English Translation Medical Device Development_edited version.pdf

PROPRIETARY. DO NOT SHARE. Transcript: Medical Device Development Welcome Welcome to the Medical Device Development course. This course will discuss the 5 phases of Medical Device Development and the steps involved in each phase from Market Opportunity Evaluation to Manufacturing Transfer. Section...

PROPRIETARY. DO NOT SHARE. Transcript: Medical Device Development Welcome Welcome to the Medical Device Development course. This course will discuss the 5 phases of Medical Device Development and the steps involved in each phase from Market Opportunity Evaluation to Manufacturing Transfer. Section 1: Market Opportunity Evaluation Section 1: Market Opportunity Evaluation Objectives By the end of this section, you should be able to: • List the five phases of medical device development. • State the goal of the Market Evaluation Opportunity phase. • Explain the various plans that must be completed before leadership can give their go/no-go decision for developing a product. Development Process Overview The five phases of the medical device development process are market opportunity evaluation, concept evaluation, engineering design process, verification and validation, and manufacturing transfer. Phase I: Market Opportunity Evaluation The essence of market opportunity evaluation is to understand the product, the user, and the market. Click the buttons to learn about each aspect of market opportunity evaluation. When you are finished click next to continue. Product A detailed product description is created that defines how the product will meet the customer’s requirements. Both the intended use as well as potential indications for use are considered. Intended-use environments are also considered. Will the device be used in the clinic? At home? In public spaces? During travel? Internationally? In an environment that offers controlled 1 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. temperature or potentially outdoors? And finally, the expected users are described. Who is the customer? Might the intended customer have specific needs or physical limitations that will impact how the device will be designed to accommodate the user? Designing a product that perfectly meets all the customers’ needs does not guarantee commercial success. User Market opportunity evaluation begins with an evaluation of customer requirements. What are the specific needs of the end user? This includes an evaluation not only of what the product will do but also of how it will do it. How precise and accurate does the device have to be to meet the user’s needs? Market A major area of evaluation for medical device development is product reimbursement. If insurance companies and government healthcare providers will not provide the reimbursement, the potential product market shrinks dramatically. The key regulator of medical reimbursement is CMS or the Centers for Medicare and Medicaid Services. Even if the product is not intended for significant use by the Medicare population (patients 65 and older), CMS heavily influences the coverage decisions of private payers. Regulatory Requirement Government oversight is also a factor in the essential requirements checklist when considering regulatory requirements. Product standards can be influenced by government standards, international standards set by groups like ISO (the International Organization for Standardization) and IEEE (the Institute of Electrical & Electronic Engineers), as well as by general industry standards. Plans To Make Go/No Go Decision The next aspect of market opportunity evaluation is planning various aspects of product risk analysis, product development, business review, and phase review. Click on each button to learn more. When you are finished click next to continue. 2 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Risk Analysis Plan/ Risk Management Plan The market opportunity evaluation also includes risk analysis and a risk management plan. At this stage in the process, a high-level evaluation of product risks and potential strategies to mitigate these risks is performed that considers the product requirements and users but not a specific product design. Product Development Plan A product development plan considers the logistics of the device development. What resources will be required? How long will the product development take? How much will it cost? Is there a clear regulatory pathway? For example, is there an appropriate predicate device that will support the 510(k)-approval pathway, or is the device likely to require Pre-Market Approval, or PMA, and the extensive clinical trials that go with it? What is the manufacturing strategy? Will the device be manufactured in-house, or will a contract manufacturing organization be used? Can the manufacturing be performed overseas? Business Review Plan A business review will also be conducted to consider the market opportunity not just today, but also how that market opportunity will have changed by the time the product launches. Phase Review Plan A phase review plan is undertaken after the completion of each plan―the risk analysis plan, the risk management plan, the product development plan, and the business review plan. The phase review plan allows the management team to review and confirm the market opportunity evaluation is satisfactorily completed. Once the market opportunity evaluation is complete, leadership makes a “go” or “no go” decision as to whether or not to proceed with the product’s development. Section 1: Market Opportunity Evaluation Summary In this section, you learned: • The five phases of medical device development are market opportunity evaluation, concept evaluation, engineering design process, verification and validation, and manufacturing transfer. 3 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. • The goal of the Market Opportunity Evaluation phase is to understand the product, the user, and the market. • The various plans that must be completed before leadership can give their go/no-go decision for developing a product include the risk analysis plan, the risk management plan, the product development plan, and the business review plan. 4 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Section 2: Phase II: Concept Evaluation Let’s assume leadership has made the “go” decision to move forward with product development. The next phase is Concept Evaluation. Let’s take a look. Section 2: Phase II: Concept Evaluation Objectives By the end of this section, you should be able to: • State the goal of the Concept Evaluation phase. • Explain what must be completed during the Concept Evaluation phase. • Discuss the purpose of the concept model. Phase II: Concept Evaluation The second phase of medical device development is concept evaluation. The essence of this phase is to confirm