I hope that the readers of DG are able to glean some useful information from Dr. D’s frequent flights of rodomontade (look it up) pertaining to the need for compliance with regulations. As I emphatically opined in the previous edition of DG, medical devices that are safe and effective are born from a robust design and development process. Although I cannot speak on behalf of the agency, it would be a subreption of the regulations if I did not continue to state the overall importance of design control for the medical device industry and the continued need for compliance with the regulations. In this edition of Devine Guidance (DG), Dr. D will continue with his dissection of the FDA’s requirements for effective design control, with a focus on design input, design output, and design review (Subsections c, d, and e).

Warning letter violation
Since the inception of Devine Guidance in January of this year, I have continued to pontificate in regards to the importance of having written policies and procedures. In just about every single warning letter I have read, a common thread observed is the lack of procedures or compliance with procedures. I have some difficulty in comprehending how a medical device manufacturer can fail to grasp a simple concept such as having WRITTEN PROCEDURES! HELLO! Ok, I have gotten that out of my system.

In this week’s warning letter extraction, multiple violations are noted against the FDA’s design control requirements, including the lack of Written Procedures! Hello!!! (Oh well, now I think I have it out of my system).

Warning Letter (February 2010): Failure to establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met as required by 21 CFR § 820.30(a). Specifically, your firm has no design control procedures to control the design process of your device. Your firm has failed to establish a plan for the changes made to your MICRON 400 UV & 800 UV devices to determine the adequacy of the design requirements and to ensure that the design that was released to production meets the approved requirements.

Failure 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 § 820.30(i). Specifically, your firm has failed to establish and maintain design control procedures for the design changes that were made to your devices during the months of May and June of 2009. For example, your firm has made changes to the design of your MICRON 400 UV & 800UV devices by adding an (b)(4) in order to verify that the UV lamps inside the device were in working condition, and also a (b)(4) to turn off or not turn on the (b)(4) when the HEPA filter is being replaced. Your firm must establish a criterion for evaluating changes in order to ensure that the changes are appropriate for its designs.

Failure to establish and maintain a design history file for each type of device as required by 21 CFR § 820.30(j). Specifically, there were no design history files for the following devices: MICROCON 400M, 400UV, 800M, 800UV, WallMAP, WallMAP PC, Ex-BB, and ExC-BB. For example, your MICROCON 800M PREPARATION LIST does not 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 (21 CFR § 820.30). Your firm has failed to document the complete history of the design process where such records are necessary to ensure that the final design will conform to the design specifications.

FDA – Response: We have reviewed your response and have concluded that it is inadequate because there is no indication that you have implemented adequate written procedures to address the design control violations documented by our FDA Investigator on the FDA-483 that was issued to you.

Quality system regulation – 21 CFR, Part 820

1. QSR – Subpart C Sec. 820.30 Design controls

(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 input (subsection c)
A fundamental concept associated with the design input requirement is the need to understand that design input equates to design requirements. As mentioned in the previous edition of DG, market specification and product specification are two key design input deliverables. Medical device manufacturers need to ensure that the device requirements defined as part of the overall design and development process are appropriate for the device. As a minimum, the requirements must focus on the intended use of the device, the user requirements for the device, and the person at the receiving end of the treatment, a.k.a., the patient.

For example, if your organization is developing catheters for the treatment of arrhythmias, some of the design inputs evaluated for consideration might be rigidity of the catheter shaft, insertion force into the introducer sheath, maneuverability of the catheter in the right atrium, or the potential length of the procedure. A test for analyzing the impact of leaving the catheter in the body for 30 days is probably not a realistic input requirement. Additionally, design inputs must be captured in a written document. That document needs to be reviewed and approved by the appropriate level of authority within the organization, including all of the usual suspects, R & D, quality, regulatory, marketing, medical sciences, manufacturing, etc; and make sure each approval signature is accompanied by a date.

Furthermore, procedures associated with design control; and specifically design inputs need to have a feedback loop built into the document. The feedback loop can be employed as a vehicle for addressing incomplete, ambiguous, or conflicting requirements. Dr. D. loves flow charts; and creating one as part of the design control process is strongly recommended.

