Академический Документы
Профессиональный Документы
Культура Документы
teixeira
Design Controls
For the
MEDICAL DEVICE
InDustry
seConD eDition
Design Controls
For the
MEDICAL DEVICE
InDustry
seConD eDition
Marie B. teixeira
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts
have been made to publish reliable data and information, but the author and publisher cannot assume
responsibility for the validity of all materials or the consequences of their use. The authors and publishers
have attempted to trace the copyright holders of all material reproduced in this publication and apologize to
copyright holders if permission to publish in this form has not been obtained. If any copyright material has
not been acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmit-
ted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented,
including photocopying, microfilming, and recording, or in any information storage or retrieval system,
without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.
com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood
Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and
registration for a variety of users. For organizations that have been granted a photocopy license by the CCC,
a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used
only for identification and explanation without intent to infringe.
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
About the Author. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Overview 1
2 Device classification . . . . . . . . . . . . . . . . . . . . . . . . 5
5 Design inputs—Part I . . . . . . . . . . . . . . . . . . . . . . 29
What are design inputs? 29
The foundation: Design input 30
Design input requirements 30
The concept document 31
Product performance specification 33
v
Design controls for the medical device industry
6 Design inputs—Part II . . . . . . . . . . . . . . . . . . . . . . 37
From feasibility to development 37
Performance characteristics 37
Product characteristics 43
Marketing requirements 58
Regulatory and contractual requirements 63
Design input: One final word 64
7 Design outputs . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
From inputs to outputs 65
Design output requirements 66
Typical design outputs 67
Device master record 67
8 Design review . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Not another meeting! 69
FDA and design review 69
Meeting dynamics 75
9 Design verification . . . . . . . . . . . . . . . . . . . . . . . . . 83
What is the purpose of design verification? 83
What is design verification? 83
Design verification requirements 83
Verification activities 84
10 Risk management . . . . . . . . . . . . . . . . . . . . . . . . . 87
Why? 87
How does risk management fit into design and
development? 87
What is a risk analysis, and what is risk
management? 88
Risk management process 89
Human factors and the risk management process 95
Risk management plan 97
11 Design validation . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Why validate? 99
What is design validation? 99
vi
Contents
12 Biocompatibility . . . . . . . . . . . . . . . . . . . . . . . . . 105
Regulatory aspects of biocompatibility 106
Biocompatibility testing programs 108
Phases of biocompatibility testing 109
vii
Design controls for the medical device industry
viii
Preface
Since the design control requirements were formally mandated by the Food
and Drug Administration’s (FDA’s) Quality System Regulation (QSR) in June
1997, and revisions were made to the International Standard ISO 13485 in 2003,
expectations for compliance with design control requirements have evolved.
Furthermore, as Regulatory Authorities and Notified Bodies have become more
familiar with the intent of the design control requirements and these persons have
assessed industry’s various methods and techniques for implementing the design
control requirements, what may have passed as acceptable a number of years ago
is often deemed unacceptable or inadequate today. As such, a company’s design
control program should be dynamic in nature and continue to evolve in accor-
dance with current expectations and industry practice.
Over the past 10 years since the book was first published, I have gained additional
practical experience in understanding the expectations for compliance of various
Regulatory Authorities and Notified Bodies by participating in numerous FDA
QSR inspections and Notified Body ISO audits. My experience with various types
of companies, both large and small, and varying in functionality and exposure to
a broader range of products and systems, has given me the insight and experience
needed to develop practical systems to meet company and external regulatory
requirements. My prime goal in writing the second edition is to keep the book up
to date with the methods used to meet design control requirements and to comply
with third-party expectations for compliance.
In this second edition, I expanded the scope of the book to include ISO 9001 and
ISO 13485 requirements for design control. The book has also undergone a major
revision in an effort to add more detail for understanding and clarity and to pro-
vide more practical examples for implementation of the concepts. In addition, the
majority of the appendices have been revised or replaced with more current and
applicable templates.
In a book such as this, which covers the design control requirements applica-
ble to a broad range of products and companies, it is often difficult, and likely
ix
Design controls for the medical device industry
x
About the Author
Marie B. Teixeira is the founder and principal consultant for QA/RA Compliance
Connection, Inc., in Odessa, Florida. QARACC is a world-class consulting com-
pany providing expert management and guidance for its clients in all aspects of
quality management and regulatory affairs.
Before beginning this venture, she was director of quality assurance and regula-
tory affairs at Bioderm, Inc., a start-up medical device company in the Tampa
Bay, Florida, area where she designed, directed, and implemented the policies
and procedures that established this company’s compliance with the FDA’s QSR
policy for medical devices, as well as Europe’s Medical Device Directive. In
addition, Teixeira established a quality management system that would allow
this company to achieve ISO 9001 certification with minimum effort. She also
directed regulatory compliance for Europe, Australia, Canada, and several South
American countries.
Teixeira was also quality systems manager for regulatory affairs at Smith &
Nephew’s Wound Management Division in Largo, Florida. In addition to direct-
ing the planning, development, and implementation of Smith & Nephew’s ISO
9001/EN 46001, FDA GMP, and MDD 93/42/EEC regulatory efforts, she imple-
mented and directed the company’s internal audit and management review sys-
tem. It was her direction and guidance that allowed Smith & Nephew’s Wound
Management Division to achieve ISO 9001 certification in less than a year, as well
as its MDD certification one year later.
Teixeira began her career as a quality engineer for Raytheon, GTE Government
Systems, and Sparton Electronics. During her tenure at these companies, she was
responsible for establishing and implementing quality assurance programs and pro-
cedures, leading supplier and customer audits, developing and performing quality
system and auditor training, initiating and managing corrective actions, and devel-
oping and implementing supplier certification programs. During her tenure at
Sparton, she managed the company through its initial ISO 9002 certification and
subsequent surveillance audits.
xi
Design controls for the medical device industry
xii
Chapter 1 Introduction
Overview
Quality system requirements apply to all organizations providing medical devices
regardless of the type or size of the organization. Medical device manufacturers
are required to establish, implement, and maintain quality systems to help ensure
that their products consistently meet applicable requirements and specifications.
In the United States, the quality system requirements for devices regulated by
the Food and Drug Administration (FDA) are codified under 21 CFR Part 820–
Quality System Regulation (QSR). Likewise, ISO 9001 is an international quality
management system standard applicable to any product, and ISO 13485 is an
international quality management system standard specific to medical devices.
ISO 13485 is considered to be compatible with the QSR. The QSR, ISO 9001,
and ISO 13485 Standard include the requirements related to the methods, facili-
ties, and controls used for designing, manufacturing, packaging, labeling, storing,
installing, and servicing finished products. Manufacturers are expected to adopt
current and effective methods and procedures for each device they design and
manufacture in order to comply with and implement the basic requirements.
1
Design controls for the medical device industry
2
Introduction
3
Chapter 2 Device classification
Before we talk about who is required to comply with design control requirements
and what those requirements are, let’s talk a little about medical device clas-
sification. Medical devices are typically assigned a device class (see Table 2.1).
In the United States, medical devices fall into three device classes. In Canada
and Europe, there are currently four medical device classes. In addition, the
European classification system includes a Class I sterile and Class I measuring
function category.
The amount of control needed for a medical device to ensure its safety and effec-
tiveness is dependent on its medical device class. A Class I device represents the
lowest risk of harm to the user and requires the least amount of regulatory control,
whereas a Class III or IV device represents the greatest amount of risk of harm to
the user and requires the most regulatory control.
The class to which a medical device is assigned is based on its safety and effec-
tiveness or “risk.” In the United States, the FDA determines and assigns the
device class by considering the following factors:
• Intended use: Who is the device intended for?
• Indications for use: What are the conditions for use of the device, includ-
ing the conditions of use prescribed, recommended, or suggested in the
labeling or advertising of the device and other intended conditions of use?
• Safety and risk: What is the probable benefit to health from use of the
device when weighed against any probable injury or illness from such
use (risk/benefit analysis)?
• Effectiveness: What is the reliability of the device?
Examples of the FDA’s classification of medical devices are shown in Table 2.2
In Europe and Canada, medical devices are also classified using a risk-based clas-
sification scheme; however, it is the manufacturer’s responsibility to determine
the device class. In determining the device classification, manufacturers must
consider the following:
• Device intended use: What part of the body is affected?
• Device duration of contact: How long is the device in continuous use?
• Device degree of invasiveness: What is the degree in which the device
contacts the patient?
5
Design controls for the medical device industry
6
Device classification
7
Design controls for the medical device industry
8
Chapter 3 Overview of
design controls
Applicability
Now that we have discussed how medical devices are classified, we can determine
who is required to meet FDA and ISO design control requirements and what those
requirements entail; that is, Who? What? Why? How?
Design controls are a component of a comprehensive quality management sys-
tem that covers the entire “life” of a device from initial approval of the device
design to disposal. Design controls are needed to ensure products meet specified
requirements and user needs and are safe and effective for their intended use. The
FDA’s QSR and ISO 9001 and ISO 13485 Standards require that you document
the method that you choose to use to control your design and development process.
In the United States, medical device companies that design and develop Class
II and Class III medical devices, as well as devices automated with computer
software and Class I devices listed in Table 3.1, are mandated to comply with the
design control requirements called out in 21 CFR 820.30. Similarly, organiza-
tions that require compliance with ISO 9001 and 13485 International Standards
must also comply with design control requirements unless exclusion of these
requirements (Section 7.3) is permitted (e.g., FDA Class I device not called out in
Table 3.1 or above).
Note that if you design and develop a Class I device, you are still subject to design
change control requirements (Section 820.30(i)).
9
Design controls for the medical device industry
application for which it is intended to be used. More important, they have been
hired to do this and generate the most profit.
All those things like comfort, safety, effectiveness, ease of use, and durability are
certainly key elements that will contribute to achieving the ultimate goal, but the
prime design criterion is whether the device will make money—at least if you buy
into the idea that being in business has profit as its prime objective. Meeting this
objective may be as simple as answering the following questions:
• Is this a viable product?
• Will anybody buy this?
• Is it reimbursable?
• Does the product fit into the company’s overall product portfolio and
business strategy?
• Can we manufacture it at a cost that will give us the desired profit margin?
The product development process must also address the purchasing, production,
marketing, financial, and customer expectations and requirements for the product
in addition to all those things that the product must do to be safe and effective in
its application. The only way to ensure that all these factors are addressed and
that they do not conflict is through the creation of some sort of master plan that
ensures that all aspects are being looked at and balanced in relation to each other;
in other words, a design control system.
Regardless of whether the design control process is mandated by a government
agency, such as it has been with medical devices, it simply makes good business
sense to control what is a very expensive process. No modern company, whether
large or small, can afford the “experiment till you drop or find an answer” approach
made famous by Thomas Edison. Today’s world simply moves too fast and is
too expensive. If your company develops and manufactures medical devices, a
design control program needs to be implemented not just because the FDA has
mandated it, but because there is really no efficient alternative for managing the
product development process. An effective design control program will reduce
the guesswork, the wrong turns, and the blind spots, and provide a structure for
sound reasoning and objective decision making.
10
Overview of design controls
Keep in mind, the design control process does not apply to basic research, at least
not in the context of this book, or to feasibility studies. However, once someone
has decided that a particular product or design will move forward toward produc-
tion, a design control process must be implemented for medical devices.
11
Design controls for the medical device industry
satisfy input requirements. In other words, the product you developed is what you
intended it to be, is what the customer wants, has been verified and validated as
meeting all of these requirements, and has been proven to be safe and effective
for its intended use.
An idea is born
If you stop to think about how much it costs to research, develop, and then manu-
facture a new product from the point at which people say they need it to the point
when the first batch of product comes off the production line, you might wish
you had a way to ensure that your new product is the right one and that it works
right the first time. Think about that whole process. There are a lot of steps, and
each step uses your company’s most valuable resource: your people. New product
development has a voracious appetite. It consumes people, and people use time
and money. Time and money are two of the things that you have to keep an eye on
if you want to make a profit and stay in business. An easy way to control this is
to do it right the first time—and that is what design controls can help accomplish.
So what typically happens when a new product is developed or, for that matter,
when an old product is improved? In an ideal world, the customers may say, “We
want this” or “We need that, and I’m willing to pay more for it.” If they’re not tell-
ing you that directly, then you need to go and find out just what it is your customers
really want or need. It’s called market research, and it costs money and it takes
time. But if it’s done correctly, you will know what kind of product you need to
develop to make a profitable sale in the first place, and you won’t waste time and
money developing something that you know how to manufacture but nobody wants.
12
Overview of design controls
you can? Do you assume you know what’s best for your customers, or do you ask
them? Although the answer may seem obvious, it should be stated. You need to
ask your customers what they want, and you need to keep asking them through-
out the development process and, in fact, throughout the commercial life of the
product. The customer’s input and, even better, evaluation and feedback during
design as well as post-production are invaluable to the acceptance and success of
the product.
