ambiguous, or conflicting requirements. The design input requirements shall be documented and shall be reviewed and approved by a designated individual(s). The approval, including the date and signature of the individual(s) approving the requirements, shall be documented.

(d) Design output. Each manufacturer shall establish and maintain procedures for defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements. Design output procedures shall contain or make reference to acceptance criteria and shall ensure that those design outputs that are essential for the proper functioning of the device are identified. Design output shall be documented, reviewed, and approved before release. The approval, including the date and signature of the individual(s) approving the output, shall be documented.

(e) Design review. Each manufacturer shall establish and maintain procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the device’s design development. The procedures shall ensure that participants at each design review include representatives of all functions concerned with the design stage being reviewed and an individual(s) who does not have direct responsibility for the design stage being reviewed, as well as any specialists needed. The results of a design review, including identification of the design, the date, and the individual(s) performing the review, shall be documented in the design history file (DHF).

(f) Design verification. Each manufacturer shall establish and maintain procedures for verifying the device design. Design verification shall confirm that the design output meets the design input requirements. The results of the design verification, including identification of the design, method(s), the date, and the individual(s) performing the verification, shall be documented in the DHF.

(g) Design validation. Each manufacturer shall establish and maintain procedures for validating the device design. Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents. Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions. Design validation shall include software validation and risk analysis, where appropriate. The results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the DHF.

(h) Design transfer. Each manufacturer shall establish and maintain procedures to ensure that the device design is correctly translated into production specifications.

(i) Design changes. Each manufacturer shall establish and maintain procedures for the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation.

(j) Design history file. Each manufacturer shall establish and maintain a DHF for each type of device. The DHF shall contain or reference the records necessary to demonstrate that the design was developed in accordance with the approved design plan and the requirements of this part.

Design transfer (subsection h)
So when does the actual transfer of a newly designed medical device occur? According to Dr. D, design transfer occurs after the successful completion of all verification and validation activities. Typically, the decision to transfer is made during the final design review. As part of this last design review, the team will make the decision to transfer the design to manufacturing and the eventual commercialization. Another important milestone needing to occur, prior to the design transfer, is the completion of all documentation needed in support of the successful manufacture of the newly designed medical device.

For example, all assembly drawings, bills of material, routers, special processes, inspection criteria, test criteria, acceptance criteria, etc. must be approved and released within the document control system. Additionally, Dr. D. insists that all procured material that will be employed in the manufacture of the newly designed medical device successfully pass First Article Inspection (FAI) and subsequent receiving inspection.

That said, the documentation required as part of the design transfer should encompass the purchasing and receiving inspection processes specific to the newly designed device, a topic Dr. D. will begin exploring in a future edition of DG. Finally, please ensure your regulatory affairs group has received proper clearance, PMA, 510(k), or IDE, prior to moving into commercialization; otherwise, you will need to commit to memory a very bad six-letter word: RECALL!

Design changes (i)
I find it amazing that medical device manufacturers continue to make changes to their devices while failing to properly validate changes, or worst yet, failing to notify the agency when significant changes are made. As many of the readers are already aware, a medical device manufacturer voluntarily withdrew their implantable devices in March, when design (process) changes were made, and the changes were not reported to the agency, via a PMA supplement, for the agency’s review and approval. The PMA supplement was quickly assembled and submitted to the agency. The agency completed their review within 30-days and issued their formal approval.

Dr. D’s rule of thumb is to become friendly with FDA’s local office and ask them for guidance when the magnitude of a proposed design or process change is in question. If FDA recommends filing a 30-day supplement for a PMA device, you file. There is no need for further discussion. Broken record time again – this is not rocket science, as the requirements for design control are cut and dry.

That said, regardless of device classification or regulatory path for clearance, all design changes need to be assessed for effect of changes on the finished medical device, including; (a) impact on the device user, (b) impact on the overall safety and efficacy of the device, and (c) the regulatory impact in regards to review and approval of all changes by the agency. Regulatory assessments should be performed by regulatory affairs’ specialists, novel concept right? Dr. D recommends creating a form for completing regulatory assessments. Additionally, ensure regulatory affairs’ specialists are reviewers and signatories on all design changes, period! Furthermore, regulatory assessments should become an attachment is support of all documentation associated with each design change.

Finally, broken record time – when in doubt – contact your local FDA office, when there is a question or concern pertaining to the specific regulatory path, in regards to notifying the FDA over potential design changes.

Design history file (j)
Lastly, but surely not the least important requirement associated with design control, is the DHF, the receptacle for all documentation associated with the entire design and development process, including design changes made after design transfer. Documentation placed into the DHF should include (not an all-inclusive list):

1. Design and development plan;
2. Market specification;
3. Product specification;
4. Verification protocols;
5. Validation protocols;
6. All procedures defining the design and development process;
7. Design reviews;
8. Test reports;
9. Drawings;
10. Specifications;
11. Bill of materials;
12. Routers;
13. Subsequent design and process changes; and
14. All remaining documentation related to device design and development.

Conclusion: Design and development a womb to tomb scenario
In conclusion, work associated with the design and development of medical devices does not end with the transfer of the design to manufacturing and the subsequent introduction of the device into commerce. In fact, design changes and updates to the DHF will continue throughout the entire life of the medical device. In reality, the design and development process becomes a womb to tomb scenario. Significant attention to detail should be given to actual design transfer activities. Few things are more frustrating for the production department then the receipt of a newly designed device that cannot be manufactured in accordance with the recently released transfer package, due to errors or omissions within the bills of material, routers, assembly instructions, etc. Additionally, when design and/or process changes are warranted, ensure the regulatory affairs group performs an adequate assessment of the changes and adheres to the proper path for FDA notification.

Finally, remember the importance of the DHF. The DHF needs to be sustained until the last medical device is entered into commerce and/or consumed, and then some. In short, Dr. D calls the DHF a forever document; and the primary source of evidence for proving compliance to the design control requirements of the regulation.

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG, when I begin discussing Subpart – D Document Controls  – cheers from Dr. D. and best wishes for continued professional success.

References:

1. Code of Federal Regulation. (2009, April). Title 21 Part 820: Quality system regulation.  Washington, D.C.: U. S. Government Printing Office.

2. Devine. C. (2009, July). Exploring the effectiveness of defensive-receiving inspection for medical device manufacturers: a mixed method study. Published doctoral dissertation. Northcentral University. Prescott Valley, AZ. 

3. FDA – U.S. Food and Drug Administration Website. (2010). Warning letters. Retrieved May 10, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/