How to Develop an Effective Design Control Program: A Life-Cycle Multi-Phase Approach

Transcription

1 GMP How to Develop an Effective Design Control Program: A Life-Cycle Multi-Phase Approach Jackelyn Rodriguez This article provides a life-cycle methodology in a multi-phase approach that includes an effective design control process. Emphasis is put on the practices employed to control the various design and development phases, the transfer phase, and the post-design control phase of new medical devices (products and accessories). The post-design control phase comprises necessary changes based on postmarket surveillance feedback. This paper discusses a systematic multi-phase, life-cycle design control program approach that will ensure full compliance with CFR , Design Controls. INTRODUCTION The US Code of Federal Regulations Title 21 CFR Design Controls (1) requires that Each manufacturer of any class III, class II, (and some specified class I devices) shall establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met. Also, medical device manufacturers are responsible for establishing and maintaining procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the device s design development. This paper discusses a systematic multi-phase, life-cycle design control program approach that will ensure full compliance with the CFR. The design control process is part of a larger system of checks and balances that the medical device manufacturer should already have in place as part of their overall development plan. Definition of the process is important because the design control guidelines are not intended to apply to the research and feasibility stages of product development. The debate lies in determining when feasibility ends and development begins. A comprehensive product development process with specific milestones and development phases can alleviate any questions. This article was written to provide a life-cycle methodology in a multi-phase approach that includes an effective design control process. Emphasis is put on the practices employed to control the various design and development phases, the transfer phase, and the post-design control phase of new medical devices (products and accessories). The post-design control phase comprises changes that are needed based on post-market surveillance feedback. One of the weakest areas in design control is in the connection to post-market surveillance and/or postproduction reviews. These post-production reviews may indicate necessary changes as a result of data trends such as complaints and adverse events. Recently there has been an increase in the number of US Food and Drug Administration Warning Letters issued to manufacturers because of inadequate design control, inadequate complaint handling, incomplete failure investigations, failure to link complaints to existing risk analysis, and more important, the failure to update the risk analysis to include new product failures (hazards) in an effort to mitigate such failures. The capturing and analysis of post-market data through complaint handling systems/trending/failure investigations should be evaluated by the firm against their original risk analysis performed during the design and development of the device. 74 Journal of GXP Compliance

2 Jackelyn Rodriguez TABLE I: Design control and risk management activities. Design Step/Phase Risk Management Activities Risk Management Output Design and development planning Design input Design Verification and validation Design reviews Design transfer Design change control Identify intended use and hazards Risk management Plan commensurate with risk Hazard identification Risk estimation Risk estimation and risk evaluation Design mitigations Determine essential outputs Traceability analysis test in normal and fault modes V&V activities commensurate with risk Risk evaluations review risk acceptability Risk and safety part of decision processes Process risk assessment Final safety decision Re-assess existing and potential new hazards/risks Hazards list Risk management plan Preliminary or initial hazards analysis Fault tree analysis Failure modes effects analysis (FMEA) Traceability matrix V&V test results Risk decisions Justify residual risk FMEA Risk summary report Updated risk documents REAL-TIME FEEDBACK FOR CONTINUOUS IMPROVEMENT The best quality system models cause a documented investigation of the problem and clearly link to the design history file for performance of risk analysis. They also have real-time feedback for continuous improvement. This kind of feedback ensures related complaints are categorized properly to aid in the investigation, risk assessment, and corrective preventative action activities. This is especially important if the original design activities did not anticipate the failure mode, and a new complaint category is needed. The best models have complaint handling codes/defect codes that correlate systematically to the design inputs and outputs for each device manufactured and are managed formally and continuously over time to ensure that any new design issues or new human factors that may impact the device are addressed adequately. Post-production review should be performed to ensure that new hazards are identified and properly mitigated thru design control changes as needed. INTEGRATING RISK MANAGEMENT AND DESIGN CONTROL Risk management is a process consisting of well-defined steps that, when taken in sequence, support better decision-making by contributing to a greater insight into risks and their impacts. It includes elements such as risk identification, assessment, mitigation, elimination, and communication. Medical device design control regulations and standards (1-5) require risk analysis according to the following: Risk analysis must begin early in the product development lifecycle (e.g., at planning phase) and as part of establishing design refinements Risk analysis must assess risk throughout development. Table I shows the design stages, the risk management activities per phase, and the deliverables expected at the completion of each phase. Figure 1 shows the design and development process. Design reviews are required to be held at the completion of each design phase. Participants at each design review must include representatives of all design Summer 2008 Volume 12 Number 4 75