13
Design controls for the medical device industry
to establish a design and development plan that identifies all of the activities that
need to occur and assign responsibility for each task.
To get started, we need to begin asking some basic but essential questions, which
may include but certainly are not limited to the following:
• Who will use it? Are special training or special skills required?
• What are the risks associated with its use or misuse?
• What kind of environment will it be used in? Is the device susceptible to
environmental influences?
• How much can it cost? Is it reimbursable?
• What are the shapes, the colors, and the sizes that are desired?
• What accuracy and precision are needed?
• What materials can be used?
• How should it be packaged?
• Is the device supplied sterile or intended to be sterilized by the user?
• Is the device intended for single use or is it reusable?
• How will it function? Is assembly needed?
• Will the device have a shelf life or a finite number of reuses?
• Does the device require any special handling or storage?
• What equipment or accessories will it be used with?
• What user constraints might there be?
• Where do we want to sell it?
• What are the statutory and regulatory requirements?
• Will the device require installation?
• Will the device require maintenance, calibration, and/or service?
The answers to these questions are your design inputs. They include the inputs
from all the work that was completed prior to deciding that the development is
past the feasibility or research phase and is a viable product that the company
would like to move forward with in development and production. The design is
now ready to enter the design and development phase and requires compliance
with design controls.
These inputs may in fact become outputs of additional testing and design pro-
totypes based on continued work. Remember the cyclical nature of the design
control process. These and other questions are associated with the design inputs.
Which of these inputs are critical and essential, which are only desires (wish
lists), which can be modified, which are incomplete or vague, and which are con-
tradictory? All this needs to be determined and documented.
14
Overview of design controls
controlled. Phase 2 is where you begin developing your design outputs: software
code, assembly processes, specifications, design validation protocols, engineering
drawings, inspection procedures, test methods, labeling, and so on. Your outputs
are generated in response to the answers to your design input requirements ques-
tions. Your design outputs need to include acceptance criteria so that you can evalu-
ate whether your device has met requirements. These outputs often become inputs
into the next design and development phase where you will need to verify and vali-
date that your outputs = inputs. Did we meet our goals? For example, you may need
to develop a test method to verify that the device meets some design performance
requirement. The test protocol is a design output and is used to perform the test.
As such, it is also a design input to the verification process. The results of the test
are also an output, for example, the test report. The test report then needs to be
reviewed to determine whether the output met the input requirement and whether
any changes are needed. Again, the test results serve as an input into the design
review process. Any inconsistencies, ambiguities, or conflicting requirements then
need to be identified, evaluated, and resolved, and any changes needed to the inputs
and design and development plan will need to be made.
15
Design controls for the medical device industry
your prototypes and subsequently verify and validate your device for its intended
use. Many companies transfer these documents for use during design and devel-
opment (e.g., approval is required) but do not officially transfer these documents
to production until all elements of the device master record are ready to be trans-
ferred prior to market and distribution.
16
Chapter 4 Design and
development
planning
17
Design controls for the medical device industry
walnuts or macadamia nuts? Wait, do you have enough gas in the car to get to the
grocery store and money in your wallet to purchase these items? If not, additional
stops will be necessary. You’re probably starting to think it’s time to abort this
wonderful plan, but don’t give up yet. The fun is only just starting.
Let’s say you’re back from the store with all of your ingredients and you are ready
to begin making the cookies. Wait, the recipe says that the butter has to soften
and the eggs have to be at room temperature. Another delay! No problem, while
you are waiting for the butter and the eggs, you can start to measure out your
ingredients and get your tools together. What equipment are you going to need
to make the cookies: mixing bowls, mixer, spoons, measuring cups, pans, oven,
and so on? Let’s just assume that you have all of these items to avoid any further
delay and headaches.
Now you’re ready. What gets mixed together when, in what order, with what
equipment, and for how long? What temperature does the oven need to be set at
and how long does it take to preheat? If you don’t want another delay, you need to
make sure that your oven is ready when you have finished mixing the chocolate
chip cookie dough and the cookies are on the baking sheet ready to be put in
the oven.
Great, the oven is preheated and the dough has been dropped in spoonfuls onto
the baking sheets. Now, how long do they need to bake? Do you want them a
little gooey or crispy? The baking time is also going to vary based on the size of
the cookie and your oven, so you better check on them periodically. No one likes
burned cookies, and you didn’t go through all this trouble just to throw them out.
OK, mission accomplished; the cookies are baked, but guess what? Now they
have to cool.
Finally, the cookies are cooled, and it’s time to eat. Wait, do you have milk? Yes!
But how are you going to pack some of them up for your coworkers so that they
don’t break and don’t melt by the time you get to work? Most important, who’s
going to clean up the mess?
As you can see, what may seem like a simple project can turn into a much more
complex project quite quickly. Many decisions and changes are likely along the
way, and often obstacles delay the completion of tasks or halt the project com-
pletely. A plan is needed to ensure the process or project is appropriately con-
trolled and objectives are met. Everybody knows that, but not everybody does it.
Many think it is a waste of time; however, there is absolutely no way to success-
fully complete a complicated project without a plan. It shouldn’t matter how long
the planning process takes; it needs to be done. Just because someone can articu-
late the product doesn’t mean he or she can tell you how to develop that product
for manufacture and sale.
18
Design and development planning
19
Design controls for the medical device industry
be performed, and for how long; and, last, what is considered to be the acceptance
criteria for an acceptable cookie.
As we will discuss in more detail in later chapters, risk analysis should be initi-
ated and addressed in part at the outset of the design and development process and
considered continually throughout the development process. With that being said,
your design plan should define when risk assessments will be conducted. Risk
assessments should be scheduled similarly to design reviews. The most opportune
times would be upon design and development approval, at the initiation of design
inputs, and after the completion and review of verification and validation activi-
ties in order to determine whether any unanticipated risks have surfaced and/or
your original assessment was inaccurate.
Your design and development plan also needs to define the technical interfaces,
both internal and external, that input into the design and development process.
These interfaces need to be managed to ensure effective communication and a
clear understanding of who is responsible for what and how activities impact each
other. This determines the dependencies and independencies. You want to make
sure that the people assigned to perform design and development activities are
qualified to perform those activities. They should be coordinating these tasks with
the appropriate functions and personnel and communicating and reporting on any
problems and the status of these activities on a regular basis. It doesn’t matter
whether those tasks are assigned to employees, consultants, or other companies.
For example, if internal resources cannot tell you if the product you are making is
sterile (assuming it has to be), then you need to find someone or someplace quali-
fied to provide that testing. But the plan goes one step further; it requires that we
show how all these resources will interact. Design controls require that we think
about and identify how groups, sometimes working independently in their own
disciplines, will be sure that what they are doing will be integrated into the tasks
of what other resources are doing. The output from one group is often the input for
one or more other resources.
It seems obvious that different groups of people working on the same project
should know what the others are doing. Everybody knows that, and for the most
part, everybody does it. It’s done most often with the big things, but we some-
times miss the smaller subtle things, and most often we miss the soft require-
ments, the expectations, and the wish list. The fact that one group may not know
what another department or group expects is not usually due to anything sinister,
but most often due to poor communication. The folks in marketing know that the
customer wants this product to be soft to the touch and have a low profile so it will
be unobtrusive when worn. They’ve talked to users, they’ve run focus groups, and
they made sure it was in the product development goals right from the beginning.
The design folks knew about it too. So how come what is being developed isn’t
soft enough or unobtrusive enough for the marketing group?
20
Design and development planning
Part of the reason may be a poorly written specification. Does “unobtrusive” mean
a profile that’s 3 cm high or 0.3 cm? If everyone knew that it meant 0.3 cm, for
example, did the design folks tell marketing (and the rest of the team for that
matter) that some of the other critical objectives couldn’t be met at a profile
that thin? There are lots of these small misunderstandings that occur. Remember
the greatest problem in communication is the illusion that it’s been achieved.
Design and development is a “live” process, and as such the design plan will con-
tinue to changes as the design evolves. As a result, the design plan is required to
be updated, and any changes to the plan must be reviewed and approved. Probably
the best way to make sure this happens is to schedule these reviews on a frequent
and regular basis. These meetings do more than just force a review of the project
plan. They force the procrastinators to update and document what they’ve done,
what they’ve discovered, and what needs to be changed and modified. It also
forces other functional groups to respond to these changes and the person respon-
sible to approve any changes or initiate a new task to resolve the fact that the input
no longer quite equals the output.
21
Design controls for the medical device industry
• The tasks: What are the major tasks or milestones, as well as the deliv-
erables associated with each task? What tasks depend on others before
they can happen?
• The resources: What will it cost? Do we have the resources (money, people,
equipment, time)? If we hire two more engineers, can we do it faster?
• The time schedule: What tasks should start first? How long does each
task take? What tasks can be done concurrently? Which critical tasks, if
late, affect the outcome of the entire project? There should be a time line
specifying a time frame assigned to each task or sequence of events so
that progress can be tracked.
• The milestones: When do we get together for a design review meeting
to find out if there has been any progress? Are there problems? Do
changes need to be made? Do major decisions need to be made? When
can we launch? Design plans should identify key decision points or
milestones in the project, for example, results of biocompatibility test-
ing, functional testing, clinical testing, or evaluation. The completion
of these tasks suggests a good time for a design review meeting.
• The communication activities: How do we tell everyone who needs to
know what just happened? When should major reports be issued? When
do change notifications occur? Design plans should identify notification
and communication activities, for example, when a design review and/or
risk assessment will take place.
Planning techniques
Design and development plans will vary depending on the complexity of the proj-
ect and the degree of risk associated with the device or product. For example,
plans may take the form of a simple flowchart, task list, or simple time line for
less-complex projects, or for larger projects, may make use of PERT (program
evaluation and review technique), CPM (critical path method), or Gantt charts.
It is beyond the scope of this book to provide an in-depth study of planning tech-
niques or even some of the planning methods. For technical projects, however,
there are a couple of techniques that have been used effectively.
Gantt and PERT charts are visualization tools commonly used to display tasks
required for task scheduling and project management. They are probably the best-
known project management charts. Gantt charts are essentially bar charts that
emphasize the time it takes to complete tasks, while PERT charts are flowcharts
that emphasize relationships between tasks (especially their dependencies).
22
Design and development planning
Gantt charts
The Gantt chart was developed by Charles Gantt in 1917. It provides a graphical
representation of the sequence of tasks and is an excellent tool for quickly assess-
ing the status of a project. Each task is listed in a column along the vertical axis
(y-axis). The horizontal axis (x-axis) is the time scale over which the project will
last (days, weeks, months, years). The time to complete each task is then repre-
sented by a horizontal bar that begins on the start date and ends on the estimated
completion date. Arrows connecting independent tasks reflect the relationships
between the tasks they connect. The relationship usually shows dependencies
where one task cannot begin until another is completed. The resources necessary
for completion of each task are identified next to each task, and often a bar within
a bar will be used to show the task status from 0 percent to 100 percent comple-
tion. If a task takes longer or less time than expected, everything slides appropri-
ately. Figure 4.1 shows the typical elements of a Gantt chart.
23
Design controls for the medical device industry
PERT charts
PERT charts were first developed in the 1950s by the US Navy to help manage
the Polaris submarine missile program. A similar methodology, the CPM, has
become synonymous with PERT. Each chart begins with an initiation node that
branches out into other nodes that represent events or milestones. Directional
lines representing tasks in the project link these nodes. The direction of the
arrows on the lines indicates the sequence of tasks. These are called dependent
tasks. Tasks that are not dependent on the completion of another task so they
can start and can be undertaken simultaneously are called concurrent or parallel
tasks. Lines diverging from the arrows of the dependent tasks may represent these
tasks. Dotted lines indicate dependent tasks that do not require resources. They
are considered dummy tasks. After all of this is laid out, it is relatively simple to
find the longest time line ending with the overall goal. This is referred to as the
critical path, and it estimates the project length. It shows the tasks that need to be
completed on time in order for the estimated project completion date to remain as
that originally calculated.
24
Manufacture Prototypes Run Clinical Trial/Evaluation
Market Survey
Engineering/
1 week Clinical Affairs 2 months
Marketing 4 weeks MFG
06/11/12 09/24/12
Marketing 1 week
02/15/12 02/22/12
25
Design and development planning
Design controls for the medical device industry
26
Design and development planning
Next, when assigning the duration time for tasks, don’t use the first time that
comes into your head. You won’t get an award for underestimating the time
required to complete your tasks, and no one will be happy when you have to
extend your product launch date. Believe me, heads will roll.
The best way to determine the time required to complete a task is to identify three
times for each task:
• What is the time in which you can expect to complete this activity if
everything works out ideally (best case)?
• Under average conditions, what would be the most likely duration of this
activity (most probable)?
• What is the time required to complete this activity if almost everything
goes wrong (worst case)?