product feasibility by developing a design that includes the key product functions chosen during the market evaluation phase. This includes a number of different factors. Click on the buttons to learn more about these factors, when you are finished, click next to continue. Product Architecture Diagram Concept evaluation often begins with a graphic representation of the system architecture. This includes all the major components and subsystems, and a description of how they inter-relate. User Interface Requirements An important consideration is the set of requirements for the user interface. This includes not only how the user will interact with the product itself but also with the product packaging, its installation, and even disposal. Potential modes of user interactions could be a graphic user interface or GUI as well as buttons, knobs, and connectors. Specific requirements for the service and maintenance of the device will also be detailed. Product Requirements Document (PRD) All of the features and physical attributes of the device will be captured in the PRD or product requirements document. The PRD is a living document that will be continually updated throughout the development process and all specifications for the product will be traced back to the PRD. 5 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Software Requirements and Software Design Description More and more often, medical devices will have a microprocessor and include a software component. A description of the software design and a summary of all software requirements will be captured during the concept evaluation process. Human Factors A regulatory requirement of medical devices is consideration of human factors. In the concept evaluation phase, a high-level review of potential user demographics, use environments, and ergonomics will be performed. Early Models Provide Proof of Concept Once the team drafts the product architecture, user interface, software requirements, and initial human factors, the engineers move on to proof of concept. This process often begins with the industrial design team creating an electronic computer design. From the computer design, the engineering team then creates a breadboard. A breadboard is a board for making an experimental model of an electric circuit. The form and user interface of the breadboard will bear little resemblance to the concept model or the final product but rather is a functional model to prove the technology exists to create the device. The purpose of making the computer design and breadboard is to provide evidence that the technology works and to identify and reduce implementation risks. These early models evaluate the ergonomics and general user interface. Completing Concept Evaluation Once the early models are developed the risk analysis plan and business review plan, drafted during the market opportunity evaluation phase, are updated. Product verification is the fourth phase of medical device development, but it is such an important part of the development process that initial verification plans are drafted during the concept evaluation phase. Upon finalizing all these activities, the management will review and confirm the concept evaluation phase has been satisfactorily completed. 6 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Section 2: Phase II: Concept Evaluation Summary In this section, you learned: • The Concept Evaluation phase aims to confirm product feasibility by developing a design that includes the key product functions chosen during the market evaluation phase. • During the concept evaluation phase, the following items must be completed: the product’s architecture diagram, user interface requirements, the product requirement documents, software requirements, and a list of human factors to be considered. • 7 The purpose of the concept model is to prove the core technology will work. Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Section 3: Phase III: Engineering Design We began the Medical Device Development course by looking at the planning and feasibility stages. Now we delve into the design phase---The Engineering Design stage. Let’s begin. Section 3: Phase III: Engineering Design Objectives By the end of this section, you should be able to: • State the goal of the Engineering Design phase. • Explain what must be completed during the Engineering Design phase. • Discuss the human factor specifications. • Describe the main challenge of engineering software. • List the prototype specifications. Phase III: Engineering Design The third phase of medical device development is engineering design. It includes the design, documentation, fabrication assembly, and testing of prototype devices. Engineering design is an iterative process in which the evaluation of each prototype enables the engineering team to improve the product design. The process cannot begin effectively without a final set of specifications for the product and subsystems. This includes specific performance metrics that are both testable and traceable. If the performance of a device requirement cannot be tested, the engineers as well as regulatory authorities will be unable to evaluate whether the device meets the users’ needs. Determining Product Requirement Specifications Product requirement specifications consider many different factors the development team will consider when authoring the product requirement specifications. What is the intended use of the device and which indications for use will the label support? Will the device only have pacemaker functionality to maintain the patient's heart rate, or will it also include a defibrillator to treat cardiac dysrhythmias? What is known about the user, patient, and clinic? Will cardiologists be knowledgeable in the use and surgical implantation of the device? Or does this new pacemaker have improved features that will be unfamiliar to the medical community? 