3 GMP Figure 1: Design and development process flow chart. Phase I Design Concept Concept Description Preliminary Schedule Marketing Plan Risk Assessment Regulatory Assessement Concept Review Phase VI Design Validation In Vitro Testing Biomechanical Testing In Vivo Testing Cadaver Testing Clinical Testing Design Validation Review Phase II Design Development Plan Flowchart / Gantt Chart Development Plan Review Phase III Design Input Product Requirements Document Software Requirement Specification Risk Analysis Phase VII Design Transfer Production Facility Qualification Production Process Validation Inspection Test Method Validation Manufacturing Procedures Production Schedules Final Risk Analysis Design Transfer Review Design Input Review Phase IV Design Output Drawings Hardware Design Description Software Code Software Design Description Purchasing Specs Component Specs Packaging Specs Labeling Bill of Materials DMRI Test Standards Loaner Product Acceptance Criteria Change Notice Form (CN) PRODUCTION Design Output Review Phase V Design Verification Hardware Verification Environmental Testing Software Verification BiocompatibilityTesting Sterilization Validation Packaging Validation Risk Trace Matrix PRD Trace Matrix SRS Trace Matrix Essential Requirements Checklist Design Change Design Change Checklist New Revs of Affected Documents Change Notice Form Updated Risk Analysis Design Change Review Design Verification Review stage functions, an individual who does not have direct responsibility for the design stage being reviewed, and any specialists needed. Table II shows a list of roles and responsibilities. DESIGN CONTROL PHASES Phase I: Design Concept The least structured of the design phases, design concept is the point at which management authorizes adoption of a design concept and commits manufacturer resources to its further development. Issues that should be considered by management in the development of a new product should include, but need not be limited to the following: Commercial viability of the product Financial analysis, including potential sales/margins versus costs of production Viability of commercial markets (e.g., US, European Union [EU], etc.) Patent position Potential risk and liability exposure versus potential benefit to public health Preliminary regulatory assessment. Design concept can be documented by a memorandum to file, or equivalent, from management. It should contain the following, at a minimum: Identification of a project leader for the design project 76 Journal of GXP Compliance

4 Jackelyn Rodriguez TABLE II: Design stage roles and responsibilities. Role Engineering Quality assurance Project leader Regulatory affairs Design review team, committee, or board Operations/purchasing Responsibilities Assigning a project leader to each design and development project having adequate qualifications and authority to manage the design and development process Assuring that the design and development process is supported by adequate staff and resources, and that all staff participating in the design and development process have adequate training in product design and related areas Assuring that adequate design protection is maintained (e.g., through patent or trade secret protection, non-disclosure agreements, etc.). Assuring that all design and development activities are conducted in conformance with applicable manufacturer policies and SOPs, and with the provisions of Title 21 CFR, Part 820, ISO 13485, and other recognized and applicable guidance Serving on the design review team Reviewing all documentation generated in the formal design review process to assure that it has been appropriately compiled, is complete, and has been reviewed and approved by the design review team Approving completed design review documentation, and forwarding same to document control for inclusion in the design history file (DHF) Maintaining all design and development documentation in an appropriately controlled DHF, in accordance with manufacturer record retention requirements. Assuring that a design and development plan is drafted, approved by the design review team, and is followed and updated as necessary throughout the design process Selecting, from appropriate and qualified persons, those individuals who will serve on the design review team in addition to the required quality assurance (QA), regulatory, and independent engineering representatives, to assure that the team embodies all expertise and experience relevant to the product under consideration Scheduling, conducting, and documenting design review meetings at appropriate times in the design process Assuring that all information subject to review by the design review team is distributed to review team members in a timely fashion Serving as chairperson in design review meetings and assuring that accurate minutes are taken to record the transactions of said meetings Assuring that all unresolved or outstanding issues identified in formal design review are resolved, and that the resolution is documented. Assuring that, where a device is intended to be distributed commercially within the US, it conforms to all regulatory requirements of the US Food & Drug Administration Assuring that, where a device is intended to be distributed commercially within the European Community, that all applicable essential requirements described in Council Directive on Medical Devices 93/42/EEC, Annex I, have been satisfied Assuring that, where a device is intended to be distributed commercially within the European Union, that a technical file has been prepared in accordance with creation of technical files requirements, to support a declaration of conformity for that device Assuring that, where a device is intended to be distributed commercially within another foreign nation, it conforms to all regulatory requirements of the health authorities of that nation. Providing input, as appropriate, to the project leader during the design and development of a new device, or a significant change to an existing device Reviewing all design and development progress at designated review times in the development process and documenting the results of that review. Participates in qualification and approval of suppliers. Participates in and approves transfer to production. Summer 2008 Volume 12 Number 4 77