With these estimates, you can use a weighted average. For example,
2 (best case) + 2 (worst case)
Most probable duration = = best case
5
Now that you have identified your tasks and the time to complete each, and
everyone has agreed and signed on to the project, you can initiate the design
and development process. Remember, there are a number of reasons why proj-
ects take longer and cost more than anticipated. Usually it is because you don’t
account for unforeseen circumstances. Things often change as you progress
through the design and development cycle. Testing may show the product doesn’t
work the way you expected it to, and some design changes and new testing may
be required. Materials may not be available from suppliers, may be too expen-
sive, or may not be compatible. Marketing may decide to add new claims that
you will need to verify and validate. All of these tasks will need to be added to
the project plan and will extend the time to project completion or product launch.
These revised plans will need to be reviewed and approved and any problems or
conflicts resolved before progressing forward.
27
Chapter 5 Design inputs—Part I
29
Design controls for the medical device industry
30
Design inputs—Part I
31
Design controls for the medical device industry
document, or other term, is a document that kicks off the early stages of the prod-
uct development process or what is typically referred to as feasibility.
Do not confuse a concept document with the formal Design Input Document that
kicks off the design and development process and design controls. The concept
document, or Product Initiation Request, is the starting point for the design and
development process. It defines the basic requirements for a product that is, or
is about to be, developed. By its very nature as a starting point, it is not usually
comprehensive in nature; however, it should be what its name implies: a written
document. It is not a verbal agreement among a few individuals to go off and
develop a new medical device. In fact, even the lone inventor would benefit from
producing a concept document; it would help him/her to begin to solidify that
“lightbulb” that went off in his/her head the day before.
The concept document is generally qualitative in terms, especially when it is being
used to define a new product or application for which little is known and when the
product being developed is “new” to the company undertaking the development.
It can, however, contain any known quantitative information, but that is typically
left for the Product Performance Specification (PPS) document.
In an ideal world, the marketing department of a company prepares the concept
document based on a perceived or real need for a product. However, it can be
initiated by anyone from any discipline. The concept document’s purpose is to
broadly define the requirements of a new product idea so that the R & D depart-
ment can begin translating these requirements into verifiable terms and perform
some preliminary feasibility/bench testing to determine whether the concept/
product is viable. Remember that inputs need to be able to be verified and vali-
dated, and therefore need to be put into terms that allow for such. The outcome of
this process, that is, feasibility, can then be reviewed by key company personnel
so that a decision can be made as to whether the project should move forward
into development. Several elements should be included in the concept document:
• A statement of product purpose or indication: Why would we want to
develop this product? Is there an opportunity? How big is the opportu-
nity, and what are our expectations?
• A statement of the market position: How is this product going to com-
pete? Where? Against whom?
• A statement of essential or desirable characteristics: What does the
product do? What does the product need to do to be successful? What
does it look like (e.g., size, shape, color, etc.)? What kind of delivery
system is required or preferred? Does the product need to be compatible
with other products, equipment, or accessories? Is the product going to
be supplied sterile or nonsterile? What method of sterilization will be
used, and will the packaging be adequate?
32
Design inputs—Part I
33
Design controls for the medical device industry
Product Requirements:
Compatible with CPR hand resuscitators and can be used with other breathing
devices (e.g. resuscitation bags, hyperinflation bags, CPAP masks, CPAP circuits).
Single patient use, disposable, and non-sterile.
Range of 0-60 cm H2O. Gauge has color coding green, yellow and red.
Lightweight. Latex-free.
Claims:
Easy to Read Dial
Measures up to 60cm H2O
Reduces the need to look away from the patient while resuscitating
Allows in-line use on most manual hand resuscitators (with adaptor)
Allows for monitoring of PEEP pressure
Allows for monitoring of Airway pressure
Attaches easily and directly to the Patient Port on standard CPR Bags
Lightweight, Cost efficient
Packaging Requirements:
Individual poly bag, 20 units per case, non-sterile.
Clinical/Technical Requirements/Consideration:
Viewable while patient is being tended to, measures up to 60 cm H2O
Product Cost:
Target production cost under $3.00, target sales price $5.00 to $10.00 each
34
Design inputs—Part I
requirements and what are “essential” requirements for the product. Although
the sales and marketing group would love to have a product with lots of bells and
whistles, the bells and whistles may not be feasible given technology, cost con-
straints, time constraints, and so on. Customer expectations, human factors, and
safety must also be taken into consideration, as should requirements that may be
required to gain access to a certain distribution market or user population.
A multidisciplinary team is essential to developing a comprehensive PPS. There
are simply too many questions that need to be answered that require an expert in
that field or area. If a company does not have the specific or adequate resources
in-house, it needs to find an alternative (e.g., subcontract). Think of the time and
the money that would be wasted if a product were developed that was revolution-
ary for the indication, but became trapped in the regulatory approval process
because developers were unaware of the regulatory requirements for the product.
It is also important that when you define your inputs they be put in layman’s terms
so that all team members can clearly understand them. Remember, not everyone
is a rocket scientist or intimately familiar with the technojargon. If you want your
team to be fully committed and provide value-added feedback, then they need
to understand what you are talking about. No one wants to be the one to raise
his hand and say he doesn’t understand. Usually people just nod their head and
pretend they get it.
Your Design Input Document (e.g., PPS) should typically consider four areas:
• Performance characteristics for the product: What does the product
need to do? Who needs to use it and how?
• Product characteristics: How does it need to look (i.e., design)?
• Marketing requirements: Where is it intended to be sold, and what
claims need to be able to be made?
• Regulatory and/or quality requirements: What standards or regulatory
or statutory requirements are applicable to the product?
These four design input areas can be grouped into three basic categories: inputs
related to device functionality, performance, and device interface. Virtually every
product will have requirements that fall into all three categories. There are, how-
ever, many instances where it may be impractical to establish every functional
and performance characteristic at this design input stage. However, in most cases
the form of the requirements can be determined, and the requirement can be
stated with a “to be determined” numerical value or a range of possible values.
Let’s take a closer look at these three areas. Your functional requirements will
define what the product does from a functional or operational standpoint. Your
performance characteristics will define how much or how well the product is to
perform. Examples may include speed, strength, response times, accuracy, limits
of operations, and so on. This also includes a quantitative characterization of the
35
Design controls for the medical device industry
36
Chapter 6 Design inputs—Part II
Performance characteristics
At this point in the process, we have completed our feasibility portion of the
development process and/or we all believe and agree that we have a viable product
that we want to develop and bring to market. Our next step is to take a look at the
results of any feasibility work and to define our product inputs in a manner that
will allow us to determine the required outputs and verification and validation
activities. It is now time to develop a PPS, a template of which can be found in
Appendix B.
Since everything has to start somewhere, let’s assume that the starting point for
our design inputs begins with defining the performance characteristics of our
new product.
37
Design controls for the medical device industry
38
Design inputs—Part II
39
Design controls for the medical device industry
This input should be easily addressed by answering the question, “Where is this
product currently used or most likely to be used?” One might also ask, “Where
might we like to see this product used?”
At this point you have already defined the indications for use. So now you need to
ask, “Where is this indication usually treated or managed?” Several answers may
come to mind such as emergency rooms, hospitals, home health care, clinics, and
nursing homes. Depending on the device being developed, the answer may be all
of the above. But those may be the standard answers. Maybe there are other cur-
rent or potential use markets such as physician’s offices, operating rooms, emer-
gency rooms, ambulances, rehab facilities, outpatient clinics, and so on. As you
can see, the answer to this question will help determine the total market for the
product. Who would’ve thought years ago that airports and airlines would be a
market for defibrillators?
Your new product may have gone through its feasibility phase aimed all the while
at the current market niche of the company. But maybe somewhere along the way
marketing realized that this new device has a much broader spectrum of use.
Or maybe this product is intended for an entirely new market that has not previ-
ously been tapped by the company. Or the new device will launch the current
company product portfolio into new use environments not previously considered.
If so, it will be important to validate that the product meets the user needs in
these environments. This new input should also trigger a check of the company’s
resources to ensure they are adequate. For example, will specialized training of
the sales force be required to ensure the device is correctly marketed and/or will
more sales personnel be needed to compensate for the increased market potential?
These tasks will need to be addressed prior to launch as part of the design process
if you want the launch to be successful.
40
Design inputs—Part II
41
Design controls for the medical device industry
42
Design inputs—Part II
to accurately read the device labeling, or the display scale or device status
indicators might not be clear to the user. What if the user is color-blind?
• How is the device powered and/or to what other devices might the device
be connected? Is it possible for the device to be connected incorrectly?
We will discuss human factors and risk assessment in more detail in Chapter 10.
Product characteristics
According to Wikipedia, “product characteristics are attributes or properties that
describe the product’s ability to satisfy its purpose in a larger system. As such,
product characteristics describe what your product ought to be, not what it ought
to do. Every product characteristic will have an impact on every basic property
of a product. The basic properties of a product are: size, shape, mass and inertia,
material and surface finish (including color).”
The PPS needs to clearly define a device’s product characteristics, that is, what
it needs to be. It is from these inputs that outputs will be generated and subse-
quently verified and/or validated to ensure that the device meets these require-
ments. Product characteristics may include the following:
• Physical characteristics
• Chemical characteristics
• Biological characteristics
• Environmental characteristics
• Sterilization characteristics
• Packaging and labeling requirements
• Equipment interface requirements
• Safety and reliability requirements
Let’s take a look at each of these types of product characteristics.
43
Design controls for the medical device industry
Don’t forget that here is where you define the different sizes or shapes that the
product may need to be available in or where you will indicate if the product is
intended to be portable and if there are any associated weight or size require-
ments or constraints. You also need to consider how energy is to be delivered
to the device: manually (e.g., manual resuscitator), batteries (e.g., laryngoscope
handle), or via hookup to an electrical outlet (e.g., ultrasound machine). Does the
device have physical characteristics that vary with time, for example, appearance,
viscosity, elasticity, tensile strength, burst strength, or electrical resistance? If so,
this may affect the device’s shelf life.
Remember to identify and/or distinguish between what the essential requirements
are for the device and the “want to have or nice to have” features. The bells and
whistles may be nice, but the basics are a necessity.
Chemical characteristics
Material and component selection is very important when developing your medi-
cal device. When selecting your materials and components, you need to consider
the possibility of chemical degradation (i.e., do any materials or components
of the device degrade over time in a manner that could adversely affect the
device’s safety or performance), chemical interactions (i.e., do materials or com-
ponents interact to alter the device and/or cause degradation or the ability of the
device to perform the intended function), and biological safety issues. Often man-
ufacturers believe they are using a “common” material in their medical devices
(i.e., the same material as their competitor); however, when pressed for evidence
of the material’s safety, manufacturers come up blank. You need to show that the
material is comparable after your manufacturing process. Furthermore, you can-
not assume that because materials meet USP Class V or VI requirements that they
are sufficiently safe for your device application.
Chemical characterization is an accepted method for comparing one finished
manufactured material to another in order to make the argument that they are
clinically equivalent or that one material is no worse than a currently used mate-
rial. ISO 10993-18 (chemical characterization of materials) provides a framework
for the identification of materials and the identification and quantification of their
chemical constituents. This process will help to justify the performance or omis-
sion of animal biocompatibility tests, measure the level of a leachable substance
in a medical device, judge the equivalence of a proposed material to a clinically
established material, or help screen potential new materials for suitability of your
medical device for your proposed clinical application.
The PPS should identify all of the materials and components that make up your
finished device (i.e., chemical formulation) and consider any potential associated
hazards (e.g., flammability, toxicity, etc.).
44
Design inputs—Part II
45
Design controls for the medical device industry
As you can see, there is a lot to consider when choosing the materials and com-
ponents for your medical device, and your choices will influence the biological
testing required for your device.
Biological characteristics
When you think about biological characteristics, the term biocompatibility should
come to mind, but what does biocompatibility mean? Simply put, biocompatibil-
ity means the effect on life and refers to the way materials interact with your body.
Biocompatibility in general is a term that is used to describe the suitability of a
material for exposure to the body or bodily fluids. A material will be considered
biocompatible (in a specific application) if it allows the body to function without
any complications such as allergic reactions or other adverse side effects. If a
material is used that is not biocompatible, there may be complications such as
the following:
• Extended chronic inflammation at the contact point or where leachates
interact with the body
• Generation of materials that are toxic to cells (cytotoxicity)
• Cell disruption
• Skin irritation
• Restenosis (narrowing of blood vessels after treatment)
• Thrombosis (formation of blood clots)
• Corrosion of an implant (if used)
Some materials, lead and mercury, for example, are naturally harmful when taken
into the body so are not suitable for implanting. Other materials are not suitable
to implant because the body fluids cause them to break down, either weakening
them or causing corrosion or other by-products. Some materials may cause sensi-
tization or irritation or may cause an allergic reaction.
A biological evaluation should be performed to determine the potential toxicity
resulting from contact of the component materials of the device with the body.