8 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Is the device intended for all patients in need of a pacemaker or only a subgroup of patients? Can the pacemaker be implanted and serviced in existing cardiac clinics? Or will additional equipment be required? What are the physical and chemical characteristics of the device? Is it a different size than currently marketed pacemakers? Are the electrodes, leads, and casing made of materials commonly used in implantable devices? Is there any risk that the battery could leak, and if so, what are the chemicals that would be released? What limits and tolerances do the engineering team need to have in place? What range of voltage and current is acceptable? Can the electrodes be attached anywhere in the heart chamber or is the area of effective attachment small, requiring more precise insertion? Does the frequency of electrical impulse have to be precise to the half-second? Nanosecond? Femtosecond? What performance characteristics does the device have to meet? Will the battery life be at least as long if not longer than currently marketed pacemakers? Is the device externally programmable after implantation to allow for post-operative adjustment? What are the risks and benefits of this new device? Does the significantly longer battery life come at the risk of an extremely toxic battery acid leaking out of the pacemaker? What safety requirements must the product meet? In the event of electrode malfunction, does the design include a backup electrode? If so, does the device alert the patient or physician that the backup electrode is in use? Permanently implanted devices in particular require a careful analysis of toxicity and biocompatibility. Have all the materials planned for use in the device previously been used in marketed implantable devices, or will this improved pacemaker introduce new material? If so, what evidence supports the material’s compatibility with the human body, and what testing will need to be performed to prove it is biocompatible and non-toxic? Electromagnetic Specifications Electromagnetic compatibility has two separate requirements. First is the question of susceptibility to electric impulses the device may be subjected to. If the patient is outside during a lightning storm will the device still function? As part of testing, the device will be subjected to specific electromagnetic stress standards to determine its susceptibility to interference. The second question is whether the device puts out electromagnetic energy that will interfere with other devices it is near. Will the pacemaker emit electromagnetic energy that will interfere with a 9 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. patient's insulin pump, or with hospital monitoring devices? Is the pacemaker compatible with potential accessories and auxiliary devices? If it is externally programmable, can the existing device interfaces be used? Can the pacemaker be implanted using existing surgical tools or will new instruments be required? What environmental factors need to be considered? Will highvoltage machinery like transformers interfere with the pacemaker's function? How will the patient be informed to avoid such power-generating equipment? Do any human factors affect the product requirement specifications? Human factors must be considered both for the patient as well as the cardiac clinicians who will insert the pacemaker and monitor the patient after surgery. How will the device be labeled, packaged, and shipped? What specifications need to be in place for installation and maintenance? Will the device transmit wireless updates to the cardiologist enabling fewer office visits? Can the pacemaker be remotely programmed if the patient's heart rate needs to be adjusted? What security measures need to be included in the design to ensure that only the patient's physician can make these changes? Specifications also take into consideration statutory, voluntary, and regulatory requirements. For example, standards for wireless transmission security. Manufacturing specifications are also carefully defined. What will the tooling tolerances for each component be? Many medical devices and in particular implantable devices must be sterilized before use. What level of sterility is required and how will the sterilization process be validated? Human Factors Specifications The human factors guidance was issued by the FDA in 2011 and is a fundamental part of the development process. The FDA requires that the design of the device must measurably support safe and accurate user performance. Human factors engineering is sometimes described as “usability engineering”. The new guidance was put into effect in large part because of product deficiencies that had been reported for medical devices. Human Factors Labeling Deficiencies The most common labeling deficiencies include inaccurate user profiles and task/error analysis. For example, will the end-user be a well-trained clinician or the general public? A general user may not recognize a flashing light as an indication of device failure. Often instructions were not written at the appropriate level of detail. By assuming a higher level of knowledge than the user 10 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. has, critical steps in the use of the device may be missed. One of the most often overlooked steps was the very first step in the use of the product. For example, removing the device from the packaging or putting batteries into the device. Instructions were also found to be written vaguely so that their execution was open to interpretation, and therefore could easily be performed incorrectly. Illustrations can be an excellent way to communicate device use to people from all different social, educational, and cultural backgrounds, but if the illustrations are not clear and easy to decipher, they can do more harm than good. Worst of all is that the use instructions are missing or unavailable. Software Design Specifications A key aspect of many new medical devices is the software design. The medical device software can be part of the device, for example, the software inside a blood glucose test device or glucometer. The software can also be an accessory to a device, such as computer software that the data from the glucometer can be downloaded to, which allows the patient to look at trends in their blood sugar levels over time. The software can also be a medical device. For example, software programs are marketed that calculate chemotherapy dosing. It is important to recognize that software and hardware design are different animals. Software is much more complex than hardware and requires special controls such as specific design practices. A separate SOP is required to design, verify, & validate the software. The computer industry has created specialized development tools for software development, such as Visual Basic and C+. These are high-level programs that assist the software developer in writing code. Ensuring the software meets regulatory requirements is a hurdle medical device developers must overcome. The FDA recognizes the ISO software development standard 62304. This is an internationally recognized standard that describes how medical device software should be architected, developed, coded, and tested for bugs. Just as documentation changes have to be tracked, all code changes have to be tracked, and the impact of the change evaluated. While more time-consuming and expensive, following ISO 62304 can speed up the final review process, because the reviewer can rely on the standard to assure the reliability of the software. Europe's Medical Device Directive or MDD also recognizes the ISO 62304 standard. Medical device software is classified according to the risk that its malfunction will lead to personal