Product Development Process (PDP)

Any company's success depends on getting the right products to the market at the right time. It is a challenge to launch the right medical device in a timely manner when a big part of the process is consumed by FDA regulations which can induce unplanned changes in the development timeline. To overcome these inconsistencies, it is necessary to follow a structured process that instills a regulatory discipline into the process without sacrificing creativity. Such a structured process that contains all the actions necessary to take a process from conception to commercialization is called the Product Development Process (PDP).

A PDP consists of many phases, each of which indicates specific tasks or activities to be completed in that particular time. Early phases emphasize concept formation, product definition and project planning, while later phases focus on development, verification, rollout and maintenance of the defined product. A medical device PDP can consist of the following phases:

Phase 0 - Concept Development
Research and identify market needs, opportunities; evaluate and prioritize; identify a strategic fit; obtain management approval.

Phase 1 - Definition and Planning (21 CFR 820)
Involves design control activities (Refer to Design Contols post); define product and project plan; convert consumer needs to product requirement specifications; maintain a Device History File.

Phase 2 - Design and Development
Complete design process and develop a prototype for testing. Regulatory submissions - 510k. Plan verification, validation and manufacturing phases.

Phase 3 - Verification and Validation (21 CFR 820)
Verify and validate the product for compliance with design requirements, customer needs and regulatory requirements. Regulatory submissions - IDE, PMA. All regulatory approvals must be obtained by the end of this phase.

Phase 4 - Commercialization
Market launch; post-launch evaluation and comparison with competition.

A more detailed interaction of the development and business activities involved in the phases of the PDP can be seen in the figure below. The activities in purple represent design control-related activities and the activities in green are non-design control activities.
(Source: www.qualityprogress.com)

Recall Management

The overall process of medical device involves the manufacturer, the FDA and the public (users, retailers). The following image depicts the actions of all parties involved in the recall process.

Source: GAO analysis of FDA information

Device Recalls

A recall is a method of removing or correcting marketed products that are in violation of laws administered by the Food and Drug Administration (FDA). Recall does not include a market withdrawal or a stock recovery (removal of un-marketed devices under the manufacturers' control). Medical device recalls are usually conducted by the manufacturer voluntarily using 21 CFR 7, to protect public health. However, if a manufacturer fails to report a malfunctioning device or initiate its recall, the FDA can issue a recall order under 21 CFR 810 and start legal action against the manufacturer.

Medical device recalls may result from manufacturing defects, labeling deficiencies, failure to meet premarketing requirements [PMA, 510(k)], packaging defects or other nonconformance problems. Recalls are of different classes depending on the relative degree of health hazard they pose to the user, class I posing the most hazard.
Class I - reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.
Class II - remote probability that the use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences.
Class III - a situation in which use of, or exposure to, a violative product is not likely to cause adverse health consequences.

A manufacturing firm may decide of its own volition and under any circumstances to remove or correct a distributed product. A firm that does so because it believes the product to be violative is requested to notify immediately the appropriate FDA District Office. Such removal or correction will be considered a recall only if the FDA regards the product as involving a violation that is subject to legal action, e.g., seizure.

When a device is found to be in violation of the FDA regulations, it is first subject to a health hazard evaluation by the FDA. Data evaluation is done to detect if the device has caused any diseases or injuries during use, or can contribute to other clinical conditions. Various assessments are conducted to evaluate
* hazards in all segments of population;
* degree of seriousness of the hazard in the exposed population;
* likelihood of hazard occurrence; and
* consequences of the potential hazard.
Based on these results and other evaluations, the FDA assigns a Recall Class to the device being evaluated.

Once the device is assigned for recall, the recall firm develops a recall strategy based on the heath hazard evaluation. The recall firm in most cases is the manufacturer of the device. The recall strategy determines the
* Depth of Recall - level of distribution chain up to which recall is to extend. Can be user level, retail level or wholesale level.
* Public Warning - to alert the public of the violative device being recalled.
* Effectiveness Checks - to verify that all consignees have received notification about the recall and have taken appropriate action.
The recalling firm is to submit periodic recall status reports to the appropriate FDA district office. The FDA assesses the progress of the recall through these reports an their frequency is determined by the relative urgency of the recall and will be specified by the FDA for each recall case. A recalling firm may request termination of its recall based on its progress. A recall will be terminated when FDA determines that all reasonable efforts have been made to remove or correct the product in accordance with the recall strategy, and when it is reasonable to assume that the product subject to the recall has been removed and proper disposition or correction has been made commensurate with the degree of hazard of the recalled product.

Complaint Handling

Any communication that points to some deficiencies in the product identity, quality, durability, consistency, security, efficiency, or performance of a product or device after it is released for distribution, is considered as a complaint. As seen under MDR, complaints concerning device-related deaths, serious injuries, or malfunctions must be reported to the FDA.