The device materials should not, either directly or through the release of their
material constituents,
• produce adverse local or systemic effects,
• be carcinogenic, or
• produce adverse reproductive and developmental effects.
Evaluation of any new device intended for human use will require data from
systematic testing to ensure that the benefits provided by the final product will
exceed any potential risks produced by the device materials. Therefore, the selec-
tion and evaluation of materials and devices intended for use in humans requires
a method of assessment to establish biocompatibility and safety.
46
Design inputs—Part II
Biological characteristics need to consider the intended clinical use of the device,
the duration of contact (i.e., how long the device is to be used), and the intended
contact (i.e., the tissues and body fluids the device and its components may come
into contact with during normal use). The answers to these questions will be
essential to determining the nature of the toxicity and biocompatibility testing
required for the finished device and its components.
Current regulations, whether FDA or ISO, require safety testing of devices
through preclinical and clinical phases as part of the regulatory clearance pro-
cess. The number and types of specific safety tests required to assess product
safety and compliance will be dependent on the individual characteristics of the
finished device, its component materials, and its intended clinical use. There are
some significant differences between the FDA’s Blue Book Memorandum G95-1
and the ISO 10993 Part 1 selection of tests; however, they are very similar. The
FDA’s Blue Book Memorandum G95-1 includes an FDA-modified ISO 10993-1
biological evaluation test matrix that designates the type of testing needed for
various medical devices. Whether you choose to use the FDA’s modified matrix
or the ISO 10993-1 matrix, know that both provide only a framework for the
selection of tests and not a checklist of every required test. Again, the particular
tests required will vary depending on the medial device, its intended use, the
duration and frequency of use, and the degree of invasiveness. As a result, this
information needs to be clearly documented in the PPS.
Duration of use Both the FDA’s Memorandum G95-1 (i.e., modified matrix)
and ISO 10993-1 matrix categorize duration of contact/use as follows:
• Limited or transient use: devices whose single or multiple use or contact
is likely to be up to 24 hours
• Prolonged or short-term use: devices whose single, multiple, or long-
term use or contact is likely to exceed 24 hours but is less than 30 days
• Permanent or long-term use: devices whose single, multiple, or long-
term use or contact exceeds 30 days
Of particular note is the Medical Device Directive’s definition of duration of use.
If you use a device, say, a wound dressing, for twenty-four hours and then change
it out with a new dressing and do this for three months, this is considered con-
tinuous use and would be classified as long-term or permanent use rather than
prolonged or short-term use.
47
Design controls for the medical device industry
invasiveness, you are talking about the nature in which the device contacts the
body of the patient. If you refer to the FDA’s Memorandum G95-1 (i.e., modi-
fied matrix) or ISO 10993-1 matrix, you’ll see the categories are broken down as
indicated in Table 6.1.
Surface-Contacting Devices
Skin: devices that contact intact skin Electrodes, external prostheses, fixation tapes,
surfaces only compression bandages, and monitors of various types
Mucosal membranes: devices that Contact lenses, urinary catheters, intravaginal and
contact intact mucosal membranes intraintestinal devices (stomach tubes, sigmoidoscopes,
colonoscopes, gastroscopes), endotracheal tubes,
bronchoscopes, dental prostheses, orthodontic devices,
and intrauterine devices
Breached or compromised surfaces: Dressings, healing devices, and occlusive patches for
devices that contact breached or ulcers, burns, and granulation tissue
otherwise compromised body surfaces
Implant Devices
Tissue/bone: devices principally Orthopedic pins, plates, replacement joints, bone
contacting bone prostheses, and bone cements
Blood: devices principally contacting Pacemaker electrodes, artificial arteriovenous fistulae,
blood heart valves, vascular grafts, internal drug-delivery
catheters, and ventricular assist pumps
48
Design inputs—Part II
frequency, and duration of exposure of the device or its constituents to the body.
Once you have determined these factors, you can use the FDA’s modified matrix
and/or ISO 10993-1 matrix to identify the testing that is recommended for your
medical device. Remember, a good first step in determining what biocompat-
ibility testing is required should include a chemical characterization of the device
materials and a comparison of these materials to materials in existing clinical
use. This chemical characterization may justify the performance or omission of
some of these tests. Most medical devices will require cytotoxicity, sensitization,
and/or irritation testing unless a risk analysis or existing data show otherwise.
In addition, the FDA’s Program Memorandum G95-1, Attachment C provides a
flowchart for use in selecting the required toxicity tests that would be required for
a 510(k) submission.
Environmental characteristics
Environmental characteristics include those environmental factors that may have
an adverse impact on the device or its components during transport, storage, or
use. It includes those environmental conditions that may affect the device itself,
the user of the device (e.g., physician, nurse, technician, etc.), or the patient in the
intended use environment.
The PPS needs to document any anticipated factors associated with transport,
storage, and use. Environmental factors to examine depend on your device, its
intended use, and the use environment and may include temperature, humidity,
atmospheric gas composition and pressure, energy, electromagnetic interference,
electrostatic discharge, radiation emissions, noise, vibration, motion, lighting,
shock, moisture, and so on.
Transport and storage Medical devices are typically transported by truck, air,
boat, or train. This means that packages and their contents will be subjected to
the following:
• Vibration and shock
• Temperature fluctuations and humidity changes
• Variation in atmospheric pressure
As a result, it is important to understand the impact the conditions of transport
and storage may have on your device and components so that the right materials
are chosen and/or actions may be taken to eliminate or reduce these effects.
Material properties may break down under certain environmental conditions; for
example, materials may soften or even melt if subjected to high temperatures or
become brittle and break if subjected to extreme low temperatures. Humidity
under most normal conditions of 0–70 percent relative humidity would likely
have no impact on a light-curable adhesive; however, anyone who lives in Florida
49
Design controls for the medical device industry
knows that humidity in the summer can reach as high as 95 percent or more. A
device or material that is subject to high temperatures and 70 percent relative
humidity or higher for an extended period of time may experience problems with
curing time, chemical properties, and/or adhesion properties.
Years ago I worked with a company in Florida that manufactured an external
continence device. Part of the manufacturing process required that an adhesive be
used to bond two component parts together. In the summer it always took twice
as long for the parts to cure, and there were often adhesion problems reported,
for example, product duration of use was shortened. Instead of the device being
able to be worn for three to five days, the components would begin to come apart
after two or three days. As this was an external continence device, product failure
could prove quite embarrassing.
Temperature and humidity can also compromise the integrity of sterile packag-
ing and affect device shelf life. Annex I of the Medical Device Directive requires
that medical devices be designed and manufactured so that sterility will be main-
tained during storage or transport, providing that manufacturer’s stated storage
and handling instructions are followed. As a result, to ensure your device can
withstand the anticipated environmental factors, it is likely that you will need
to conduct accelerated aging studies and various environmental challenge tests
to establish and justify any expiry dates given on the package label. Any known
restrictions or constraints on storage and handling should be stated in the instruc-
tions for use or on the device labeling.
Problems attributed to the improper storage of medical devices are not new
phenomena. Back in 1999, the Medicines and Healthcare Products Regulatory
Agency (MHRA) issued a safety notice regarding the storage of sterile medical
devices. It indicated that medical devices manufactured using plastics, polymer
materials, and latex compositions and their packaging materials may become
embrittled, perished, stained, or malodorous due to the following:
• Excessive cold or heat
• Dust or other particulate contamination
• Excessive humidity or other wet conditions
• Direct sunlight or other strong light source (e.g., UV light)
• Prolonged storage
50
Design inputs—Part II
used in noisy environments, the user might not be able to notice alarms if they
are not sufficiently loud or distinctive. Similarly, motion and vibration can
affect the degree to which people are able to perform fine physical manipu-
lations such as typing on the keyboard portion of a medical device. Motion
and vibration can also affect the ability of users to read displayed informa-
tion. Important considerations for displays and device labeling should include
ambient light levels, viewing angles, and the presence of other devices in the
use environment. If the device will be used in low light conditions, display
scales or device status indicators might not be clear to the user. Other dis-
play information can be lost under brightly lit conditions because of insuf-
ficient contrast.
If a device is expected to be used in a room with an MRI machine (e.g., wheel-
chair, pressure gauge) or to be implanted into a patient who may be subject to an
MRI scan (e.g., intracranial aneurysm clip, bone screw), then you need to make
sure that all of the device materials are MRI compatible, and that appropriate test-
ing is performed to verify compatibility.
As you can see, there is a lot to consider during the design input stage, and this
process can take up to 30 percent of the total design and development time.
Sterilization characteristics
Many medical devices are provided sterile or require sterilization prior to use or
reuse. As a result, the PPS needs to identify the sterilant or sterilization method
and any associated parameters. For example, if sterilization is to be performed
using radiation, then the radiation dose needs to be indicated; if sterilization is to
be performed using ethylene oxide, then the maximum levels of EO residuals that
may remain on the device need to be indicated; if sterilization is to be performed
using moist heat (e.g., autoclave), then the configuration (e.g., gravity displace-
ment or prevacuum), temperature, and time need to be indicated. The sterility
assurance level (SAL) should also be indicated. An SAL of 10 –6 is expected for
most devices, unless the device is intended only for contact with intact skin. The
FDA recommends an SAL of 10 –3 for devices that only come into contact with
intact skin.
51
Design controls for the medical device industry
52
Design inputs—Part II
Packaging characteristics
A description of the specific packaging materials and the packaging configuration
needs to be defined from several points of view. First, the packaging needs to pro-
tect the device from the environment during transport and storage, and protect the
product’s sterility as appropriate. Second, the packaging should be clearly defined
in terms of its ease of use for the end user or patient.
A device intended for use in a sterile operating room will find few happy users
if the device is difficult to remove from its package when the user is wearing
surgical gloves. If the device’s intended user is physically handicapped, then it is
important that the package can be easily opened without necessarily requiring the
assistance of another person.
There are a number of questions you might want to ask when it comes to device
packaging requirements. The answers to these questions will of course trigger the
identification of outputs for verification and/or validation. For example:
• Is your device sterile? If so, you need to make sure that your packag-
ing materials are compatible with the method of sterilization chosen or
recommended in the instructions for use. Is it likely that there would be
an interaction between the device and its packaging that would have an
undesirable affect?
• How will the device need to be packaged to ensure protection from dam-
age and deterioration during shipping? Will transit trials be necessary?
• Does the device have a shelf life? If so, you need to make sure that the
packaging will appropriately maintain the device and ensure its func-
tionality for that stated period of time; you will likely need to conduct
accelerated aging studies and perform functionality testing.
53
Design controls for the medical device industry
A device’s shelf life should not be confused with its “useful life.” The FDA defines
the useful life of a device as the duration of actual use or the number and duration
of repeat uses before some change results in the device’s inability to achieve its
intended function. Shelf life is defined as the term or period during which a device
remains suitable for its intended use. An expiration date is the termination of
shelf life, after which the device may no longer function as intended.
To determine if a particular device requires a shelf life and the assignment of an expi-
ration date, you must consider a number of different parameters. The device must
be analyzed to determine if it is susceptible to degradation that would lead to func-
tional failure and the level of risk that the failure would present. For some devices,
for example, tongue depressors, it is not reasonable to assign a shelf life because of
the small likelihood of time-dependent product degradation and the lack of serious
consequences if it did fail to perform as designed. For certain devices susceptible to
degradation that are intended to treat life-threatening conditions, for example, pace-
makers, the failure rate should approach zero within the labeled shelf life.
54
Design inputs—Part II
(laser, ultrasound, radio frequency)? Will your device be used with a medical gas?
If so, a gas-specific noninterchangeable connection is recommended. Is a safety
or shutoff valve required to prevent accidental over- or underflow (e.g., pressure)?
Some medical devices require routine maintenance or calibration (e.g., ultrasound
equipment). If this applies to your device, it will need to be accompanied by
instructions for maintenance and repair in order to maintain the safety level of the
medical device. This is specifically called out by the European Medical Device
Directive in Annex I. The maintenance and repair instructions should include the
nature and frequency of maintenance, safety checks, calibration requirements,
and internal and external quality control.
Among the most common errors reported to the FDA with regard to equipment
interface problems are improper installations of device accessories. Some com-
monly reported errors are as follows:
• Tubing connected to the wrong port
• Loose connections
• Accidental disconnections
• Electrical leads inserted into an improper power source
• Batteries or bulbs inserted incorrectly
• Valves or other hardware installed backward or upside down
This problem is made worse by the fact that many manufacturers sell a wide range
of accessories for a given type of device. Accessories for different models are
often similar in appearance and/or difficult to install, leading to misconnections
and disconnections. Such accidents can often be prevented through design solu-
tions. To do this will require that you look at device components and accessories
as part of a system and not as isolated elements.