injury. If no injury is possible, the software is classified as class A. Most device software is class B, for example, control software for most laboratory test instruments. A 11 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. malfunction of software that controls life support equipment could result in the patient's death and therefore is categorized as Class C. Software Engineering Medical device software development typically follows a cyclic, iterative process, and it is expected that the software will be upgraded throughout the lifetime of the device. First, the software requirements are analyzed and verified. The software architecture, or high-level structures of the software system, are designed and then carefully verified to confirm that they support the device requirements detailed in the PRD. Once the high-level architecture is complete, the software can be designed in detail, and the detailed design verified against the requirements specifications. This detailed design is then implemented through the process of software coding. As with the software architecture and design, the code is also verified to confirm it supports the device use and specifications. The software architecture will include many different units that accomplish specific functions, and each of these software units is tested to verify functionality. The ability of the units in a subsystem to interact effectively is confirmed through integration testing. Then, the interaction of all of the software subsystems is evaluated in a system test. Finally, the software is added to the physical device to enable beta testing. Detecting Software Defects One of the challenges of software development is detecting defects in the software. These defects can be inherent in the code or can be defects in how the software interacts with the operating system or device hardware. Finding software defects is a challenging task and it is generally recognized that finding every single defect in a software package is not feasible. Therefore, the product is released to the market with software defects or bugs. Decreasing Software Defects The process of searching for defects in medical device software is very thorough. This is accomplished by testing the software early and often. A common practice is to use Monte Carlo simulations, in which the software is bombarded with random information in order to verify that the only output results are the intended outputs. The most common software-related recalls come not from the first product release, but rather from version updates. One of the biggest challenges 12 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. is for a device that has several mechanical/electronic versions in the field, and software must be written that is compatible with all of them. Requirement And Specification Relationships Importantly, the requirements and specifications for each component and subsystem of the device must support one another, as well as their combined use, to meet all the product requirements. In the example shown, the product has both a durable and permanent analysis system, as well as disposable analysis cartridges. The specifications for both the durable analyzer as well as disposable cartridges will support the device function described in the PRD and will support their combined use. For example, the durable analyzer has to be built to accommodate variations in cartridge dimensions inherent in their manufacture as well as inherent variation in reagent chemistry. If multiple chemical reactions in the analysis have to be performed at different temperatures, the electrical design and control software must support proper temperature regulation. This example demonstrates how the subsystem specifications are interrelated and must be carefully tracked and traced to ensure that the different components work together to create a functional device. Complete Specifications Save Money Specification setting is a step in the design process that should not be rushed. A well-considered, complete specification will ultimately save the developers time and money. Having a complete specification allows the engineering team to design for all requirements including manufacturing & assembly, aesthetics & ergonomics, maintenance, inspection & calibration, and even end-oflife processing. Careful specification setting can also decrease production costs by keeping the end goal in mind from the beginning. The cost of implementing a design change increases the later it is implemented. A change that may cost $100 to implement in the design phase could cost $100,000 if it is introduced in production. Finalizing Specifications Once the specifications are finalized, the prototype can be designed, built, and tested. This iterative process will be repeated until all the device requirements are met. A number of details are considered during the prototyping process in addition to the product specifications. Does the design of the prototype change the risk analysis or risk mitigations? At every point in the design 13 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. project, engineers must be cognizant of regulatory requirements and safety standards for the potential countries in which the device will be sold. Failing to do so can significantly increase development costs and timelines as the design will have to be changed. The manufacturability and serviceability of the device are also evaluated to control manufacturing and maintenance costs. Small changes in the design can have a 10-fold impact on the cost of manufacture. Human factors considerations are sometimes vetted by inviting potential users to evaluate the prototypes or to answer a questionnaire detailing their needs and device requirements. This process is often referred to as the voice of the customer. Human factors analysis is an important regulatory requirement of medical devices so let's take a closer look at this design consideration. Prototype Specifications An important part of the prototyping process is to carefully document the process to capture all the information gained. This includes, of course, the product requirements and specifications, as well as verification test protocols and test results. The manufacturing requirements and processes are documented so that they can be traced to the product requirement document or PRD to confirm the manufacturing process will produce a device that meets the product requirements. At this stage of development, a draft label is also authored. The label is really what the FDA approves, and so the product design, specifications, and requirements, as well as potential clinical trials all must support the final label. Creating a draft label that is continually updated throughout the device development process improves the odds of gaining regulatory approval. Testing Prototypes The engineering team will typically build two to three prototypes. The very first prototype rarely works to meet all the product requirements but provides valuable information for subsequent designs. Not only is device functionality tested, but also failure modes. Testing product failure modes is an important part of the learning process and can help avoid product failure when it reaches the customer. The time and cost of prototyping have been significantly decreased by advances in 3D printing. 