Manufacturers are to maintain a detailed record of all complaints and solve them in a timely and efficient manner. The complaint handling system of a company can define the efficiency of its Quality System. Each manufacturer must establish and maintain procedures for receiving, reviewing, and assessing complaints by an officially designated unit. A good complaint handling system can
* Provide a suitable solution to the problem;
* Improve customer relations and customer satisfaction;
* Evaluate weaknesses in the product and help resolve it;
* Increase company's accountability and transparency;
* Reduce medical device reporting;
* Reduce costs and improve production schedules;
* Reduce employee confusion.

The GMP regulations state certain requirements that are to be included in any complaint handling system. All manufacturers should:

1. document, review, evaluate, and file all complaints;
2. formally designate a unit or individual to perform these activities;
3. determine if an investigation is necessary;
4. record the reason if no investigation is made;
5. assign responsibility for deciding when not to investigate; and,
6. determine if the complaint requires an MDR report.

A sample complaint handling system is depicted in the image below:
(Source: http://www.assurx.com/software-solutions/complaint-handling-management.htm)

All complaint records should have some basic details like
* sequential number of the complaint;
* origin of the complaint;
* customer information;
* product information;
* any corrective actions already taken;
* details of the complaint;
* and dates, signatures, assignments, etc.
These records should be maintained by the company for review during FDA audits.

Medical Device Reporting

Although manufacturers and importers of medical devices have been required since 1984 to report to FDA all device-related deaths, serious injuries, and certain malfunctions, numerous reports show widespread under reporting. The Safe Medical Devices Act (SMDA) was brought about in 1990 to increase the information that the FDA and manufacturers receive about serious problems involving medical devices. To implement SMDA, the FDA established the MDR regulations after several amendments.

Medical Device Reporting (MDR) is the mechanism for the FDA to receive reports from manufacturers, importers and user facilities detailing significant medical device adverse events, so they can be detected and corrected quickly. These reports can be of different types, and the user facilities (hospitals, clinics, etc) and manufacturers are required by law to report any significant adverse events or findings.

User Facilities - Should report (i) device related deaths to both FDA and the Manufacturer within 10 days; (ii) device related serious injuries to the manufacturer of the FDA (in case manufacturer is not known) within 10 days. Annual reports of deaths and serious injuries are to be filed to the FDA systematically. In addition, user facilities are to report any information that reasonably suggests that a medical device has caused or contributed to a MDR reportable event and provide all information that is reasonably known to them (no evaluation or investigation is necessary). Records related to an adverse event, whether reported or not, must be kept for two (2) years from the date of the event for FDA access.

Manufacturers - Should submit (i) 30-day reports of deaths, serious injuries or malfunctions to FDA within 30 days of being aware; (ii) baseline report to the FDA to identify and provide basic data on the device being reported (along with 30-day report); (iii) 5-day reports on events that require immediate actions/reforms to FDA within 5 work days. Following the FDA Modernization Act (FDAMA), domestic distributors are not required to file MDR reports, but must maintain complaint files. However, importers must continue to file MDR reports.

Failure to comply with the MDR regulations is a punishable criminal offense and is prohibited under the Food, Drug and Cosmetic Act FD&C Act. The MDR form or the MedWatch 3500A Form is available online and can be filed electronically. To make the process more specific, the FDA has developed a coding manual for completing FDA Form 3500A. The manual contains hundreds of codes for adverse events and will be updated as needed. Most of the MDR information other than trade secrets and financial information are available for public review. As seen, the medical device industry is highly regulated with immense emphasis given to safety and efficacy.

FDA Dispute Resolution Process (CDRH)

Regulatory science is often considered a tricky subject since it mostly involves absolutes or issues that are not distinctively black or white. In such cases, regulators make decisions based on the basis of their best judgements formed in the context of the law, implementing regulations, and previous decisions on similar cases. In some cases, regulations are not sharply drawn and can lead to more than one conclusion. These can lead to strong differences in viewpoints between the FDA's decision and the officials of the medical device industry.

Such disputes with the FDA decision can be reviewed or reconsidered by the Dispute Resolution Processes. These processes are explained in Title 21 of the Code of Federal Regulations (CFR). These processes are applicable to resolve disputes involving 510k, PMA, IDE or PDP. The primary processes are often informal involving submission of a petition requesting change or internal review. The advantages and disadvantages of these processes are seen in the image below.

Other, more formal processes can be considered. These are often time-consuming and involve hearings either in a court, or before a board of scientists, an advisory committee, or the FDA Commissioner. The advantages and disadvantages of these processes are seen in the image below.

Other specific appeal processes are available for issues involving:
*Premarket Notification
*Investigational Device Exemption
*Product Development Protocol
*Premarket Approval
*Humanitarian Device Exemption
*Post-Market Surveillance Issues
*Regulatory Compliance Issues
*Product Designation Issues and other
*Miscellaneous Issues
These appeal processes can be seen explained in the "Medical Device Appeals and Complaints" document of the FDA. (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM094523.pdf)

Six Sigma Process

Six Sigma Processes can be of two types depending on the stage of the business. The process used for a developed/developing business is DMAIC, while the process used for new business is DMADV. Both processes are explained in detail.