The FDA’s guidance document Do It by Design recommends seven “Rules of
Thumb” for reducing the likelihood of confusion between similar components
and accessories and making improper connections. These rules are as follows:
1. Cables, tubing, connectors, luers, and other hardware should be designed
for easy installation and connection. If these products are properly
designed, incorrect installations should be impossible, extremely diffi-
cult, or so obvious that they can be easily detected and remedied.
2. User instructions should be understandable, and warnings should be
conspicuous.
3. If a hazard cannot be eliminated by a design solution, color codes or
other markings will help the user achieve proper connections and com-
ponent or accessory installation.
4. Positive locking mechanisms are desirable whenever the integrity of
connections may be compromised by such factors as component dura-
bility, motion, or casual contact.
55
Design controls for the medical device industry
56
Design inputs—Part II
57
Design controls for the medical device industry
Marketing requirements
The purpose of this section of the PPS is to clearly define the marketing require-
ments applicable to your device based on where you want to market the device,
contractual requirements, regulatory or statutory labeling requirements, and the
claims you want to make for your device.
Intended marketplace
At this stage of the game, marketing staff should have a pretty clear idea of where
they want to sell the device in terms of geography. You would expect their fore-
cast to be based on market research and detail not only where they would like to
sell but also the anticipated market share or volume. Do not accept an answer of
“everywhere” or “internationally.” We would all like to sell our medical devices
globally, but it’s just not that simple. Generally speaking, each country has its own
governing regulatory body and regulatory requirements that must be met prior
to a medical device being allowed for sale in that country, and these regulations
are changing regularly. Sometimes a staggered approach is advantageous, as it
can take a significant amount of time to gather the required information for each
country and then receive approval.
Contractual requirements
Contractual requirements also need consideration, as these requirements will
likely result in additional steps or changes to the project plan. These may include
requirements or inputs related to special packaging, storage, handling, and deliv-
ery. These may also include quality management system agreements (e.g., ISO
13485) or even supply and pricing agreements with distributors and contract
manufacturers. For example, many distributors in Europe do not want to stock
a device that has less than an 18-month shelf life remaining on the device. As a
result, if your plan is to release your device to the market with accelerated aging
testing that justifies only a one-year shelf life, you will not meet this requirement.
Customers (e.g., doctors) may want the device packaged as a convenience kit,
in which case you will need to ensure that all components of the kit are appro-
priately controlled and regulated. Devices that are privately labeled will either
require you to generate the labeling and have it reviewed and approved by the
customer or the customer to provide the labeling for you.
58
Design inputs—Part II
Claims
This section of the PPS should include the specific claims that will be made about
the device; that is, what is your device indicated for and intended to do? Per 21
CFR 801.61 (Code of Federal Regulations), the principal display panel of an over-
the-counter medical device in package form is required to include a statement
of the device’s identity and a statement of the principal intended actions of the
device. In addition, the indications for use are to be included in the directions for
use of the device. If you market your device in the United States, any claims you
make regarding intended use are typically dictated by the FDA and the regulation
number the device falls under. Any claim over and above what is stated by the
regulation number will require subsequent approval (e.g., new 510(k) or PMA).
For example, per the FDA’s product classification database, the devices listed
below have the following intended uses:
1.
Sec. 868.5800, tracheostomy tube and tube cuff: A tracheostomy tube
and tube cuff is a device intended to be placed into a surgical opening of
the trachea to facilitate ventilation to the lungs.
2.
Sec. 892.2050, picture archiving and communications system: A pic-
ture archiving and communications system is a device that provides one
or more capabilities relating to the acceptance, transfer, display, storage,
and digital processing of medical images.
3.
Sec. 878.5650, topical oxygen chamber for extremities: A topical oxy-
gen chamber for extremities is a device that is intended to surround
a patient’s limb and apply humidified oxygen topically at a pressure
slightly greater than atmospheric pressure to aid healing of chronic skin
ulcers such as bedsores.
4.
Sec. 880.5210, intravascular catheter securement device: An intravas-
cular catheter securement device is a device with an adhesive backing
that is placed over a needle or catheter and is used to keep the hub of the
needle or the catheter flat and securely anchored to the skin.
In this section you will need to identify what performance claims you intend to
make for your device and whether or not you will be claiming compliance with
any performance standards.
You will likely want to consider the claims your competitors are making so that
you can make the same claims. You should specify all claims that are intended
to appear on the product label and instructions for use; in advertisement slicks,
posters, videos, tradeshow booth signage, and catalogs; and on your website.
Remember, however, that any claims you make need to be supported with data.
The wording of the claims should be done carefully and accurately represent any
scientific and clinical findings that are known and verifiable about the device and
its use for a specific indication.
59
Design controls for the medical device industry
Clinical information
Per MEDDEV 2.7/4 Clinical Evaluation: A Guide for Manufacturers and Notified
Bodies,
60
Design inputs—Part II
Manufacturers are expected to demonstrate that their medical device achieves its
intended performance during normal conditions of use and that the known and
foreseeable risks, and any adverse events, are minimized and acceptable when
weighed against the benefits of the intended performance, and that any claims
made about the device’s performance and safety are supported by suitable evi-
dence. Generally, confirmation of conformity must be based on clinical data and
the kind and amount of clinical data needed will primarily depend on the specifics
61
Design controls for the medical device industry
Warnings/Cautions
Single use only.
Sterile if package is unopened and undamaged.
Test inflate cuff, pilot balloon, and valve prior to use (if present).
Deflate cuff before intubation or prior to repositioning the tube. (To aid insertion and avoid cuff damage.)
Do not overinflate cuff. Maximum air pressure of 25 mm Hg.
Prescription use only. Federal law restricts this device to sale by or on the order of a physician.
Exposure to elevated temperatures and ultraviolet light should be avoided during storage. Keep dry.
Store less than 49ºC, 120ºF.
Contains DEHP.
Do not resterilize.
Verify proper assembly/attachment of respiratory equipment prior to use.
Tracheostomy tube is recommended to be replaced within thirty days.
Contraindications
Care must be taken to avoid contact of a LASER beam or an electrosurgical active electrode with this
and other tracheostomy tubes.
62
Design inputs—Part II
63
Design controls for the medical device industry
This section of the PPS should also include any relevant standards and test meth-
ods that you plan to comply with. These may include ASTM, ANSI, IEC, UL,
CANCSA, ASQ, EN, ISO, and so on related to labeling, packaging, sterilization,
biocompatibility, hardness, color, electromagnetic compatibility, risk manage-
ment, usability, and so on.
Financial requirements
An area that the PPS should likely include but I do not plan on covering here con-
cerns financial requirements. Financial requirements that should likely be consid-
ered and documented include the following:
• Potential market/volumes
• Cost projection
• Competitive environment (e.g., competitors, strengths, and weaknesses)
• Proposed forecast/profit
• Capital projection (e.g., tooling)
• Percent share of market (e.g., estimated shares)
• Total opportunity
• Resource assessment (e.g., facilities/space, personnel, systems, etc.)
• Medicare/reimbursement
64
Chapter 7 Design outputs
As stated in this definition, each phase of the design and development process is
going to have outputs. These outputs will vary depending on the design phase and
the activities being performed and will often serve as inputs to the next design
and development stage. For example:
• At the end of the feasibility phase, the design output is your Product
Performance Specification (PPS). The PPS then initiates (i.e., serves as
an input to) the design and development process.
• Prior to performing any type of biocompatibility testing (i.e., entering
the verification phase), you will need to develop a test protocol or method
(output). The protocol will then be used to conduct the testing (input).
• Prior to conducting a user study (i.e., entering the validation phase), you
will need to manufacture a prototype (output). This sample device will
then serve as the input to the user study or validation (input).
• At the end of the design transfer phase, your design outputs will include
the device, its packaging and labeling, and the DMR. These outputs
serve as inputs to manufacturing and product realization.
65
Design controls for the medical device industry
It is important to note that there may not be an output for every input, but there
should be an input traceable to each output.
I O
I O
I O
Your design outputs are confirmed as meeting design input requirements during
design verification and validation. They are ensured during design review.
66
Design outputs
to identify the tasks and activities that need to be performed and captured on the
design and development plan.
67
Design controls for the medical device industry
The FDA defines the requirements of a DMR in 21 CFR Part 820.181 as follows:
Each manufacturer shall maintain Device Master Records (DMRs). Each manu-
facturer shall ensure that each DMR is prepared and approved in accordance with
document control requirements. The DMR for each type of device shall include, or
refer to the location of, the following information:
Device specifications including appropriate drawings, composition, formula-
tion, component specifications, and software specifications;
Production process specifications including the appropriate equipment spec-
ifications, production methods, production procedures, and production
environment specifications;
Quality assurance procedures and specifications including acceptance crite-
ria and the quality assurance procedures to be used;
Packaging and labeling specifications, including methods and processes
used; and
Installation, maintenance, and servicing procedures and methods.
Think of it this way: if you want to tell people exactly what your product is, what
it is made of, how to make your product correctly and what equipment they will
need to do it, what constitutes acceptable quality and how to test for that quality
level, and even how to maintain and install the proper equipment, then simply
give them the DMR for the product. This makes the DMR one of the most propri-
etary files in your entire company. It essentially contains everything, even those
trade secrets that allow your manufacturing process to work better than conven-
tional processes. Treat the DMR with a high degree of confidentiality.
Remember the DMR is not a single document, like the Product Initiation Request
(PIR) and the PPS; it is a compilation of all documents that relate to the finished
product. Take advantage of this and the fact that the FDA and ISO allow the DMR
to refer to the location of the contents of the DMR and do not require that all of
the documents need to be kept in one discrete file or location.
68
Chapter 8 Design review
69
Design controls for the medical device industry
development cycle to provide assurance that an activity or phase has been com-
pleted in an acceptable manner and that the next activity or development phase
can begin. The design stages must be formally defined in design control proce-
dures (see Appendix A), and the timing of design reviews should correspond in
most cases with completion of milestones and design phases. The design reviews
should also be indicated on the development project plan.
The design review meeting should include representatives of all functions con-
cerned with the design stage being reviewed. This is intended to prevent “over-
the-wall” designs from entering production. For example, what your R & D person
found to be feasible from a bench-testing standpoint may not be feasible in the
production environment at a large volume. Unless your production representative
is present at the design review meeting, he or she will be stuck with specifications
that may be impossible to meet.
Each design review needs to also include an individual who is independent
(objective) from the design stage being reviewed. This is done simply to ensure a
fresh perspective based on the principle that those who are too close to the design
may overlook design errors. In addition, any specialists who might be needed
should also be present. The specialist may have no particular responsibilities
within the company but could be a leading expert in sterilization, for example,
and his or her participation could be invaluable.
Design reviews must be comprehensive for the design phase being reviewed, and
the results need to be documented and maintained.
70
Design review
71
Design controls for the medical device industry
and any other accessories, (3) the customer needs have been met, (4) the safety
requirements are achieved, (5) the reliability and maintenance requirements are
being met, and (6) the manufacturing, installation, and servicing requirements
are compatible with the design specifications.
The design review meeting should also be used to identify and resolve any prob-
lems encountered thus far in the design and development of the device; for exam-
ple, has the device failed a critical test? The design team should be encouraged
to work together to find solutions to any problems identified. The team should
then discuss the concerns raised during the evaluation portion of the meeting
and decide on an appropriate action for each one.
Not all identified concerns and problems will result in corrective action. The team
may decide that the issue is erroneous or immaterial. In most cases, however,
resolution will involve a design change, a requirements change, or a combination
of the two. Any actions identified and taken as a result of a problem (e.g., change
in specification, labeling, packaging, etc.) need to be documented, reviewed, and
approved. Some actions or changes may also require verification and/or vali-
dation of effectiveness. If the solution is not obvious, an action item should be
assigned to study the problem further, and any action taken should be reviewed
for effectiveness at a subsequent design review.
72
Design review
artificial stages and look at what the purpose of the review would be at that point
in the developmental project and some of the more important points that might be
included in an agenda.
Stage 1: Review immediately after initial design inputs are approved The pur-
pose of this initial design review meeting is to formally define and confirm the basic
requirements for the device (design inputs and expected outputs). It is also used to ini-
tiate the development and manufacturing phase and the beginning of design change
control. The initial design review meeting will also formally define the design proj-
ect team (see Appendix E: Project Approval Form). All the members of the project
team must be present at the initial design review meeting. In addition, an individual
who does not have direct responsibility for the design stage being reviewed needs
to be present. The presence of specialists who are capable of providing specific
expert guidance in critical areas may also be needed. The Product Performance
Specification (PPS) will serve as a critical element of the initial design review.
A typical agenda for this initial design review might include a review of the
following:
• The design inputs
• The expected outputs and any known outcomes
• The project plan: activities, resource assignments, and time lines for
completion
• The risk analysis
• The PPS
• Any other pertinent information
73
Design controls for the medical device industry
Stage 3: Final design review meeting After all verification and validation activ-
ities have been completed, a final design review meeting should be conducted.