3D printers are now so affordable that even small start-up companies can have their prototyping equipment. Completing Engineering Design Phase: The Design History File 14 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. At the completion of the engineering design phase, a number of documents will have been authored to capture the details of the design process and to verify that all aspects of the design are traceable to the product specifications listed in the PRD or product requirements document. These documents will be showcased in the design history file DHF. The DHF was first mandated by the FDA in 1990 as part of the Safe Medical Devices Act; it contains all the product development documentation pertaining to a finished medical device. Although there isn’t an established template to prepare a DHF, the following are the usual contents an FDA inspector will be looking for: • Design Plan • User Needs • Design Inputs • Design Outputs • Risk Analysis – Including Hazard Identification • Human Factors Analysis • Design Verification – with Acceptance Criteria • Design Validation - with Acceptance Criteria • Design Changes • Software Validation—If Applicable • Design Reviews • Design Transfer The best practice for ensuring that these documents are created is to document each design review. The DHF demonstrates the device was developed in accordance with both the design plan and the requirements. Completing Engineering Design Phase: The Design Master Record While the design history file (DHF), is a compilation of all the instructions, drawings, and other records that must be used to produce a product; the device master record (DMR), outlines how to actually build the device. A device master record (DMR) is a compilation of all the instructions, drawings, and other records that must be used to produce a product. The device master record is focused on building the device and ensuring that all necessary items are included to build, test, package, and service it. 15 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Section 3: Phase III: Engineering Design Summary In this section, you learned: • The goal of the Engineering Design phase is to fabricate, assemble, and test the prototype. • The following are completed during the Engineering Design phase product requirements and specifications, verification of test protocols and test results, manufacturing specifications and processes, and development of the draft label and the prototype. • The human factor specifications require the device’s design to support safe and accurate user performance. • The challenge of engineering software is detecting and fixing defects in the software; the effects can be inherent in the code or can be defects in how the software interacts with the operating system or device hardware. • The three types of models made during the Engineering Design phase are the computer design, the breadboard, and 2-3 prototype interactions. Section 4: Phase IV: Verification and Validation 16 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Once the Engineering Design is approved the product moves into the testing phase of Verification and Validation. This section takes a closer look at phase four of Medical Device Development. Section 4: Phase IV: Verification and Validation Objectives By the end of this section, you should be able to: • State the goal of the Verification and Validation phase. • Explain what must be completed during the Verification and Validation phase. • Discuss the three stages of validation. • Describe the main challenge of engineering software. • List the prototype specifications. Phase IV: Verification and Validation The fourth phase of medical device development is the process of verification and validation. Verification Verification is demonstrating that the device works as designed. Objective evidence is gathered and documented to prove that the product meets every specification that was established during the engineering design phase. And traceability analysis ensures that every specification is tested. Validation Validation proves that the device meets the user’s needs. The product will be tested under real or simulated conditions of intended use as well as unintended use in order to prove that the device works as intended and cannot be easily misused. This testing demonstrates that the device performs satisfactorily and meets the needs of the end user. Testing 17 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. It is important that the testing uses a production equivalent product, not a prototype so that the final commercial product does not have untested features. This production equivalent product will be built as described in the final design, following the final manufacturing documentation and manufacturing processes. Re-testing If the product design or manufacturing process is changed after validation testing is performed, re-testing is required. The extent of re-testing will depend on how significant the change was and will be guided by a risk analysis. Process Validation The FDA process validation guidance specifies that any process that cannot be tested must be validated. Validation has 3 stages, click on the buttons to learn more about these 3 stages. When you are finished click next to continue. Stage 1: Process Design Validation begins with process design. The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. Stage 2: Process Qualification In the process qualification stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. Stage 3: Process Monitoring Finally, continued process verification provides ongoing assurance during routine production that the process remains in a state of control. Studying variation is an important part of validation. The goal is to detect the presence & degree of variation, find the sources of variation, and try to control variation commensurate with the risk it represents to the process and product. This risk is evaluated by understanding the impact of variation on the process, and ultimately on the product attributes. Phase IV: Verification and Validation 18 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Over the next few screens, we will discuss all of the steps of verification and validation in detail. The verification and validation process begins with the engineering builds. The engineering builds are supported by phase three