1.Six Sigma DMAIC: A systematic Six Sigma Process used to perfect business processes already in place.

D: Define M: Measure A: Analyze I: Improve C: Control

Define Phase : Define a goal for the project. This is done by identifying issues causing biggest problems and setting up requirements to define the goal-.

Measure Phase: The goals defined in the previous phase are quantified to make them real and achievable. Pertinent data is collected and stored for future reference.

Analyze Phase: Statistical tests are performed on the data collected. Other six sigma tools are also applied to collect concrete information that undoubtedly shows areas that need improvement. This step involves determining the causes of any errors, evaluation of corrective measures already in place or those that have been planned to be implemented.

Improve Phase: This step aims at implementing the solutions created based on data analysis and brainstorming. The solutions are implemented and the information is disseminated to the employees.

Control phase: This deals with any obstacles that occur and takes care of it properly and promptly.

2. Six Sigma DMADV: A systematic Six Sigma Process used to create and perfect brand new products or services.

D: Define M: Measure A: Analyze D: Design V: Verify

The first three phases, Define, Measure, and Analyze are the same as the DMAIC process.

Design Phase: This step involves design of new processes that will provide stronger support by correction or elimination of the identified error at its root to reach the goals set in the Define phase.

Verify Phase: It involves monitoring and simulation. Simulation is done before the plan or process is implemented to ensure that the error or errors have been eliminated. Once the plan is implemented, the changes are monitored to determine its effectiveness or the necessity for corrections.

Six Sigma

Six Sigma is a quality management methodology that uses different theories and tools to improve upon the processes of a certain business such that greater output is realized with less input. This results in near perfect products and services that meet and/or exceed the expectations of customers or end users, while simultaneously reducing the amount of time, money, and resources put in. In 1980's, the Motorola Corporation first created and implemented this methodology and have profited immensely since then.

Statistically, ‘Sigma’ (σ) is used to represent the statistical term ‘standard deviation’ which measures the deviations from average in a particular business process.
As the deviation from the normal increases, there is an increase in defective products or services. These ‘defects’ require resolution, which costs businesses increased time, money and resources in the long run. It is possible and practical to improve all business processes to 99.9997% perfection with the Six Sigma Methodology. The percentage of defects decreases as the number of sigma increases. The Defects Per Million Opportunities (DPMO) is only 3.4 when 6σ is employed, as opposed to 6,210 using 4σ which is the current industry standard.

Six Sigma = 3.4 DPMO, or 99.99% defect-free
Five Sigma = 233 DPMO, or 99.98% defect-free
Four Sigma = 6,210 DPMO, or 99.4% defect-free
Three Sigma = 66,807 DPMO, or 93.3% defect-free
Two Sigma = 308,538 DPMO, or 69.1% defect-free
One Sigma = 691,462 DPMO, or 30.9% defect-free

One of the most important things to note about the Six Sigma Process is that it does not rely on quick-fix programs to temporarily mask a business problem. It is a systematic methodology of hard work that is fused with a disciplined, factual, data-based and statistical problem-solving method. The amount of guesswork and product testing can be cut to a fraction, saving time and money. Therefore, it affects almost all aspects and levels of a company. Six Sigma can be applied in any field, if there is a process involved, it can be streamlined with Six Sigma.

Steps for manufacturing successful product

According to the FD&C Act, it is required that domestic or foreign manufacturers have a quality system for the design and production of medical devices intended for commercial distribution in the United States. The regulation requires that various specifications and controls be established for devices; that devices be designed under a quality system to meet these specifications; that devices be manufactured under a quality system; that finished devices meet these specifications; that devices be correctly installed, checked and serviced; that quality data be analyzed to identify and correct quality problems; and that complaints be processed. Thus, the QS regulation helps assure that medical devices are safe and effective for their intended use. More details can be obtained from
◦ The Quality System Regulations – 21CFR 820(QSR’s)and
◦ ISO Standard 13485:2003.

The QS consists of four major actions: Design -> Manufacture -> Distribute -> Monitor performance. The FDA's QSR manual shows how any new entrepreneur can start a successful medical device company by sequentially following the steps below.

1. Obtaining information on GMP requirements;
2. Determining the appropriate quality system needed to control the design, production and distribution of the proposed device;
3. Designing products and processes;
4. Training employees;
5. Acquiring adequate facilities;
6. Purchasing and installing processing equipment;
7. Drafting the device master record;
8. Noting how to change the device master records;
9. Procuring components and materials;
10. Producing devices;
11. Labeling devices;
12. Evaluating finished devices;
13. Packaging devices;
14. Distributing devices;
15. Processing complaints and analyzing service and repair data;
16. Servicing devices;
17. Auditing and correcting deficiencies in the quality system; and,
18. Preparing for an FDA inspection.

It is to be noted how each of the steps is a comprehensive process in itself. These steps if followed according to the FDA protocols will ensure production of a successful medical device.