5 GMP TABLE III: Design input phase deliverables. Product requirement document Design input can be documented in a product requirements document Software requirements specification If the device contains software, a software requirement specification (SRS) should be prepared. The SRS lists all requirements for the device software and is used as a basis for functional testing. In this phase, a system risk analysis (SRA) should be prepared which contains a detailed hazard analysis (e.g., FMEA and/or FTA). This hazard analysis is a thorough identification of all hazards associated with Risk analysis the device and the measures to be taken to mitigate those hazards. Any product requirements necessary to implement these mitigations should be captured in the SRA. Upon completion of the documentation of requirements, a design review meeting should be held to review the requirements. The review shall be documented on a Design Input Review Form (see Figure 2). Design input review The completed review form, signed PRD, or any alternative requirements documents, SRS, and hazard analysis should be approved by the design review team and placed in the design history file. Note: Any changes to design input(s) made after review and approval by the design review team must be treated as formal design changes. A preliminary concept description of the product to be designed Preliminary schedule including project timelines or milestone objectives A marketing plan including identification of projected markets (e.g., US, EU, other) A preliminary risk assessment in accordance with a risk management program Identification and assessment of the regulatory path Any other documentation necessary to support a decision to develop the product. Upon completion of any phase, a design review meeting should be held to review the phase deliverables. The review can be documented on a Design Phase X Review Form (see example of a Review Form in the design input section). The completed review form and any supporting documents should be placed in the design history file. Phase II: Design and Development Planning Upon adoption of a product concept for development, the project leader should draft a design and development plan (DDP) as well as the phase deliverables. This phase must be documented with a DDP in one of the following forms: A Gantt Chart An alternative outline form wherein all development activities, dates of initiation and completion, assigned responsibilities, and milestones are delineated. The DDP should satisfy the following criteria: Describe the development of the device design in accordance with 21CFR part , and assure appropriate documentation thereof at all stages in the process Provide a schedule of development, with all tasks, design review stages, and milestones clearly defined Identify all contributors to the development process, their responsibilities, and as necessary, interrelationships Assure that all reasonable steps are incorporated to identify and manage potential hazards and risks associated with the new product in accordance with the risk management program. Phase III: Design Input In this phase, the design input is documented as a list of all requirements for the device. This may be prepared as a product requirements document (PRD) or in an alternative form. The project leader is typically 78 Journal of GXP Compliance

6 Jackelyn Rodriguez responsible for resolving ambiguous or conflicting requirements with the appropriate individuals. Table III provides a list of design input phase deliverables. If a device is expected to be distributed in the EU, design input requirements should address all essential requirements identified in the chosen Annex of the Medical Device Directive (MDD) (4). In addition to Annex I, manufacturers may choose a conformity route under Annex II EC Declaration of Conformity for Full Quality Assurance System. Phase IV: Design Output Design output is a set of written specifications that describe how the device is built. In this phase, all design specifications are created and reviewed to verify that they exist and meet the requirements set out in the previous phase. The design output should be in a form (see Figure 3) so that it may be verified that the design output conforms to all design output requirements (see Figure 4). The design output must consist of the following, if applicable: Engineering drawings Hardware design descriptions Software design descriptions Software executable and source code (on disk) Purchasing specifications Component specifications Packaging specifications Labeling Bill of materials (BOM) Device master record (DMR) Updated risk analysis Figure 2: Design input checklist. Inspection and acceptance instructions, including raw materials and components Testing standard for the finished device Change notice (CN) For design output documents that are released through the CN process, a change notice should be prepared and approved in accordance with a change notice procedure. Design input requirement Intended use /indications for use Functional or performance requirements Accuracy and tolerance requirements Human factors requirements Interface requirements (e.g., with other devices, the patient, the user) Biocompatibility of materials requirements Electrical safety and electromagnetic compatibility (EMC) requirements Mechanical safety requirements Sterility requirements (e.g., sterile/non-sterile; singleuse/reusable) Environmental requirements for storage, shipping, and use Packaging requirements Labeling requirements Shelf life (if supplied sterile) Durability requirements Reliability requirements All harmonized and/or industry standards to which the device must conform Safety requirements as identified by the risk analysis Input Req. addressed? Yes No Comments or justification for omission of input requirement Phase V: Design Verification In this phase, a production version of the device is tested to verify that all design input requirements from Phase III have been satisfied. Figure 5 provides an example of the design verification review form. The following documents should be completed to establish design verification if applicable: Summer 2008 Volume 12 Number 4 79