pre-verification testing so that verification testing of the product will hopefully not generate any surprises. Product Build Strategies for Testing The medical device will be tested at multiple points during the development process, and the degree of completeness of the product for different tests will vary. Initial subsystem tests can be performed using early prototypes or concept models. Human factors testing needs to be done early on in the development process, and the first human factors testing rarely uses fully functional products. For example, a new thermometer may be tested when the form is complete, but the device doesn't measure body temperature. Systems verification testing needs to use products that are as fully functional as possible but won't have been built using validated manufacturing processes. When the fully functional unit is available, final human factors testing can be performed. A fully functional device is actually not required for human clinical trials. For example, the software may not be the final version or the device may have a simple on/off switch rather than an advanced user interface. The final, commercial-ready device is of course tested as part of the verification and validation process. Traceable Testing is a Requirement An important regulatory requirement of medical devices is traceability. This means that every design feature, subsystem requirement, manufacturing process, and product test, be traceable back to the product requirements document or PRD. Part of the device submission for approval will be a complete analysis of this traceability. Let's look at an example of a hand-held medical device. As we move down the requirements/specification tree, we'll see that the descriptions become more and more detailed and precise. The customer requirements document may state that the device is small and easy to use in a clinical environment. The product requirements document or PRD will specify that the device be operable using a single hand, similar to the ability to operate a cell phone by both holding and manipulating it in one hand, leaving the user's second hand free. The product requirement specification for the device's durable goods includes a specification that the device survives a 2-meter drop test. In order to design a device that passes the 2-meter drop test, the mechanical requirements specification will detail the use of an 19 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. elastomeric bumper on the case. There are several ways to manufacture an elastomeric case and so the mechanical design description will specify, for example, the use of an overmold, with the elastomeric bumper bonded to the hard-plastic case. Following manufacture, the case will be tested to verify that the elastomeric bumper is tightly adhered to the hard-plastic case. Specifically, a 100 Newton separation pull test will be utilized to test the integrity of the bumper. The device manufacturer has to be able to trace the pull test specification back to the customer's requirements, in this case supporting the requirement that the device be small and easy to use in a clinical environment. Phase IV: Verification and Validation Following a successful engineering build and verification testing, the product packaging is designed. Packaging Regulation The FDA has specific regulations in place for medical device packaging. For example, the packaging must protect the device from adulteration and damage during product processing, storage, handling, and distribution. The packaging must include product identification by the UDI, or unique device identifier, a numeric or alphanumeric code specific to the device that can be used for post-market surveillance. If the device requires sterilization, the packaging must support the sterilization process, and be able to maintain sterility. The device packaging is one of the design outputs and just like the device itself, the packaging and all associated processes are subject to QSR, or quality system regulations. Accordingly, the packaging design as well as manufacturing and use processes must be validated. Finally, the process for inspection of all incoming packaging components must follow a standard operating procedure to ensure that defective components are rejected. Tamper Resistance/Evidence Similar to pharmaceutical packaging, medical device packaging design must include tamper resistance and or tamper evidence. This is required of the primary, secondary, as well as tertiary packaging. The two key requirements of tamper resistance/evidence are a clear visual indication of a broken seal, and that the packaging cannot be resealed. Phase IV: Verification and Validation 20 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. What the FDA approves is the device label, essentially agreeing that the design, manufacture, and testing support the printed label. The product label includes everything that is printed on the device itself and the device packaging as well as the instructions for use and service manual. Labeling Verification Labeling verification is the process of testing all device labeling, including the packaging, instruction manual, service manual, and any graphical user interface, for accuracy, adherence to regulatory requirements, and usability. Volunteers representative of the intended user will be given the device with all labeling materials to determine if they can use the device correctly simply by reading the product labeling. Many symbols used in medical device labeling have been internationally harmonized, and a subset of these is recognized by the FDA. The industry trend is moving towards using just the symbol on the package without the accompanying written description. Labeling and Unique Device ID (UDI) The FDA also released their guidance for the use of UDIs, or unique device identifiers. The impetus for the UDI stems from 2007 legislation, in which Congress instructed the FDA to create a system of unique product identification for medical devices. The specific guidance was proposed in 2012 and put into effect in late 2013. The purpose of a UDI is to support post-market surveillance of products; making it easier for device users to find information about devices, to report problems with the use of a device including adverse events, and potentially to recall devices. The actual numeric or alpha-numeric UDI will follow ISO standards and be issued at least in part by accredited agencies. Phase IV: Verification and Validation Once the engineering build is complete and the product has been packaged and labeled, human factors testing can be performed. Human Factors Testing 21 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. An example of human factors testing is a simulated use test. This will use a product that is as close to the final commercial device as possible. A minimum of 