Finally, guess where all of the documents and deliverables associated with defining the design inputs are going to be stored? Can you say Design History File (DHF)? As you continue through the entire design control and development process, the DHF becomes a living receptacle, capturing the entire process. Remember, FDA will dive into the DHF, either at submission time or during one of their friendly visits, so it should be deemed a mission-critical activity keeping the contents of the DHF current.

Design output (subsection d)
The logical predecessor to the design input is a design output; and yes, Dr. D thought that up all by himself. Claiming the “this is not rocket science clause,” the design outputs consists of determining if the design inputs meet their predefined requirements.

Dr. D would like to introduce a new FDA acronym now. The Device Master Record (DMR) can be categorized as a design output document, along with all of the protocols and validations that will be employed to verify the design inputs. As part of the evaluation of design inputs and the resultant outputs, the acceptance criteria employed as part of evaluating the design outputs must be defined. Using the catheter example, working length is probably important. Defining how the working length will be evaluated becomes part of the design output. If the catheter’s working length is 100cm long, employing a 6-inch steel rule for ascertaining the actual working length is probably not a reasonable approach. In fact, have fun validating that test method. Once the quality manager stops laughing hysterically, he will probably throw you out of his office.

Similar to the previous section on design input, all characteristics that reflect the proper operation of the proposed design need to be identified and validated. Additionally, the design outputs shall be documented, and the results reviewed, approved, signed, dated, etc. Similar to the design input deliverables, all design output documentation and deliverables shall be placed securely into the DHF. Can you see the trend? 

Design review (subsection e)
Medical devices are typically not designed or developed in a short period of time or in a vacuum. The design and development process typically occurs in phases with actual stop gates put into place so reviews can be held to ascertain the progress against the actual design and development plan. Design reviews are employed as tools to ensure adequate oversight is exuded over the entire design process, from design inception to initial market release. As a medical device manufacturer, you never want to reach a point in the design and development process where: (a) the organization finally realizes that too much money has been spent; (b) the device will never work as designed; or worse, (c) there is no potential of any possible return on the investment, regardless of the benefits of the newly designed medical device.

That said, design reviews need to be a structured event with all of the key stakeholders in attendance. Attendance should be mandatory and if a quorum is not in attendance, the review needs to be rescheduled (after remembering to send out flame mails to the offending individuals that failed to make attending the review a priority).

Dr. D strongly recommends allowing outsiders, no not competitors or family members, but organizational members not connected to the specific design and development project to attend the reviews. For example, a manufacturing supervisor, inspection supervisor, clinical affairs person, procurement manager, or an individual not close to the project may bring some additional insight into the review that the design team may have missed. Specialists such as a polymer engineers, chemists, toxicologists, etc. can be added to support the review.

Now comes Dr. D’s broken record time. The entire design review process shall be documented by a WRITTEN PROCEDURE; and the entire design review captured in meeting minutes, including the results of the review, decisions made, attendees, dates, etc. and placed into the DHF.

Conclusion: Compliance premised on well-written procedures
I do not find compliance to the quality system regulations particularly challenging or complex. Compliance, in Dr. D’s opinion, is premised on well-written procedures, training, accurate documentation/records, and the ability to pursue corrective action when systemic adjustments are warranted. Effective design control essentially contains these same four elements. As I have stated several times over the past two weeks, “an effective design and development process results in the creation of medical devices that are safe and effective.

In closing, thank you again for joining Dr. D. I hope you find value in the guidance provided. Until the next installment, when I continue discussing Section 820.30 Design Controls, subsection (f) design verification and (g) design validation, 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 April 30, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/  

About the Author:
Dr. Christopher Devine has 30 years of experience in the field of quality assurance, working in several industries. Currently, he works as a Senior Manager for a Fortune 500 Medical Device Company, where he manages the recertification of medical devices sold outside the United States, and was one of the principle contributors in the development of his organization’s supplier quality system. Additionally, Dr. Devine received his doctorate from Northcentral University titled, “Exploring the Effectiveness of Defensive-Receiving Inspection for Medical Device Manufacturers: A Mixed-Method Study.”  He also holds a graduate degree in organizational management (MAOM) and an undergraduate degree in business management (BSBM). Dr. Devine is a senior member of the American Society for Quality (ASQ) a member of the Regulatory Affairs Professionals Society (RAPS) and a member of the Project Management Institute (PMI).