Combination Products

In addition to medical device regulation, the FDA also regulates food, drugs, vaccines, blood and biologics, animal and veterinary products, cosmetics, radiation emitting products and tobacco products. With respect to medical and healthcare products, the three main FDA centers for regulation are:
• CDRH: Center for Devices and Radiological Health
• CBER: Center for Biologics Evaluation and Research
• CDER: Center for Drug Evaluation and Research

In some cases, a therapeutic or diagnostic product might combine drugs, devices, and/or biological products. The FDA classifies these products as combination products. This may be,
(i) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; or
(ii) Two or more separate products packaged together in a single package or as a unit.
Example: Drug eluting stent - It combines device and drug.

In such scenarios, it is essential to determine which FDA center gets jurisdiction of the product. It is usually determined by two main questions:
– What is the primary mode of action of the product?
– Is it a drug, biologic, or device?
If there still is any confusion, the FDA allows the manufacturer to submit a Request For Designation (RFD) form, so that the FDA can decide the primary jurisdiction for the combination product. This is to be done before filing any other device-related document to the FDA. The FDA considers the
• Primary Mode of Action
• Previous Determinations for Precedent and
• Sponsor's request with a justification
before it makes a determination.
Example: In the case of a drug eluting stent, it was classified primarily as a device, since its primary mode of action is to prevent localized vessel/flow constriction. The drug is eluted as a secondary action to prevent fibrosis and eventually re-stenosis. Hence, the product was primarily assigned to CDRH and was to consult CDER as well.

Institutional Review Board (IRB)

Institutional Review Boards (IRBs) are made up of people qualified to evaluate new and ongoing clinical trials on the basis of scientific, legal, and ethical merit. They include medical specialists as well as lay members of the community. The IRB determines whether the risks involved in a study are reasonable with respect to the potential benefits. In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. This group review serves an important role in the protection of the rights, safety and welfare of human research subjects.

FDA requires IRB registration. It is important to determine if the institution conducting the study has its own IRB. If the study is conducted at a site that does not have its own IRB, the investigators should be queried to see if they are affiliated with an institution with an IRB that would be willing to act as the IRB for that site in the study. There are also independent/contract IRBs that can be contracted with, to act as the IRB for a site. Additionally, an IRB can be established in accordance with 21 CFR 56.

The purpose of IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights, safety and welfare of humans participating as subjects in the research. If an IRB determines that an investigation involves a significant risk device, it must notify the investigator and, if appropriate, the sponsor. The sponsor may not begin the investigation until approved by FDA.

Phases of Clinical Trials

Clinical trials mostly occur in four phases.
Phase 1: Screening for safety
Phase 2: Establishing the testing protocol
Phase 3: Final testing
Phase 4: Postapproval studies

Phase 0:
Laboratory and animal testing. This is done to understand the potential of the new approach and its possible success in humans.

Phase 1:
It is done to test the new approach in humans and hence is done in a small population. The subject sample size can range from 20 to 100 depending of the extent of the study. The process involves lab tests to determine the effect of the new approach and its benefits to the patients. It is also used to determine the safe usage criteria and side effects, if any, for using the new agent in Phase 2.

Phase 2:
It is done in a larger population, 20 - 300 people. The new approach is tried in groups of people suffering from a disease/condition under the safety criteria found in Phase 1. If the new approach proves to be effective and safe, it enters Phase 3.

Phase 3:
The new approach is now introduced to large groups of people (300-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely. Randomization is used to maintain validity of the data.

Phase 4:
The last phase of clinical studies is done after the device is approved and marketed. It is done to obtain additional information on the optimal use, risks or benefits of the new approach.

Informed Consent for clinical trials

About 3% of the US population participate in Clinical Trials. Also, new treatments or interventions under study are not always better than, or even as good as, standard care. Even if a new treatment has benefits, it may not work for every patient. In addition, health insurance and managed care providers do not always cover clinical trials. It is therefore essential for patients to understand all the risks involved in a clinical trial before being a part of it. The FDA requires that all subjects of a clinical study sign an informed consent before starting the clinical trial.

Informed Consent (21 CFR Part 50) is a written notification to human subjects involved in clinical investigations that provides them with sufficient opportunity to consider whether or not to participate in the study. The basic elements of an informed consent are:

1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental.
2. A description of any reasonably foreseeable risks or discomforts to the subject.
3. A description of any benefits to the subject.
4. Disclosure of appropriate alternative procedures or courses of treatment.
5. A statement describing the extent to which confidentiality of records identifying the subject will be maintained.
6. For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available.
7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights.
8. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

The FDA follows strict regulations for clinical trials. No clinical investigator may involve a human being as a subject in research unless the investigator has obtained the legally effective informed consent from the subject.

Clinical Trials

Clinical trials are defined by the FDA as, "trials to evaluate the effectiveness, safety and toxicity of medications or medical devices by monitoring their effects on large groups of people". Clinical trials have to be approved by the IRB and they are an essential part of PMAs. Good Clinical Practices (GCPs) are employed to maintain a regulated approach to clinical trials.

