The design control requirements delineated within 21 CFR, Part 820 – Section 820.30 continue to cause significant consternation for the medical device industry. The regulation is very specific in regards to the elements required for an effective design control process. Long gone are the days of working off the proverbial napkin drawings or the concept of a freewheeling research and development (R&D) group operating in the proverbial vacuum. In today’s medical device manufacturing environment, FDA expects compliance with all aspects of 21 CFR, Part 820. Yes – I know Dr. D is probably sounding like a broken record; however, fail to adhere with DG Rule # 1 – Compliance to regulations is not optional, compliance is mandatory and dictated by law; and you will find your organization facing the wrath of the agency.

That said, the design control portion of the regulation is too much material for Dr. D to cover in one week, so I will spend the next few weeks breaking it down into smaller sound bytes. In this edition, I will examine subparts (a) general requirements, and (b) design and development planning.

Warning letter violation
While surfing FDA’s warning letter database, the violations noted against design control and documented within FDA issued warning letters were numerous. In fact, the agency is so concerned about design control and the overall effect this exudes on the safety and efficacy of medical devices that it is possible to receive several Form 483 observations for failing to comply with multiple subsections of design control.
In this week’s edition, I present one example in which the offending manufacturer received a warning letter depicting SIX specific violations of the code, including subsections. Premised on the warning letter extraction presented in this edition, the investigator was thoroughly displeased with the level of compliance exhibited by this medical device manufacturer.

Warning Letter (March 2010):
1. Failure to establish and maintain adequate 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, as required by 21 CFR 820.30(c). For example procedures for Version (b)(4) EGG machine in (b)(4) or for the upgrade made to the Research Version device in (b)(4) which included a new Research Waterload Version and a Waterload Version.

2. Failure to establish and maintain adequate procedures for defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements, as required by 21 CFR 820.30(d). For example:

a. When requested, design output procedures and/or requirements for the upgrade from Version (b)(4) to Version (b)(4) done by (b)(4) and for the upgrade from Version (b)(4) Research device to Versions (b)(4) Research, Research Waterload device (b)(4) done could not be provided.
b. When requested, no evidence that design outputs were established and evaluated against design inputs document (b)(4) was provided.
c. There is no record of review and approval of device labeling, including review and approval of the labeling for the Research Version (b)(4) released (b)(4)

3. Failure to establish and maintain adequate procedures to ensure that formal documented reviews of 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, procedures were not established to ensure formal documented reviews of the design during the design planning process.

4. Failure to establish and maintain adequate procedures for verifying the device design and documenting the results of the design verification, including identification of the design, method(s), the date, and the individual(s) performing the verification, as required by 21 CFR820.30(t). For example:

a. When requested, no documentation to confirm that the finished product conformed to specified requirement as stated in the (b)(4) was provided.
b. The design plan identifies what testing will be done to ensure general assembly requirements are met; however, when requested, the documentation to support testing that was performed on the following activities could not be located: (1) Test Type CF EGG Lead on CWE Head Stage, (2) Test Type B on Respiration Connection, and (3) Verify Cart – Tip Test.

5. Failure to establish and maintain adequate procedures for validating the device design, as required by 21 CFR 820.30(g). For example:

a. When requested, no evidence to show that the validation test was performed as stated in Test Report (b)(4) was provided.
b. When requested, no evidence to support that the finished device was validated to include validation with the EGGSAS software was provided.
c. The Failure Modes Effect Analysis FMEA described in (b)(4) does not define the Average Likelihood of Occurrence (ALOO) for each value.

6. 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). For example:

a. When requested, no procedure identifying how design changes made to the device are processed was provided.
b. When requested, no evidence that the changes made to the finished device or the Research, Research Waterload, or Waterload software versions were verified or validated to ensure that the changes are effective and did not adversely affect the finished product was provided.
c. When requested, no evidence to support the device software update from Research Version (b)(4) to Version (b)(4) was verified to meet design requirements as stated in the (b)(4) was provided.
d. When requested, no documentation to support that the changes to EGGSAS software were verified to demonstrate the functionality was provided.