The final design review should be held immediately prior to the transfer of the
device to manufacturing for production. The last design review meeting is the
final confirmation that the overall design output has met the overall design input.
All project team members should be present at the final design review meeting.
Any remaining changes or conflicting, ambiguous, or incomplete requirements at
this stage will need to be identified and resolved.
A typical agenda for a final design review meeting should include the following:
• A final review to ensure that the final design (output) satisfies design
input requirements
• Confirmation that all analyses, calculations, and tests have been suc-
cessfully carried out and that the final product can be manufactured,
inspected, assembled with adequate tolerances, stored, delivered, and
installed reliably, safely, and cost-effectively and will perform as expected
• Verification that all documentation for manufacturing, safety, installation,
operation, and maintenance of the device is ready for transfer to production
• A final review of the risk analysis to assess and ensure any additional
real or potential hazards associated with the device under normal and
fault conditions have been addressed
• Implementation and approval of any necessary changes needed prior to
transferring the design and development specifications and procedures
to production specifications and procedures
74
Design review
Min flow rate = 500 ml/hr Protocol 123 using ASTM Summary Report No action required
Method 123XYZ FR>500 ml/hr - Pass
Non-cytotoxic Protocol 100B - using Summary Report - Pass No action required
Agar Diffusion Method
Package integrity 49 CFR 173.465 & DOT Ship Testing Report - Change to foam packaging to
49 CFR 178.608 Fail eliminate damage & retest
2 Year Shelf Life Stability Protocol Shelf Life Stability Report - Stability data to support a 2
# 10-17-001 Pass year shelf life
Verification/Validation
Meeting dynamics
As a successful design review depends almost as much on conducting a success-
ful meeting as having accurate data, it seems appropriate to review some things
that can be done to ensure a successful meeting. The comments and concepts
reviewed in this section should prove useful to all members of the design review
team, including managers. They are in fact useful, tested, and verified concepts
that will work in any business communication setting.
75
Design controls for the medical device industry
Communication skills
The design review runs on information. People need clear, concise, and complete
information to plan, organize, and execute their responsibilities. Whether you’re
leading the meeting, evaluating the outcome, or making a presentation, you will
succeed or fail based on your ability to communicate. Words are the vehicles
people use to communicate their goals, objectives, and performance standards.
Unfortunately, many words are ambiguous and are often interpreted in differ-
ent ways. The definition of what’s a “good wage” may depend on whether you’re
paying it or receiving it. The 500 most commonly used words in the English
language have an estimated 10,000 different meanings. When an engineer says,
“I will complete this assignment as soon as possible,” does that mean in the next
two minutes, two hours, two days, or two months? We need to define our terms to
make sure the receiver and sender are on the same wavelength.
Being sure that the product has “superior quality” is a great idea, but it may not
explicitly communicate the desired behavior or results the team hopes to accom-
plish. Staff members may have their own idea of what “superior quality” means.
Each person may leave the meeting ready to implement his or her own definition
of “superior quality.” When sending and receiving information, make sure the
meaning is clear. Try saying something like, “My definition of superior quality
is …” or “As it applies here superior quality means ….”
The vocabulary of product development includes many abstract ideas and con-
cepts like superior quality. Not only should you define the terms, but you should
also provide concrete examples to help explain the abstract idea. Examples and
illustrations can provide tangible reference points to drive home the point.
Abbreviations and jargon also pose potential hindrances to effective communica-
tion. In technical areas that cannot always be avoided, but as the design team is
composed of people from different disciplines, be sure that terms are explained
and clear. “The team is writing a revision to the PPS. We have new information
from ASQC and ANSI that suggests this will be wise when we prepare the PMA
for CDRH.” Chances are some people will not know what all the initials mean.
Spell out or define what abbreviations mean. This extra step can be the difference
between understanding and confusion.
76
Design review
Verifying the message is a simple technique whereby the sender of the message
asks the receiver to explain his or her interpretation of the message. If the receiv-
er’s interpretation is accurate, then a successful communication has occurred. If
the interpretation is inaccurate, the sender needs to clarify and correct the mis-
understanding. People are much more likely to pay attention, concentrate, and
listen carefully if they know they may be called on to give their understanding of
the message.
Going one extra step to check out the receiver’s understanding can often save a
lot of grief. If the mirrored response is incorrect, the sender knows the message
needs to be restated. Of course, some breakdowns occur simply because the lis-
tener wasn’t paying attention.
The design team sits at the communication center of the development program
and is particularly vulnerable to communication breakdowns. The difficulty
of consistently verbalizing clear and accurate messages is immense. Never
underestimate that problem. Even the most carefully worded message can be
misunderstood. Periodic message verification can eliminate confusion and mis-
understanding and can prevent the small and large blunders that result from com-
munication breakdowns.
77
Design controls for the medical device industry
speaker their understanding of what is being said. Factors like the complexity
and importance of the message determine how often validation should occur. In
the design review setting, it is something that should occur frequently. There are
three levels of validation:
• Level I: Validate by feeding back the exact words used by the speaker.
• Level II: Validate by feeding back a paraphrase of the message.
• Level III: Validate by feeding back your interpretation of the words and
body language.
Team members need to listen, not only to the words of the message but also to the
tone of voice and body language. At times, it’s necessary to feed back what you
think the sender really means but has not said. As shared understanding builds,
the sender is often motivated to share additional thoughts and feelings.
78
Design review
information should be verified for accuracy with feedback received from others
and from personal observations. The purpose is not to affix blame but rather to
determine the facts. Given all the facts, almost anyone can make a proper decision.
Meeting minutes
Many design meetings end with confusion as to who has to do what and when.
During a design review meeting, as new and different action items are identified,
they can be written down on a flip chart or whiteboard. The due date and person
or people responsible for each item should also listed. At the end of the meeting,
the team leader can do a quick review of all action items on the list. The team
members can then leave the meeting with a clear understanding of who is respon-
sible for which action items and when they are due.
79
Design controls for the medical device industry
The ability to define and solve problems leads to progress and improvement.
Dealing with symptoms only wastes time, effort, and money. The process includes
the following steps:
• Define the problem
• Collect and analyze data
• Generate alternatives (i.e., brainstorm)
• Evaluate alternatives
• Select an alternative
• Implement the alternative
• Evaluate the result
In design review meetings, it is imperative to identify where the project is at any
given time so that a correction can be made if necessary. Many problems may
require multiple meetings, and different team members will frequently be at dif-
ferent points in the process. Little progress is made when everyone comes at a
problem from a different point in the process. An effective team leader brings the
group together by defining where they are in the process. Doing that improves
productivity by focusing the group to concentrate on one task.
Team leaders usually prepare what they are going to say but often don’t pre
determine what questions they will ask. An important aspect of leadership is the
ability to ask the right questions at the right time and to insist on answers that
make sense.
The answers to the right questions provide the team leader with the informa-
tion he or she needs to make decisions. These questions often touch on sensitive
or unpleasant topics. The questions should be simple, direct, and focused. They
should be framed to elicit a concrete, specific response. How the questions are
asked (choice of words, tone of voice, body language) is critical. It must be done in
a way that doesn’t cause defensive or adversarial responses. The questions should
be straightforward and asked from a neutral point of view, meaning not aggres-
sively or with strong emotion but not from a weak or passive position either.
Follow-up questions are often essential to achieve specific answers to the ques-
tions asked. If a person is unresponsive or vague, be persistent. Keep asking and
probing. Rephrase the question to get to the core of the issue.
Beware of people who know the solution before they understand the problem.
There is a tendency by some to go off designing systems, forms, and procedures
without understanding the real problem.
Design teams are confronted with a wide range of problems ranging from broken
machinery, to late deliveries, to unhappy customers, to conflicts among target
properties or people. Some problems are defined in such a way so that there is
only one obvious solution: “The problem is that the engineers aren’t working hard
80
Design review
enough.” Other problems are really symptoms of more basic underlying prob-
lems. Still other problems can be defined in such grand or global terms that it
paralyzes the ability to act.
In addition, design teams are often presented with problems that inspire futility.
After all, if the presented problem didn’t inspire futility, it would have already
been solved. Right?
The hardest part of problem solving is figuring out what the real problem is. As
indicated, sometimes the presented problem really isn’t the problem that needs
to be solved at all. Assess the accuracy of the data. Come to grips with reality,
as opposed to the images and perceptions. Break through the generalizations.
Complex problems should be broken down into smaller, simpler ones.
The problem statement should be free of either causes or solutions. The problem
should describe what currently exists versus what is desired. The more specific
and measurable the description, the better that description is. A problem state-
ment such as “How to reduce the scrap rate from 5 percent to 3 percent?” provides
specific and measurable criteria in the problem statement.
Once the problem is defined, the additional steps include the following:
• Collect and analyze the data
• Generate options or solutions
• Evaluate those options or solutions
• Make a decision
• Implement that decision
• Evaluate and measure the result to see if the problem has been solved
81
Chapter 9 Design verification
Design verification confirms whether the outputs meet the functional and opera-
tional requirements for the device; that the device is both safe and reliable; and
that the labeling and other regulatory requirements are satisfied.
In other words, did I make the product right (i.e., to specification), and can I
prove it?
83
Design controls for the medical device industry
Design verification activities should be conducted at all stages and levels of device
design and development and should be identified on the design and development
plan. Design verification is always conducted against specifications.
Manufacturers are expected to select and apply appropriate verification tech-
niques based on the generally accepted practices for the technologies employed in
their devices (e.g., look at what testing was done on predicate or similar devices).
Verification activities are required to be performed in accordance with estab-
lished procedures, and verification methods should clearly define (or reference)
acceptance criteria so that results can be evaluated to confirm whether the design
input requirements have been satisfied. This last statement cannot be stressed
enough. At this stage in the process, you are verifying the acceptability of the
device design, hence you need to know what is considered acceptable. There may
be some tweaking to the specifications that will result from this step, but this is
not the time to actually determine what is acceptable. This should have already
been determined. Some verification methods are highly standardized (e.g., steril-
ization to ISO 11135, 11137; biocompatibility to ISO 10993; medical device safety
to IEC 60601; etc.); however, in other cases manufacturers may choose from a
variety of applicable methods.
The results of all verification activities and any subsequent actions must be
recorded and include identification of the design, methods, date, and individual
performing the verification. This forms part of the Design History File. This will
include review and approval of protocols and results.
Verification activities
Any approach that establishes conformance with a design input requirement is an
acceptable means of verifying the design with respect to that requirement. The
nature of verification activities will of course vary depending on the design input
that you are verifying. Some verification activities will likely be pretty straight-
forward and simple (e.g., verifying device dimensions to an engineering drawing);
however, others will prove more complex (e.g., verifying device cleanliness and
sterility of a reusable device). The test methods that you use to conduct design
verification activities should be evaluated to ensure that they provide sufficiently
accurate, precise, and repeatable results under their usual conditions of use.
Analytical methods intended for identification, purity, or assay should be vali-
dated, as should methods developed to ensure cleanliness and sterility of devices.
Physical, electrical, mechanical, and performance measurement methods (other
than direct measurement by a capable, standard calibrated instrument) should be
considered for appropriate validation, especially if the method is for evaluating an
essential design output, that is, test method validation.
84
Design verification
85
Chapter 10 Risk management
Why?
Risk management has become a hot topic as of late with both government
Regulatory Authorities (e.g., FDA) and Notified Bodies. With the increasing
number of adverse event reports and recalls, it becomes more important than
ever to manage and control risks associated with the use of medical devices.
Consequently, the earlier in the design and development process that you begin
examining device risk, the better for everyone—especially the bottom line. We
all know that the earlier you can identify a potential and/or real problem and
fix it, the less costly and certainly less damaging to the company’s reputation.
It does absolutely no good to rush a device to market only to have to recall it
shortly thereafter.
87
Design controls for the medical device industry
No
D&D Yes
Verification Do Have
Determination of
Yes individual any new Individual
individual
residual risks meet Yes safety design residual risk review
residual risk after the No
the acceptability requirements been – Are residual risks
application of risk
criteria? identified during acceptable?
control
verification?
Yes
D&D No
Validation Have any
new safety design Do the Does the
requirements been benefits of use of the overall
identified during
No device out-weigh the No residual risk meet the
validation?
risks of using the overall acceptability
Project cancellation criterion?
device?
or device redesign
Design
Design transfer Yes
Transfer
Yes GHTF.SG3.N15-R8, P.20
The Global Harmonization Task Force, Study Group 3 provides a flowchart that
illustrates how risk management should be integrated into the design and develop-
ment process (see Figure 10.1).
88
Risk management
Given this definition we can then look at the terms risk analysis and risk manage-
ment. Risk analysis is really just a subset of risk management. In simple terms,
risk analysis is the process of collecting and examining information or data in
order to identify real and potential hazards associated with the use and misuse of
a device and then estimating the risk associated with those hazards. Risk manage-
ment includes risk analysis and the process of evaluating the individual risks and
the overall risk for acceptability, controlling any unacceptable risks or justifying
them, and then managing risks through postmarket experience.