Clinical trials can be categorized into different types based on what they are done for.
1. Treatment trials - These seek to find new treatment approaches or compare to identify the most effective treatment available.
2. Prevention trials - They are done to identify approaches to prevent a specific type of disease from developing in people not exposed to it previously.
3. Early detection/screening trials - They are done to find new ways to identify a specific disease/problem in people even before they develop symptoms.
4. Diagnostic trials - These are done to figure out how new tests or procedures can be used to identify a specific disease in suspected population.
5. Quality of life/ supportive care trials - These trials try to identify ways of improving the comfort and quality of life for people with a disease/problem.

The results of a clinical trial is of much significance. Irrespective of the number of subjects or data involved in a clinical trial, the outcome is usually one of the following four types (in case of treatment trial):

Positive trial ‐ Superior (new treatment is better than standard treatment)
Non‐inferior trial ‐ Equivalence (new treatment is equivalent to standard treatment)
Inconclusive trial ‐ Neither superior nor inferior (new treatment is not clearly better nor clearly worse than the standard treatment)
Negative trial ‐ Inferior (new treatment is worse than the standard treatment)

A clinical trial usually starts with a clear investigational plan and an IRB approval for the study. Some components to be considered in the investigational plan are:
– Clinical study protocol - Study, hypothesis and design; Primary and secondary endpoints; Inclusion/exclusion criteria; Sample size and statistical analysis. It is essential to have a clearly defined and firm study protocol that cannot be changed during the course of the study.
– Risk analysis
– Informed consent form
– Case report forms
– Investigator agreement
– Clinical sites (number of sites / investigators / IRBs)
– Bibliography
– Instructions for Use
– Clinical study duration

Failure Modes and Effects Analysis (FMEA)

Failure modes and effects analysis (FMEA) is a tool used for identifying all possible failures in a
* design,
* manufacturing or assembly process,
* product or
* service.
It follows a step-by-step approach to detect possible failure modes and based on its priority, corrective actions are applied.

“Failure modes” denotes the ways in which something might fail. Any potential or actual errors or defects that can affect the customer are termed failures. The consequences of those failures are studied and described under “Effects analysis”.

Once the failures are identified they are prioritized according to the seriousness of their consequences are, their frequency and the ease of their detection. The FMEA aims to take actions to eliminate or reduce failures, based on their priority.

The steps involved in the FMEA process are:
1. The scope of the FMEA is identified. The scope can be a design, process or service.
2. Identify key functions of the scope.
3. List potential failure modes of each of the function. (How can this function go wrong)
4. Identify the effects for each failure mode. (How will this failure affect the manufacturer, customer..)
5. Rate the severity(S) of each effect on a scale of 1 to 10, 10 being most severe.
6. Identify the causes of all the failure modes. (Why does the function go wrong)
7. Rate the causes for each failure mode in terms of occurrence (O), 10 denoting the most frequent cause.
8. Identify the controls in the scope to detect the cause.
9. Rate the controls on the basis of detectability (D), 10 denoting extremely weak or no control.
10 Calculate Risk Priority Number (RPN). This is done by multiplying the ranks of severity, occurrence and detection (S*O*D). If, we had a severity of 10 (very severe), occurrence of 10 (happens all the time), and detection of 10 (cannot detect it) our RPN is 1000. This is a serious issue with great priority.
11. Identify the most critical issues by sorting the RPNs.
12. Assign corrective actions and deadlines.
13. Perform corrective actions and re-score the S, O and D numbers as applicable and calculate new RPNs.

A sample FMEA template can be seen in the figure above. It is a template specific for process FMEA as seen in http://lssacademy.com/2007/06/28/10-steps-to-creating-a-fmea

Corrective Action Preventive Action (CAPA)

CAPA focuses on the systematic investigation of non-conformances (failures and/or deviations) to prevent their recurrence or their potential occurrence.

Corrective Action aims to correct any event of non-conformance that has already occurred and to prevent its re-occurance.
Preventive Action is a proactive measure taken to identify and eliminate potential causes of potential non-conformances.

The FDA requires that all manufacturers find their problems, fix them and prevent their recurrence. The procedure for implementing CAPA includes requirements for:
1. Analyses of all sources of quality data to identify existing and potential causes of non-conformance.
2. Investigation of the causes of non-conformance.
3. Development of corrective actions to correct or prevent the occurrence of non-conformance.
4. Verification and validation to ensure effectiveness of corrective and preventive actions. The effect of these actions should not adversely affect the finished device.
5. Implementation of the changes in the methods or procedures needed to correct and prevent the quality problem identified. These changes are also recorded.
6. Dissemination of the CAPA information to the quality team.
7. Submission of relevant information on quality problem identification and the corrective and preventive action for management review.
8. Documentation of all activities required for the CAPA procedure.