15 volunteers will be recruited from each potential user population. Typically, these prospective users will be recruited from three different sites. The facility in which the simulated use testing is performed will be set up to mimic the actual use environment as closely as possible. Previous testing and analysis will have generated information about the most likely user errors, as well as errors that carry the most significant risk of injury or harm, and these device uses, or tasks will be given the highest test priority. The testing will be carefully planned out and a specific test protocol will be authored prior to testing. The test protocol will be precisely followed, and of course, the outcome tracked and documented. If the device is intended for use in the US, the FDA requires human factors testing with US consumers. Phase IV: Verification and Validation The next step in verification and validation is to evaluate the manufacturing tooling and equipment. This includes analysis of the manufacturing work instructions as well as equipment IQ/OQ: installation qualification and operational qualification. Manufacturing Testing An important aspect of manufacturing verification & validation is equipment IQ/OQ. All instruments and equipment used in the manufacture of the medical device must be tested to first demonstrate that the equipment is installed correctly and is functioning properly upon installation. This is known as installation qualification & operational qualification or IQ/OQ. All steps in the manufacturing process, including assembly, must be documented. This will include work instructions and SOPs, or standard operating procedures, which describe exactly how each step of the device manufacture is accomplished. The bill of materials or BOM, is also a critical manufacturing document as it will be used to confirm that the correct materials and components are ordered. Quality control metrics will be documented to specify how the product, intermediates, and manufacturing processes will be tested. Finally, the employees will be trained on the work instructions and SOPs, and the training will be documented. Phase IV: Verification and Validation 22 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. The final step in verification & validation is the pilot production build. The FDA requires that three pilot production builds to be completed to ensure that the manufacturing process is robust. The production build will include validation of any sterilization processes, as well as product biocompatibility testing, packaging validation, and shelf-life testing both under real-time as well as accelerated conditions. Sterilization Many medical devices require sterilization to lower the number of microorganisms to a "safe" level by public health standards. Disinfection is the elimination of most harmful microorganisms (but not their spores) from surfaces. Sterilization is the killing of ALL microbes, whether harmful or not, as well as their spores. There are many different ways to sterilize medical devices. The device can be exposed to gas or plasma such as ethylene oxide, hydrogen peroxide, chlorine dioxide, or ozone. These toxic gasses will kill microorganisms making them evacuated from the chamber so that they do not contaminate the device. The device can be irradiated with gamma, e-beam, or x-ray radiation. Perhaps the most common form of sterilization is wet or dry heat sterilization. Autoclaving is a wet sterilization process in which the device is exposed to steam in a highpressure chamber at temperatures exceeding 121 degrees Celsius. This exposure kills microorganisms as well as their spores. Exposure to liquid chemicals such as bleach, glutaraldehyde, peracetic acid, hydrogen peroxide, and cidex can be very effective at killing microorganisms, as can exposure to intense UV radiation. If the medical device has a liquid component that is either in the final device or used in the manufacturing process, the liquid will be filtered to remove microorganisms. Sterilization Validation Because testing the product for sterility would negate its sterility, the sterilization process must be validated. The test protocol will be specific to the type of sterilization, whether irradiation, autoclaving, ethylene oxide, or other method is used. A statistically significant quantity of product from at least three separate manufacturing lots must be tested. The product must be tested in its final intended packaging, and a representative production size must be tested. Following sterilization, the product is tested both for live bacteria as well as for bacterial spores. The validation tests the process and product limits. For example, multiple runs will be conducted to 23 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. test sterility at maximum as well as minimum capacity, using the highest temperature and pressure as well as the lowest, to ensure that the entire expected range of conditions will properly sterilize the product. Biocompatibility Testing Biocompatibility testing is required for all medical devices. The purpose of this testing is to ensure that the product is not toxic or injurious, causing either tissue or immune response in the user. Testing is generally accomplished by adhering to or implanting the device in animals. As with sterility testing, the guidelines require biocompatibility testing of samples from 3 production lots. The international standard for biocompatibility is ISO 10993-1 although the FDA often requires additional tests, and final approval is subject to the expert opinion of the regulatory reviewer. Appropriately, the test duration and types of tests required will depend on the device. Generally, the testing is determined by the type of body contact the device will have. If the device will only be in contact with the body’s surface the duration of testing can be anywhere from hours to up to a month, and the number and complexity of the required tests will be minimal. If the device will be transiently inside the patient test duration will be longer, up to six months, and the number of tests and test complexity will increase. Finally, long-term or permanently implanted devices will undergo extensive testing, with contact durations of up to a full year. The cost of biocompatibility testing can range from $20K to in excess of $100K. Packaging Validation Not only is the device validated, but the device packaging also undergoes validation. This validation is especially rigorous for sterile medical devices. If the package seal integrity is lost, the product is no longer sterile. Therefore, the instrument used to seal the bag is rigorously tested. Variations in the length of time the bag sealer is in contact with the package will be tested, as well as the sealer's temperature and pressure. More modern bag sealers must be able to detect band breaks, and breakage of the heating element due to increased brittleness from the heating cycles. The seal itself will be evaluated for wrinkles which can cause a seal breach. Current ISO standards require bag sealer IQ/OQ/PQ or ongoing validation that the sealer is functioning properly. Not only is periodic performance qualification required, but also continuous in-process monitoring. Today's bag sealers are highly complex instruments that offer continuous in-process monitoring of band temperature and sealer pressure as well as optical analysis for seal wrinkles. 