89
Design controls for the medical device industry
(i.e., affect the safety of the device) under normal and/or fault conditions. This
might require that the team formulate a series of questions concerning the man-
ufacture, sterilization, intended use and application, intended users, reasonable
foreseeable misuse, accessories and connectors to the device, environmental influ-
ences, device packaging, transport and storage, and ultimately device disposal.
These questions should be considered from the point of view of all individuals
involved with the device (e.g., assemblers, users, service providers, patients, etc.).
Again, Annex C of ISO 14971 provides a list of potential questions. The team
then needs to identify the hazards associated with the device characteristics if
used correctly, as well as incorrectly, and determine the degree of risk associated
with each hazard. Hazards and contributing factors associated with a device may
include environmental hazards, biological hazards, hazards relating to use of the
device, and hazards arising from function and aging. Most people have no trouble
identifying the really big problems. Actually, most design engineers “design out”
major hazards from the beginning. The problems and risks that are often over-
looked are the minor ones or the ones that are associated with misuse. As medical
device manufacturers, we can’t always account for every dumb or unexpected use
that someone tries with a product, but we must try. Although these minor prob-
lems don’t necessarily render the device unsafe or ineffective, they are often the
difference between a good product and a great product.
Risk analysis is not difficult if the team remembers to think of the customer. The
new device design has accomplished all of the hard stuff, but what happens to the
patient when he or she puts it on? It may help manage or treat whatever problem it
was intended to address, but shouldn’t it be as comfortable as possible? It should
also be as reliable as possible; does the design account for that? What about the
needs of the physician, the nurse, or the caregiver in the home health environ-
ment? Does the device become ineffective and perhaps create a hazard for any
of them? What happens to the device if it is used exactly as you intended and
instructed? It should work perfectly, and most design teams think about that. What
happens if someone uses the device in a manner that isn’t typical? What happens if
the device is used in an environment that the team did not take into account? What
happens when you put all these things together—the user, the environment, and
the device—and they interact in a manner that you didn’t think of?
The reason for risk management is to answer questions such as these. If the haz-
ard created by an atypical use of a device can be reduced or eliminated in the
design stage, then do it.
Hazards traditionally considered in risk analysis include the following:
• Mechanical hazards
• Operational hazards
90
Risk management
• Chemical hazards
• Biological hazards
• Electrical and energy hazards
• Storage and transport hazards
• Informational hazards
These hazards, however, typically result not from device use but rather from
instances of device or component failure.
Once you identify a hazard, it is important that you determine the source of the
hazard. If you do not know where or how or why the hazard is likely to occur, then
it is unlikely that your mitigating actions will be effective. Common techniques
that may be used to assess risk include the following: fault tree analysis (FTA),
failure mode and effects analysis (FMEA), failure mode effects criticality analy-
sis (FMECA), and a hazard and operability study (HAZOP).
Remember, risk = probability + severity. As a result, once you identify the possi-
ble hazards that may occur, you need to estimate the chance or probability that the
hazard will occur and the resultant consequences or harm in order to determine
the level of risk. It is the manufacturer’s responsibility to determine and establish
probability levels and severity levels and associate each level with some type of
descriptive or semiquantitative or qualitative measure. The number of levels is up
to you. A simple probability matrix and severity matrix are shown in Table 10.1
and Table 10.2.
91
Design controls for the medical device industry
92
Risk management
eliminate the risk or reduce it to an acceptable level. There are a few different
ways in which you can reduce the risks associated with a medical device. Risk
control measures may be taken to reduce the severity of the harm or reduce the
probability of occurrence of the harm, or both. Some regulatory schemes pre-
scribe a fixed hierarchy for controlling risk that should be examined in the fol-
lowing order:
1. By direct safety means: Modify the device design to remove a hazard or
reduce its consequences.
2. By indirect safety means: Add protective measures or safeguard against
the hazard. For example, restrict accessibility (e.g., for radiation hazards),
shield users from the hazard by means of a protective cover (e.g., like
when you go in to get an X-ray), have a backup mechanism in case of
failure, use automatic cutoff or safety valves, or use visual or audible
alarms to alert the operator to hazardous conditions.
3. By redefining the intended use: Modify the use of the device to pre-
clude the hazard.
4. By descriptive safety means: Warn the operator of the hazard via warn-
ings in the labeling (see following text), restrict the period or frequency of
use of the device, or restrict the application, lifetime, or environment by
providing training to users and specifying necessary maintenance and
maintenance intervals, maximum expected product service life, or how
to dispose of the device properly.
Note that reducing the level of risk by descriptive safety means should be consid-
ered as a last resort. You should always try to fix potential problems and hazards
rather than put bandages on them. A bandage approach such as adding a warning
to an instruction for use (IFU) or reformatting the IFU rarely effectively prevents
use errors, as there is no assurance that the users will even read it. A combina-
tion of strategies is recommended. I saw a demonstration of this not too long ago.
A friend was doing rounds with a nurse in a veteran’s hospital. The nurse was
to inject insulin into a diabetic patient and was using a new type of device. The
nurse, however, did not bother to read the IFU because IFUs are typically just
thrown in a drawer somewhere, and she didn’t have time to go find it. My friend
said she watched the medicine spread out underneath the skin rather than go
into the vein. She was certain of this because of the change in coloration under
the skin and her professional experience. The nurse then proceeded to mark the
patient’s chart to show that the medication had been given and was about to go
on her way. Luckily my friend, who is a very well-educated medical professional,
insisted that the nurse take another look and remedy the situation. But had she not
noticed the error herself, the patient’s chart would have shown that the medica-
tion had been given to the patient, which would have left the professional staff in
a quandary if the patient began to exhibit symptoms related to a drop in insulin.
As you can see, even if you put all the detail in the world into the IFU, there is no
93
Design controls for the medical device industry
guarantee that anyone is going to read it. Consequently, even though your device
may be the latest and greatest thing and may be way better than the competition’s
device, if your device isn’t designed with the user in mind, and correct use of the
device isn’t known or shown to the user, the patient may suffer the consequences.
Keep in mind that the actions needed or taken to reduce risk may entail a great
deal of work and possible redesign of the product itself. It seems almost conde-
scending to mention it, but there are risks associated with most medical treat-
ments, and there may be risks and hazards associated with the use of a particular
device. However, these major risks are almost always known to the people doing
the design development and are either eliminated or minimized by the design
itself or handled in the labeling if the associated risk is outweighed by the benefits
delivered to the patient when using the device. Most engineers have completed a
reliability analysis related to the use of a particular device. They know what will
happen to the patient, the user (if other than the patient), and the surrounding
environment should there be a device failure. What usually needs more attention
is what will happen if someone tries an unexpected use of the product.
Remember, the team has been designing the device for use in a very particular
way and most likely with a specific environment in mind, but someone could use
the device in an entirely different way or in an unexpected environment. Suppose
that you manufacture a skin cleanser that has been formulated into a cream. What
will happen if the end user confuses the cleanser with his toothpaste tube and uses
it to brush his teeth? You may not be able to prevent the occurrence, but have you
done anything to minimize it? Both the development team and the manufacturer
have an obligation to minimize risks associated with the use of the device even if
the end user uses the device inappropriately.
It should be noted at this point that this is not often easy to do, since it is some-
times considered impossible to anticipate every way that a device may be used.
Even when a set of circumstances can be envisioned, it is often difficult to then
estimate how severe that particular hazard may be. But it must be done.
Remember that any action taken to reduce a risk may create a new risk or hazard
or increase the significance of other existing risks. As a result, you need to iden-
tify and evaluate any possible change in risk after implementing a risk control
measure by examining the residual risk. If the level of risk is still not acceptable,
further risk control measures or mitigation may be necessary, and/or a risk-benefit
analysis should be performed to justify the risk.
Once all individual hazards and associated risks have been identified and appro-
priately controlled (i.e., the residual risk is acceptable and/or justified), you need
to determine if the overall or total risk from all sources is acceptable. Just because
the individual risks may all be within the acceptable range, the summation of all
of these risks may not be acceptable. Think of an engineering drawing where
94
Risk management
each part in an assembly has its own individual dimensions and tolerances. If all
of the parts are at their maximum tolerance, the finished assembly or device may
not fit together, or it may no longer meet the user’s needs.
* Bogner, M.S. “Medical Devices and Human Error.” In Human Performance in Automated Systems:
Current Research and Trends, edited by M. Mouloua and R. Parasuraman, 64–67. Hillsdale, NJ:
Lawrence Erlbaum, 1994.
† Nobel, J.L. “Medical Device Failures and Adverse Effects,” Pediatric Emergency Care 7 (1991):
120–23.
95
Design controls for the medical device industry
* “Applying Human Factors and Usability Engineering to Optimize Medical Device Design,” FDA
Draft Guidance, June 22, 2011.
96
Risk management
97
Chapter 11 Design validation
Why validate?
Validation goes beyond the technical issues of verifying that output meets input
requirements. Validation is needed to demonstrate that the medical device meets
the user’s requirements and the intended use; that is, it is a product the market-
place needs. As a result, its purpose is to provide objective evidence that design
specifications (outputs) confirm predetermined user needs and intended uses,
given expected variations in components, materials, manufacturing processes,
and the use environment.
99
Design controls for the medical device industry
100
Design validation
101
Design controls for the medical device industry
If you are looking to sell your product in Europe, you should be pretty familiar with
the requirements of a clinical evaluation, as a clinical evaluation is required for all
medical devices entering the European market per Annex I of the Medical Device
Directive. Appendix H includes a template for documenting a clinical evaluation.
It is based on Appendix E of the European Commission’s MEDDEV 2.7.1 guid-
ance document on clinical evaluation. A clinical trial, also referred to as a “clinical
investigation” or “clinical study,” is defined as any systematic investigation or study
in or on one or more human subjects, undertaken to assess the safety and/or per-
formance of a medical device with the objective to assess the safety and clinical
performance of the device in question and evaluate whether the device is suitable
for the purpose(s) and the population(s) for which it is intended (GHTF SG5/N1R8).
During design validation, deficiencies in original assumptions (e.g., device specs
and outputs) regarding user needs and intended uses may become apparent.
Design validation may also uncover new risks or hazards. As a result, any actions
taken to resolve deficiencies need to be addressed and resolved prior to the trans-
fer of the device design to production.
Including validation activities in a traceability matrix helps to demonstrate how
user needs were translated into design inputs and then linked to the validation
activities. Each test should link to a test report or study protocol and its final report.
102
Design validation
103
Chapter 12 Biocompatibility
Ensuring that medical devices and their components and materials are biocom-
patible is an essential element of any design control program. Biocompatibility is
generally determined by using tests that answer two fundamental questions:
1. Is the material safe?
2. Does it have the necessary physical and mechanical properties for its
proposed function?
A biomaterial is usually a complex entity, and the material toxicity is affected by
both physical and chemical properties. Toxicity from a biomaterial or polymer
formulation often comes from components that migrate to the surface and are
extracted from the material. Material testing is performed to determine the toxic-
ity of the material, if there are any leachable substances, and if the material or
device is subject to degradation over time and in different environments.
Biocompatibility cannot be defined by a single test. As a result, it is necessary to
test as many biocompatibility parameters as possible. It is also important to test
as many samples of the material as possible. Suitable positive and negative con-
trols should be used and produce a standard response in repeated tests. The use
of an exaggerated challenge, such as using higher dose ranges and longer contact
durations or multiple insults that are more severe than the actual use condition, is
important to ensure patient safety.
Most of the biocompatibility tests to establish acute toxicity are short-term tests.
Data from these short-term tests should not be overextended to cover the areas
where no test results are available. Biocompatibility testing should be designed to
assess the potential adverse effects under actual use conditions or specific condi-
tions close to the actual use conditions. The physical and biological data obtained
from biocompatibility tests should be correlated to the device and its intended use.
Accuracy and reproducibility of these tests will depend on the method and equip-
ment used and often on the investigator’s skill and experience.
There are several toxicological principles that you should consider before plan-
ning biocompatibility testing. Biocompatibility depends on the tissue that contacts
the device. For example, the biocompatibility requirements for a blood-contacting
device would be different from those applicable to an external urinary catheter.
The degree of biocompatibility assurance also depends on the degree of invasive-
ness and the duration of contact with the human body. For example, some materi-
als, such as those used in orthopedic implants, are meant to last for a long time in
the patient. In this case a biocompatibility test needs to show that the implant does
105
Design controls for the medical device industry
not adversely affect the body during the long period of use. The possibility of bio-
degradation of a material or device should also not be ignored. Biodegradation by
the body can change an implant’s safety and effectiveness. For example, the mate-
rials leached from plastic used during a single hemodialysis procedure may be
very low, but the patient who receives dialysis three times a week may be exposed
to a total of several grams during his or her lifetime. Therefore, the cumulative
effects should also be assessed when appropriate.