7 GMP Figure 3: Design output review form. All supporting documentation and meeting minutes to be attached. Design output attached or referenced? _YES _NO Design output complete per attached checklist? _YES _NO If not, explain:... Comments/action Item(s) Note: Include reference to applicable CN numbers. Design review approval: Mechanical and electronic hardware verification. Hardware prototypes are tested to verify that they meet PRD requirements. This must be done with the same hardware design that is used in production. Software verification. Software code is tested to verify compliance with SRS requirements. This must be done with the same version code that is used in production. Environmental testing. Production hardware is tested to verify that it meets environmental requirements. Biocompatibility testing. Patient contact materials are tested or qualified for biocompatibility. Sterilization validation for devices to be provided sterile, or to be sterilized prior to use. Validation of a sterilization cycle as effective in providing the necessary Sterility Assurance Level of Packaging validation to establish packaging compliance with PRD requirements. Includes shipping tests and where appropriate, shelf life, and stability testing. Risk trace matrix. A cross reference of hazard mitigations to validation testing is completed. PRD trace matrix. A cross reference of PRD requirements to verification testing is completed to verify that all requirements have been met by the device. SRS trace matrix. A cross reference of SRS requirements to software verification testing is completed to verify that all software requirements have been met by the code implementation. Essential requirements checklist. Where the device will be introduced in the EU, this list will be completed in accordance with Creation of Technical Files requirements to establish that all requirements of Annex I of the MDD have been met. Process validation. Inspection and testing to demonstrate process capability. Phase VI: Design Validation In this phase, the device is tested in simulated or actual clinical use conditions to assure that the design satisfies user requirements. The design validation testing must be done with production units. The device may not be released as a clinical product until completion of the design validation phase. Figure 6 shows an example design validation review form. Validation testing is documented in engineering test reports or equivalent. Validation testing may be of the following types: In vitro or bench testing Biomechanical testing In vivo (animal) testing Human cadaver testing Clinical testing. Other activities that may be added to the plan and undertaken to support design validation may include the following: Historical database/literature searches 510(k) database searches MDR database searches Labeling validation via comparison with labeling or 80 Journal of GXP Compliance

8 Jackelyn Rodriguez promotional materials for commercialized product. Phase VII: Design Transfer In this phase, the design is transferred from engineering to production. Production may be performed either inhouse or by an outside supplier. Activities documented in the design transfer phase are primarily concerned with qualifying the supplier and the manufacturing processes. Figure 7 shows an example design transfer review form. The design transfer documentation includes the following, at a minimum: Production facility qualification Process validation (e.g., first article inspection) Inspection/test procedures written and verified Manufacturing procedures written and verified Production schedules Final risk analysis, including identification of any risks associated with production processes. Figure 4: Design output review checklist. Design output requirement Engineering specifications (Drawings, purchasing specs for components and packaging) Hardware design description Software design description Software executable and source code Component specifications Packaging specifications Labeling Bill of materials (BOM) Device master record (DMR) Updated risk analysis Inspection and acceptance instructions, including testing standards Output complete? Yes No N/A Checklist completed by: Comments or justification for omission of ouput requirement Date: DESIGN CHANGES Design changes can be initiated for any number of reasons, including those originating with both internal and external sources. Internal cause of design change can include product nonconformance tracking, product complaint investigations, management review actions, clinical advisor input, or to enable production improvements. External cause of design change can include (but need not be limited to) data derived from post-marketing surveillance activities such as review of published literature, MDR records, etc. Design changes can occur at any phase of development. When a design change occurs, the design team must review all previous design phases to determine if the change affects any previously reviewed and approved documentation. All affected documentation must be revised to include the design change and re-approved in the design change review. With all design changes, the risk analysis must be particularly reviewed to determine if the change has created new hazards or removed mitigations to existing hazards. After a design change, a production version of the new device must be tested to verify compliance with requirements. The following design change deliverables are required: Design change checklist. A list of all the documents that have been affected by the design change. Revised documents. Any previously released documents that have been affected by the change must be revised and re-approved in the design change review. Change notice. If the revised documents have been previously released through the CN process, a new Summer 2008 Volume 12 Number 4 81