24 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. These instruments log all monitored readings and provide alarms if any aspect is out of specification. Finally, the package itself is tested to confirm integrity, strength, and microbial barrier. This testing can include bubble or dye testing in which the packaged product is submerged in water to look for bubble egress or submerged in dye to look for dye ingress. Peel testing determines how much force is required to peel open the seal, while burst testing pressurizes the packaging to determine if the package will burst if it is subjected to particular pressures for different lengths of time. The microbial challenge is typically accomplished by adding microbial dust to the tertiary shipping container, shipping the package, cleaning the packaging, and then testing the device for microbial ingress. Shelf-Life: “Use By” Analysis An important part of product validation is to test the product’s shelf life. Medical devices require a “use by” date if the product is sterile or disposable. Durable goods and equipment typically do not require "use by" dating, but battery life analysis is typically considered. Shelf-life consideration typically begins with failure mode analysis. By determining the most likely ways in which the device can be expected to fail, the team can develop tests to detect those failure modes. Often the shelf life of similar devices can provide an appropriate guideline for the expected shelf life of the new device. Importantly, the shipping and storage conditions the device will be subjected to must also be considered. If the device will be shipped as non-pressurized air freight, low-pressure exposure must be considered. Product shelf life is analyzed using both real-time as well as accelerated studies. There are several standards for stability testing, all of which will include storage of the device in chambers that expose the device to high temperature and possibly high humidity. Chemical reaction rates roughly double for every 10-degree Celsius rise in temperature, so storage at high temperatures for short periods can simulate longer storage at lower temperatures. This can enable the development team to detect potential stability failures more quickly. Phase IV: Verification & Validation 25 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Following completion of the lengthy verification and validation process, a phase review is performed to confirm that the product is ready for manufacture. Section 4: Phase IV: Verification and Validation Summary In this section, you learned: • The goal of the Verification and Validation phase is to verify the product works and validate the product meets user needs. • Verification and validation of engineering build, packaging design, labels, human factor testing, manufacturing tooling, and equipment, and pilot production builds are completed in the Verification and Validation phase. • The FDA process validation guidance specifies that any process that cannot be tested must be validated. Validation has 3 stages process design, process qualification, and process monitoring Section 5: Phase V: Manufacturing Transfer 26 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Let’s finish the class by learning about phase five – Manufacturing Transfer. Section 5: Phase V: Manufacturing Transfer Objectives By the end of this section, you should be able to: • State the goal of the Manufacturing Transfer phase. • Explain what must be completed during the Manufacturing Transfer phase. • Discuss the purpose of the Investigational New Drug Application (IND) and the Clinical Trials Application (CTA). Phase V: Manufacturing Transfer The final step in medical device development is manufacturing transfer. Most of the verification/validation has been performed in non-production facilities because the cost of using these production-scale facilities for small-scale testing is prohibitive. Following verification/validation, the manufacturing process is transferred to a large-scale facility capable of the high volume necessary for commercial launch. This transfer can be to an internal facility or a contract manufacturer. A cross-functional technology transfer, or tech transfer team, is assembled to verify that the design is suitable for manufacturing. The team will consider every step of the manufacturing process in great detail and will carefully document the transfer plan as well as the results. The transfer itself will be meticulously planned, using small-scale verification prior to the manufacturing launch. This will include confirmation that the manufacturing facilities, equipment, and tooling have been designed and built to support manufacture. Any changes in process design from the pilot scale will be analyzed and qualified. Every step in the manufacturing process must be controlled, and these manufacturing processes are not only verified initially but a plan for ongoing verification will be created prior to the manufacturing launch. Proper device design and verification of manufacturing processes ensure that quality, safety, and efficacy are built into the product. The manufacturing process will include multiple points of inspection to test product quality throughout the manufacture, and any process that cannot be inspected must be validated. Throughout the manufacturing transfer process, the tech transfer team keeps in mind that their documentation, as well as the facilities and manufacturing process, can be inspected by the FDA at any time. Section 5: Phase V: Manufacturing Transfer Summary 27 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. In this section, you learned: • The goal of the Manufacturing Transfer phase is to transfer small-scale manufacturing to large-scale manufacturing of the product. • During the Manufacturing Transfer phase, the design must be verified that it is suitable for manufacturing to confirm that the manufacturing facilities, equipment, and tooling have been designed and built to support large-scale manufacturing. • The purpose of the Investigational New Drug Application (IND) and the Clinical Trials Application (CTA) is to gain regulatory approval in the United States and the European Union to use experimental drugs in humans. 28 Copyright 2023 Biotech Primer, Inc.