Quality System Regulation – 21 CFR, Part 820

1. QSR – Subpart C – Design Controls: 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 Control General Requirements
Design Control regulation (subpart a) specifically requires that medical device manufacturers establish, in writing I might add, procedures that delineate the manufacturer’s specific requirements for designing Class II and Class III medical devices, and Class I devices, as depicted in the above table. Basically, the agency wants to ensure all of the design requirements, for medical devices, are achieved. The fundamental logic here is simply that “adherence to a strong design control philosophy will result in the development of medical devices that are safe and effective.”

Additionally, most medical device manufacturers employ the concept of a market specification, and not a napkin drawing to convey the basic requirements for a device. This market specification drives the specific product and design requirements that ultimately reside within the product specification. Finally, the product specification drives the design verification and validation testing and delineates all of the critical characteristics that require monitoring throughout the entire design, development, manufacturing, and post-market surveillance processes.

All of the specifications, drawings, test results, reports, validations, inspections etc., in support of design, need a home. In the eyes of FDA, this home is the design history file, or the DHF. Rest assured, the agency will review DHFs during each friendly visit and may make the review of the DHF the omphalos (look it up if you have to) of their visit. Remember, the DHF is a dynamic receptacle for documents. The FDA requires that all relevant information influencing the device design be captured during the entire product life cycle, including product labeling, with the resultant data, reports, etc. placed into the DHF and retained as proof of compliance. Just like any process a good rule of thumb to remember is, “garbage in equates to garbage out.”

Design and Development Planning
The path toward compliance with Subpart b is the creation of a fundamentally sound plan for design and development. The design and development plan should contain sufficient granularity in regards to clearly specifying all of the required deliverables associated with a specific design project. Additionally, the design and development plan is a controlled document and should be reviewed and approved by a cross-functional team. For example, R&D, quality, manufacturing, regulatory affairs, clinical, marketing, etc., should have input and ultimate approval authority for this plan, apart from including management in the approval cycle to ensure that there will be no surprises when the design reviews are held. Finally, ensure the plan becomes a part of the DHF.

So what are the salient deliverables associated with a well-defined design and development plan? First and foremost, a project charter and contract are warranted which delineate scope of the program, deliverables, timelines, exemptions, etc. Additionally, all project team members, stakeholders, and the appropriate management representatives should review and approve the contract.

The next phase is to create an actual design and development plan. Dr. D has witnessed multiple approaches to this phase: Some organizations create a high-level project plan that points to subservient plans for accomplishing specific tasks, e.g., design validation, quality, regulatory, etc. I prefer one plan that contains sufficient granularity to support the design and development process, while complying with QSR requirements. Besides, all of the protocols and reports will be individual deliverables anyway.

As part of the design and development plan, the following list (while not all-inclusive) captures potential activities that should be assessed for inclusion in the plan:

1. Design verification activities;
2. Design validation activities;
3. Quality requirements;
4. Regulatory requirements;
5. Creation of DHF;
6. Design approval and transfer activities;
7. Labeling requirements;
8. Clinical requirements;
9. Special testing requirements, e.g., DEHP; and
10. All additional requirements deemed relevant by the project team.

Remember, adhering to a robust design and development process should result in the design of a quality medical device that is safe and effective.

Conclusion: No perfect model, only a compliant one
There is no perfect model in regards to the design and development process, only a compliant model. Contents of the design control system will be driven in part due to organizational structure and the type of medical device being designed. The key for compliance to the regulation and the successful design and development of a medical device, that is safe and effective, is the planning. As always, detailed and accurate documentation is required to support claims of compliance to the QSR. The agency will want to review the DHF, especially if product problems result in recalls. Remember, DG Rule # 3 – Document the results of all events in writing, because if it is not documented, in writing, the event did not occur.

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment, when I continue discussing Section 820.30 Design Controls; subsections (c) design input, (d) design output, and (e) design review, 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 27, 2010, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/
   

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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).