9 GMP Figure 5: Design verification review form. Figure 6: Phase VI design validation review form. All supporting documentation and meeting minutes to be attached. Hardware verification complete _YES _NO _N/A Software verification complete _YES _NO _N/A Environmental testing complete _YES _NO _N/A EMC and electrical safety testing complete _YES _NO _N/A Biocompatibility testing complete _YES _NO _N/A Packaging/shipping validation complete _YES _NO _N/A Sterilization validation complete _YES _NO _N/A Risk trace matrix attached _YES _NO _N/A Essential requirements checklist complete _YES _NO _N/A PRD trace matrix attached _YES _NO _N/A SRS trace matrix attached _YES _NO _N/A Process validation / first article inspection _YES _NO _N/A Updated risk analysis attached _YES _NO _N/A Comments/action Item(s) Design review approval All supporting documentation and meeting minutes to be attached. Design validation supported by: In vitro (bench) testing report attached _YES _NO _N/A Biomechanical testing report attached _YES _NO _N/A In vitro (animal) testing report attached _YES _NO _N/A Human cadaver testing report attached _YES _NO _N/A Clinical testing report attached _YES _NO _N/A Updated risk analysis / trace matrix attached _YES _NO _N/A Other: Comments/action Item(s) Design review approval CN will be prepared and approved to release the changed documents. This may include recommendations as to the disposition of any pre-change inventories. Revised risk analysis, if affected. The project leader should schedule a design review meeting to review the proposed change. The review must be documented on a design change review form. The completed review form, and any supporting documents, should be placed or referenced in the design history file. RECORDS AND REPORTS As identified previously, records of design and development planning consist of the following documents: Design history file. Formal records of design input, design output, design verification, design validation, design transfer, and when applicable, design change reviews and technical files. All such documents must be forwarded to quality assurance for approval based upon an assessment of completeness, and thereafter to document control for processing and filing in the design history file for the product in question. All records must be maintained in accordance with a record retention program. Device master record. When complete, appropriate elements of the design output (as amended by any subsequent design changes) released in accordance 82 Journal of GXP Compliance

10 Jackelyn Rodriguez Figure 7: Phase VII design transfer review form. Properly instituted, a robust design control process can provide the manufacturer with the opportunity to address and/or correct problems early in the process. All supporting documentation and meeting minutes to be attached. Effective Date of Transfer: Production facilities qualified _YES _NO _N/A Process validation _YES _NO _N/A Manufacturing procedures / inspection and test procedures _YES _NO _N/A Production schedules _YES _NO _N/A Final risk analysis attached & PFMEA _YES _NO _N/A Other: _YES _NO _N/A Comments/action Item(s) Design review approval with change notice procedures should be employed to create the device master record for the device. CONCLUSION It is believed that the intrinsic quality, safety, and effectiveness of a device are established during the design phase. Statistics show that a large number of medical-device recalls are a result of inadequate design controls. Design input is the starting point for product design. A frequent complaint of developers is that there s never time to do it right, but there s always time to do it over. The consequence of a recall should not be limited to the end-user, because it can result in losses for the manufacturer. Therefore, it is in everyone s interest to do it right the first time. Good design controls lay the foundation for the healthy design and development of medical devices in general. REFERENCES 1. FDA, 21 CFR Parts , FDA Quality System Regulations, Subpart C Design Controls. 2. ISO 13485: Medical Devices Quality Management Systems Requirements for Regulatory Purposes Design & Development, FDA, Guidance for Industry and FDA Premarket and Design Control Reviewers Medical Device Use-Safety: Incorporating Human Factors Engineering into Risk Management; Document issued on July 18, FDA, Council Directive on Medical Devices, 93/42/EEC, July ISO14971:2007, Medical devices Application of risk management to medical devices. GXP ARTICLE ACRONYM LISTING BOM CN DDP DHF DMR ER EU FDA FMEA IDE MDD PRD SRA SRS QSR Bill of Materials Change Notice Design and Development Plan Design History File Device Master Record Essential Requirements European Union US Food and Drug Administration Failure Modes Effects Analysis Investigational Device Medical Device Directive Product Requirements Document System Risk Analysis Software Requirement Specifications Quality System Regulation ABOUT THE AUTHOR Jackelyn Rodriguez has over 27 years of experience in all facets of quality assurance and regulatory compliance and is currently the president of Monarch Quality Systems Solutions. Ms. Rodriguez has served as a member of the Board of Examiners for the Malcolm Baldridge National Quality Award program. She has published numerous validation and compliance-related articles and has been a global industry presenter on several compliance topics. Ms. Rodriguez can be contacted by at jackelynr@comcast.net. Summer 2008 Volume 12 Number 4 83