The inputs for the CAPA procedure can be obtained from audits, customer complaints, process improvement projects, nonconformance reports, waste/rejection rates, FMEA, etc. The controls in CAPA to handle these inputs are:
* Design control
* Process control
* Facilities control
* Documentation and change control
* Materials control
All closed CAPA procedures should be audited to verify effectiveness.

Usability Testing

Usability testing culminates the full testing of a product to ensure that the product is ergonomically designed according to user needs. This process involves iterative prototyping of the product such that all components of the design can be tested, refined and retested throughout development. Usability testing requires;

1. A prototype - A working model of the device is essential to simulate the device-user system and the user interface as defined by the device hardware and software. Mock-ups, storyboards, screen prints or other interactive computer models can be used to evaluate the efficiency of the user with the interface design.

2. Scenarios - Some usability testing requires written scenarios to allow participants simulate a working environment (like a operating room) where the device is used. This would allow for checking the realism and accuracy of the device. Physicians or other healthcare professionals can help with this step.

3. Requirements and Measures - Requirements are based on user interviews, observations, manufacturer’s experience, market analyses, and literature reviews. These should be quantitative and linked to safe device use. Measures used for testing enable the detection of errors or other events of non-conformance with the requirements. This might be as simple as a verbal response or a subjective impression of usability.

4. Facility - It is important to simulate the environment of device use. Test facilities can be a regular usability lab or a medical facility depending on the resources and the nature of the test.

5. Test Participants - Small testings can be done using two or three employees as participants. However, full usability tests would require larger samples drawn from the user population. For a device intended for a fairly homogenous population, most problems can be eliminated from data obtained with about 10 individuals representative of that population.

Also, it is crucial to obtain performance data from actual device users. If the device cannot be safely and effectively used by test participants under test conditions, healthcare professionals will definitely have problems with the device under actual conditions of use. Thus, thorough development of requirements and usability testing of the design would ensure safe and effective use of the device in its use environment.

HFE and Risk Management

Studies show that the frequencies and consequences of use-related hazards of medical devices might far exceed those resulting from device failures. This necessitates the incorporation of Human Factors Engineering (HFE) principles in the device design process. HFE identifies and addresses potential use-related hazards that arise due to interactions between the user and the device.

Most designers only consider the most apparent (e.g., fire) or well-known use problems and thus limit to only relatively few user actions that cause device failure. According to the FDA, use-related hazards occur for one or more of the following reasons:
• Use of devices in ways that were not anticipated,
• Devices are used in an anticipated way, but inadequately controlled,
• The user's physical, perceptual, or cognitive abilities are not sufficient for the device use,
• The user’s expectations or intuition about device operation are inconsistent with actual device use,
• The effects of the use environment on device operation is not understood by the user, or
• The user’s physical, perceptual, or cognitive capacities are exceeded when using the
device in a particular environment.

The device-user system, thus consists of three major components:
1. Use environments,
2. User characteristics and
3. Device user interface characteristics.
The interactions of these components can thus result in a safe, effective, or unsafe and ineffective use of the device. This can be depicted in the following image.

HFE approaches can be incorporated into the design of medical devices within the risk management process to account for the changes in the device-user system. FDA defines risk management as the systematic application of management policies, procedures, and practices to the tasks of identifying, analyzing, controlling, and monitoring risk.
HFE incorporation into risk management can be achieved by four steps:
• Identify use- related hazards that are anticipated (derived analytically) and unanticipated (derived empirically),
• Describe the hazardous use scenarios that can occur,
• Develop and apply strategies that can control these use-related hazards, and
• Demonstrate safe and effective use of the device (validation).
The risk management process by which use-related hazards can be addressed is shown below,

A more detailed description of the process can be found in the FDA document, "Medical Device-Use Safety: Incorporating Human Factors Engineering into Risk Management."

Human Factors

Human factors is a discipline that seeks to improve human performance in the use of a device/equipment by developing a hardware and software design compatible with the user's abilities. It is often referred as human engineering or ergonomics. A medical device can be used safely and effectively only if the interaction between the operating environment, user capabilities, stress levels, and device design is considered when the manufacturer designs the device.

Device design should take into account the basic physical and sensory capabilities, perceptional and cognitive abilities, device expectations, user's mental model of the device capabilities and design, use environments, and all possible categories of users, including the patients themselves.

User interface designing is an important aspect of an ergonomic design. Some basic considerations include,
* Control/Display Layout and Design
* Simple device logic, microprocessing and software design
* Design and code systems to avoid device mis-installation
* Alarms and alert systems
* Device maintenance
* Packaging

The following figure gives a brief outline of the steps involved in usability engineering or human engineering.

Human Factors Standards and Resources
AAMI HE75 – Design Reference
AAMI HE74 – Human Factors Process
IEC 62366 – (Process) Application of usability engineering to medical devices
FDA.gov; FAA.gov

Design Controls

Design controls are a system of checks and balances for systematic assessment of the design during all phases of development. It consists of an interrelated set of practices and procedures that are incorporated into the process of design and development. As a result, discrepancies between user requirements, design and the product can be avoided to create a design that will translate into a successful device. The application of design controls to a design process can be depicted in the figure below.

* Design Input - It consists of physical and performance requirements that are the basis of device design. The design input requirements are unambiguous, self-consistent and expressed with quantitative limits of tolerance. The device use environment is also properly characterized and all requirements are thoroughly reviewed.

* Design Output - It consists of the results of each design phase and the total design effort. The finished design output is usually the device master record. Design output includes production specifications as well as a description of the materials which define and characterize the design. The total finished design output is the device with its packaging, labeling and the device master record.

* Design Review - It consists of a documented, comprehensive, systematic examination of a design to evaluate the adequacy of the design requirements, to evaluate the capability of the design to meet these requirements, and to identify problems. Formal design reviews can be designed to detect problems early in the development process. As the design nears completion, the flexibility of implementing optimal solution decreases and the cost to correct design errors increases.

* Design Verification - It is the confirmation by examination and provision of objective evidence to show that the device meets the manufacturer's requirements. It follows a three-pronged approach employing tests, inspections and analyses and is to be documented systematically.

* Design Validation - It is the process of establishing that the device specifications conforms with user needs and intended use. It usually follows design verification and it provides assurance that the design will conform with user needs and intended uses.

All changes made during the design process are documented as the design history file, which is a compilation of records describing the design history of the finished device. Design validation is followed by design transfer where the device design is translated into production specifications. Manufacturing processes are employed to produce a device based on the production specifications. The device is then sterilized, packaged, labelled and marketed, with the FDA approval.

Good Laboratory Practices (GLP)

GLP's are regulatory guidelines designed to prevent malpractices in research and development. The GLPs are designed to promote the quality and validity of the test data. GLP was imposed on the industry by regulatory authorities, in the same way as good manufacturing practice (GMP) had been before, and followed by good clinical practice (GCP) afterwards. FDA issued mandatory requirements for GLP on June 20, 1979 and they apply for all non-clinical studies used to evaluate safety. It is also instituted by all OECD(Organization for Economic Co-operation and Development) countries.

The fundamental requirements of the GLPs focusses on standardization of 5 categories:
1. Resources: organization, personnel, facilities and equipment.
2. Rules: protocols and written procedures.
3. Characterization: test items and test systems.
4. Documentation: raw data, final report and archives.
5. Quality assurance unit.

The main goal of the GLPs is to make results reliable, repeatable, auditable and recognized by scientists worldwide.

It aims at making False Negatives and False Positives markedly obvious to validate results better and to promote mutual recognition and comparison of study data universally.

Investigational Device Exemption (IDE)

An IDE is obtained when it is necessary to conduct clinical trials on a device to collect safety and efficacy data. This data is mostly used to support the PMA or in very few cases, the 510k. IDE documents are approved by the Institutional Review Board (IRB), a committee designated to review and approve/deny and monitor study involving humans. In cases involving significant risk devices, the FDA is also required to review the IDE. All clinical studies of investigational devices, unless exempt, must have an approved IDE for the study.

An IDE approval requires
* informed consent from all subjects;
* clear labeling that states that the device is to be used for investigational purpose only;
* monitoring of all studies;
* maintenance of all data, records and reports.

Biocompatibility Testing

Biocompatibility of a device is based on device component materials, part of body exposed to device and the duration of exposure.

Device classification based on contact:
* Surface Devices - Devices in contact with skin (electrodes, external prosthesis, fixation tapes), mucous membrane (contact lens, colonoscopes) and breached or compromised surfaces (dressings, occlusive patches).
* External Communicating Devices - Devices in contact with blood path indirectly (blood administration sets, transfer sets), tissue/bone/dentin communicating (laparoscopes, dental fillings, skin staples) or circulating blood (intravascular catheters, immunoadsorbents).
* Implant Devices - Devices principally in contact with tissue (pacemakers, drug supply devices) or bone (orthopedic pins, plates) or blood (heart valves, stents).

Device Classification based on exposure:
* Limited Exposure: < 24 hours * Prolonged Exposure: > 24 hours but < 30 days (single, multiple or long-term use) * Permanent: > 30 days (single, multiple or long-term use)

The biocompatibility tests required for a device is decided based on the biocompatibility matrix.

FDA Pre Market Approval (PMA)

The purpose of a pre-market approval (PMA) is to demonstrate the safety and efficacy of a Class III device through a scientific, regulatory documentation to FDA. According to FDA, "Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury." Therefore, in addition to the General and Special controls, these devices need PMA to obtain marketing clearance.

A PMA should contain sufficient valid scientific evidence to assure that the device is safe and effective for its intended use(s). An approved PMA is like a private license granting permission to market the device in question. The PMA applicant should ensure that the documentation is scientifically sound and presented in an organized manner. The PMA is usually contains technical sections organized into:

(i) Non-clinical Laboratory Studies Section - microbiology, toxicology, immunology, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests.
(ii) Clinical Investigations Section - study protocols, safety and effectiveness data, adverse reactions and complications, device failures and replacements, patient information, patient complaints, tabulations of data from all individual subjects, results of statistical analyses, and any other clinical investigations.

The FDA specifies a timeline of 180 days to process a PMA, though it usually takes longer. The FDA, during this time, reviews the data, discusses with an appropriate FDA committee and makes a determination. After announcing the result, approval or denial of the PMA to the applicant, the FDA posts the data based on which the decision was made on the Internet and gives 30 days for petitioning a reconsideration of the decision.

FDA Special Controls

Special controls are established for Class II devices which require additional checks on safety and efficacy (in addition to general controls) to provide sufficient assurance.
Special controls may include, but is not limited to:
• special labeling requirements,
• mandatory performance standards and
• postmarket surveillance.

Pre-market Notification 510K

The purpose of the 510k is to establish safety and efficacy of the new device by proving its substantial equivalence to a predicate device. The predicate device can be a pre-amendment device (devices prior to May 28, 1976 Medical Devices Amendment) or a post-amendment device that is substantially equivalent (with respect to intended use, component materials, etc.,) to a pre-amendment device. If substantial equivalence is established then the new device is subjected to the same regulations as the device to which substantial equivalence has been established. The comparison with the predicate device should include similarities/differences, identification of materials, design considerations, energy expected to be used or delivered by the device, and a description of the operational principles of the device.

In addition, all 510k submissions also require to state:
device name - proprietary and common name
device classification
device description
its intended use
proposed label, labeling, advertisements, directions of use
sterilization techniques
results of biocompatibility testing

Once submitted, the FDA takes 90 days to process the 510k and it can permit or deny the marketing of the device.

FDA General Controls

General Controls:

Minimum requirements for all device classes. Includes
• Registration of all domestic device manufacturers and importers.
• Listing of all marketed devices by domestic and foreign manufacturers.
• Adhering to Good Manufacturing Practices (GMP’s).
• Filing of Premarket Notification (510k): To notify FDA of the intent to market a medical device.
• Proper device labeling.
• Maintenance of all device records and reports.

General Controls include the provisions of the Act pertaining to:
Adulteration;
Misbranding;
Device registration and listing;
Premarket notification;
Banned devices;
Notification and repair, replacement, and refund;
Records and reports;
Restricted devices; and
Good Manufacturing Practices.

Medical Device Design Process

The process of designing a medical device consists of the following steps:

1. Identifying user needs - This may involve identifying problems with existing diagnostic tools, prosthetic or surgical devices, or recognizing a whole new unexplored market (novel device based solutions for diseases). The primary user of medical devices are physicians who either prescribe or incorporate these devices on/in patients.

2. Reviewing marketed solutions - The next step is to understand the technology and the shortcomings of existing solutions(if any) to the problem.

3. Developing possible solutions - This is the major brainstorming step where solutions are conceived for the problem based on the user needs. Many possible solutions can be obtained to solve the problem.

4. Identifying the best possible solution - In this stage, the results of the previous step are compared and the solution which best satisfies the user needs is selected.

5. Device Design Criteria - The solution selected is translated into design inputs for the design process.

6. Device Design Process - This is a comprehensive step where the design inputs are manipulated to develop a product design.

7. Developing a Prototype - The design is now engineered to produce a working model or prototype of the device.

8. Verification and Validation - This prototype is tested to check its compliance with the design needs and user needs. Based on the outcome of this step, the steps 6-8 might undergo several iterations.

9. Packaging and Marketing - Once the device is ready, it is sterilized and packed according to FDA standards and is ready for marketing.

The FDA regulatory process must also go hand in hand with the device design process. This would enable timely release of device into the market.

Biomedical Devices and Device Classes

According to the FDA (Food and Drug Administration), "A medical device is an instrument, apparatus, implant, in vitro reagent, or other similar or related article, which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or intended to affect the structure or any function of the body and which does not achieve any of its primary intended purposes through chemical action within or on the body."

Medical devices can be as simple as a bandaid or as complex as pacemakers. Based on the level of complexity and the level of control required to ensure the safety and efficacy of the device, medical devices are classified into three classes. This classification is done by the FDA Classification Panels.

• Class I Device: Minimal potential risk to patient, simple design. Eg: bandages.
• Class II Device: Medium potential risk to patient, design is more complicated than Class I device. Eg: surgical instruments, powered wheelchair.
• Class III Device: Potential high risk to patients, these are often devices that support and/or sustain life, highly complex designs. Eg. Implantable devices like pacemakers, stents, knee or hip implants.

There are no risk-free devices – the goal is to minimize the risk while maximizing benefit to patients. The FDA, therefore, has controls to ensure the safety and efficacy of all devices in the market. This makes the medical device industry a regulated industry. The controls applicable depends upon the class of the device.

• Class I Device: General Controls
• Class II Device: General Controls + Special Controls
• Class III Device: General Controls + Special Controls + Pre-market Approval (PMA).