It is also important to note that two materials having the same chemical compo-
sition but different physical characteristics, for example, particle size, may not
induce the same biological response. Past biological experience with seemingly
identical materials is also not necessarily a guarantee of biocompatibility in a
new application. Toxicity may come from leachable components of the material
because of differences in formulation and manufacturing procedures.
The challenge of biocompatibility testing is to use existing data as far as feasible
to reduce the degree of unknowns and to help make the logical decisions. The
hazard presented by a substance with its inherent toxic potential can be truly
known only when the material is actually exposed to a patient. Therefore, risk
is a function of toxic hazard and exposure. The safety of any materials that may
migrate from a device or be contained in the device or on its surface can be evalu-
ated by determining the total amount of a potentially harmful substance, estimat-
ing the amount reaching the patient’s tissues, assessing the risk of exposure, and
performing a risk versus benefit analysis. When the potential harm from the use
of biomaterial is identified from the biocompatibility tests, this potential must be
compared against the availability of an alternate material.
* Medicines and Healthcare Products Regulatory Agency, “Guidance on the Biological Safety
Assessment,” London, January 2006.
106
Biocompatibility
Sub-chronic Toxicity
Pyrogenicty (Rabbit)
Duration
Hemocompatibility
Chronic Toxicity
1=Limited
Carcinogenicity
Acute Systemic
(<24 hr)
Implantation
Genotoxicity
Sensitization
Body Contact Cytotoxicity
2=Prolonged
Hemolysis
Irritation
Toxicity
(24hr –30days)
3=Permanent
(>30 days)
External Intact Skin 1
Devices 2
3
Intact 1
Mucous 2
Membranes 3
Breached 1
Surfaces 2
3
External Blood Path 1
Communicating Indirect 2
Devices 3
Tissue°Bone/ 1
Dentin 2
Communicating 3
Circulating 1
Blood 2
3
Implant Tissue/Bone 1
Devices 2
3
Blood 1
2
3
various medical devices (see Table 12.1). Whether you choose to use the FDA’s
modified matrix or the ISO 10993-1 matrix, know that both provide only a frame-
work for the selection of tests and not a checklist of every required test. Again,
the number and types of specific safety tests required to assess product safety and
compliance will be dependent on the individual characteristics of the finished
device, its component materials, and its intended clinical use. The FDA’s Blue
Book Memorandum G95-1 also includes a chart to assist manufacturers in identi-
fying the toxicity tests that may be required for a 510(k) (see Figure 12.1).
Medical device manufacturers need to also be careful about using “generally rec-
ognized as safe” (GRAS) substances. GRAS substances can be found in 21 CFR
Part 182 and are applicable to food. As a result, any material or substance in
the GRAS list cannot automatically be assumed as safe and effective for medi-
cal devices.
107
Design controls for the medical device industry
Start BIOCOMPATIBILITY
REQUIREMENTS MET
Does the
device contact the No
body directly or
indirectly?
Yes
Is the
Same Same Same
material same as Same body
Yes manufacturing Yes chemical Yes Yes sterilization Yes
in the marketed contact?
processes? composition? method?
device?
No No
No No
No Yes
Acceptable
No Yes
justification or
test data?
Yes Yes
No
Consult device specific Adequate
tox profile for No justification
appropriate tests provided?
Figure 12.1 Biocompatibility flowchart for the selection of toxicity tests for 510(k)s.
108
Biocompatibility
• Monitor incoming raw materials, the final product, and the manufactur-
ing process
• Define the product release tests and the pass–fail criteria.
In addition, manufacturers should select reliable, state-of-the-art bioassays to
demonstrate safety for the intended use of the device.
Regulatory issues are equally as complex as the scientific considerations. Some
regulatory issues are as follows:
• Anticipated human exposure to the device
• Biological resistance to chemical insult
• Testing variables
• Species differences
• Relevance of the test to the device and its use
• Substantiating the accuracy and predictive values of the test
• Proper interpretation
• The use of no observed biological responses (negative results) to chemi-
cal insult(s) to predict biocompatibility
Undesirable extremes should be avoided during the design of biocompatibility
testing programs. As indicated previously, it is important not to attempt to demon-
strate biocompatibility by a single test. More importantly, your biocompatibility
program should be based on the intended use of the device. Performing a large
number of tests with a number of test samples is as important as the accuracy,
specificity, significance, and economy of the testing. Medical devices vary widely
in their types, uses, functions, exposures, and contact ions. Therefore, one test
system cannot accommodate all applications. Manufacturers do not, however,
have to repeat extensive biocompatibility testing programs simply to fill the files
with evidence of safety if the device is constructed of well-known, previously
well-tested materials or only uses materials with a long, safe history for the same
intended use. Some tests may be inappropriate or unnecessary for the intended
use of the device. For example, pyrogenicity tests are appropriate for intravenous
catheters but not for topical devices that contact only intact external surfaces.
109
Design controls for the medical device industry
Level II
Chronic Implantation
Reproductive and developmental
Carcinogenesis
Additional tests based on Level I (e.g., pharmacokinetics)
all other testing conducted. These tests have broad application and low
resolution and are recommended for screening during the early stages of
development and continued monitoring of new lots of materials.
• Level II tests include acute toxicity tests and some subchronic and
chronic tests, if needed. Level II testing is basically an extension of
Level I and involves a variety of in vitro and in vivo testing of devices
that require additional testing based on the Level I screening test results.
This includes extensive preclinical tests such as pharmacokinetic stud-
ies and lifetime bioassays or special testing due to the complexity and/or
intended use of the device.
• Level III testing is the highest level of testing for a medical device and
involves clinical studies. This is especially important for implantable
devices. Manufacturers should determine whether to proceed to Level II
or Level III testing depending on the results of Level I tests.
110
Biocompatibility
Screening tests
There is a risk in testing finished devices without first developing data on com-
ponent materials. If an adverse event occurs, it may prove difficult to determine
which component is causing the problem. Screening device materials minimizes
this risk, allows a rapid and relatively inexpensive rejection of incompatible mate-
rials at an early stage, and can be used as a monitoring device of the manu-
facturing process. Cytotoxicity tests, intracutaneous and/or skin irritation tests,
and hemocompatibility tests are good candidates for screening material safety. In
addition, there are many cell or tissue culture methods that can be custom tailored
to biomaterials. Unless clearly contraindicated, both direct contact tests and tests
with extracts with polar and nonpolar extraction media should be considered.
Note these screening tests are intended not to demonstrate that the material is
biocompatible but to reject grossly incompatible materials.
Systemic toxicity
The risk of a medical device causing systemic toxic reactions during short-term,
long-term, or continuous application on or in the human body depends mainly on
the risk that relevant quantities of toxic substances may be released from the prod-
uct to become systemically available during its intended use. Systemic toxicity
refers to the way the animal/human body is affected as a whole. In systemic
toxicity testing, the animal is exposed to the test article or the extract of the test
article. Four categories of systemic toxicity testing exist, and each is based on the
duration of exposure:
• Acute toxicity: a toxic effect resulting from a single, short-term (24 to 72
hours) exposure to a chemical substance.
• Subacute toxicity: a toxic effect that results from a single dose or mul-
tiple doses to a chemical substance for 14 to 28 days (~ 1 month).
• Subchronic toxicity: a toxic effect resulting from prolonged exposure to
a chemical substance for up to 90 days (1 to 3 months).
• Chronic toxicity: a toxic effect from continuous and prolonged exposure
for over 90 days (typically 6 to 12 months).
Toxicity testing should be used in conjunction with chemical and physical analysis
to prevent costly development of unsatisfactory materials. Most medical devices
will not require chronic toxicity testing. The category of testing required should
be similar to the clinical intended use of the medical device.
The most common cause of acute toxicity of biomaterial is the presence and
leachability of toxic substances. Therefore, the detection of leachable substances
should be the principal focus of the test systems.
111
Design controls for the medical device industry
Tests for acute toxicity include but are not limited to the following:
• ISO 10993-11: Tests for Systemic Toxicity
• OECD 423: Acute Oral Toxicity
• USP <88>: in vivo Biological Reactivity Tests
• ASTM F-750: Standard Practice for Evaluating Material Extracts by
Systemic Injection in the Mouse
Acute systemic toxicity tests use extracts of the device or device material to detect
leachables that produce systemic (as opposed to local) toxic effects. The extracts of
the test material and negative control blanks are injected into mice (intravenously
or intraperitoneally, depending on the extracting media). The mice are observed
for toxic signs just after injection and at four other time points. The materials
biocompatibility matrix recommends this test for all blood contact devices. It may
also be appropriate for any other device that contacts internal tissues.
Subchronic toxicity tests are used to determine potentially harmful effects from
longer-term or multiple exposures to test materials and/or extracts during a period
of up to 10 percent of the total life span of the test animal (e.g., up to 90 days in
rats). Actual use conditions of a medical device need to be taken into account
when selecting an animal model for subchronic toxicity. Subchronic tests are
required for all permanent devices and should be considered for those with pro-
longed contact with internal tissues. Subchronic systemic toxicity tests include
ISO 10993-11.
A fourth type of systemic toxicity testing is pyrogenicity testing. It is used to
determine whether a test article has the ability to cause a fever-like response when
introduced into the blood. Devices in contact with circulating blood or cerebro-
spinal fluid are required by the FDA to be nonpyrogenic, as are intraocular lenses.
In the United States there are two types of tests for pyrogenicity: one is in vitro,
and the other is in vivo.
• The bacterial endotoxin (LAL) test is an in vitro test that detects pyro-
gens that are bacterial in origin, called endotoxins. The LAL test is used
for lot release testing and must be validated for each device or material
(USP <85>: Bacterial Endotoxins Test/ISO 10993-11).
• The rabbit pyrogenicity test is an in vivo biocompatibility test that detects
bacterial endotoxins and material-mediated pyrogens that may be found in
test materials or extracts (USP <151>: Pyrogen Test/ISO 10993-11).
112
Biocompatibility
(extracts). Several highly specialized cell culture techniques are available to mon-
itor the biocompatibility of the raw materials used in manufacturing the device or
auditing the manufacturing process.
Cytotoxicity testing provides a rapid, inexpensive, reliable, convenient, sensitive,
and reproducible screening method to detect, at an early stage in the testing pro-
cess, cell death or other serious negative effects on cellular functions. Test results
should be used for evaluating and screening biomaterials prior to conducting
in vivo tests. If a sample is going to fail any of the biocompatibility tests, it is said
that 90 percent of the time it will fail the cytotoxicity test first. Cytotoxicity testing
is not a pass–fail test. Failure in cytotoxicity is generally grounds for performing
a confirmatory test such as an implantation or intracutaneous reactivity test.
There are many cytotoxicity test methods available for testing biomaterials. These
tests can be divided into three categories: tests using extracts, direct contact tests,
and indirect contact tests. Which test(s) to be performed will depend on the nature
of the sample to be evaluated, the potential site of use, and the intended use. The
three common in vitro tests discussed in ISO 10993-5 include the following:
• Minimum Essential Medium (MEM) Elution Assay
• Direct Contact Assay
• Agar Diffusion/Overlay Assay
113
Design controls for the medical device industry
114
Biocompatibility
Irritation tests
Once in vitro testing has been completed (e.g., cytotoxicity testing), in vivo
biological testing can be done based on the device’s intended use. Irritation or
intracutaneous tests estimate the irritation and sensitization potential of devices,
materials, and/or extracts using appropriate site or implant tissue such as skin and
mucous membranes in an animal model and/or human. The route of exposure
(skin, eye, mucosa) and duration of contact should be appropriate to the antici-
pated clinical use of the device. For example, if the product is a contact lens case,
then ocular irritation should be performed.
115
Design controls for the medical device industry
Irritation and intracutaneous reactivity tests include but are not limited to the
following:
• USP <88>/ISO 10993-10/ASTM F-749: Intracutaneous Reactivity Test
• ISO 10993-10/OECD 404: Dermal Irritation (Draize Skin Test)
• ISO 10993-10: Mucosal Irritation Tests (vaginal, rectal, oral, penis)
• ISO 10993-10/OECD 405/FDA: Ocular Irritation Test (Draize Eye Test)
Testing of intracutaneous reactivity, dermal irritation, and ocular irritation are
the three most common irritation test procedures. However, depending on the
intended use of a medical device, other test procedures may be considered.
The intracutaneous test is a sensitive acute toxicity screening test for detecting
potential local irritation by using extracts of the test material and blanks and inject-
ing them intradermally. The injection sites are scored for erythema and edema
(redness and swelling). This procedure is recommended for devices that will have
externally communicating or internal contact with the body or body fluids. It
reliably detects the potential for local irritation due to chemicals that may be
extracted from a biomaterial.
The primary skin irritation test is performed to demonstrate the potential toxicity
of the device through its contact with the skin. As such, it should be considered
for topical devices that have external contact with intact or breached skin. In this
procedure, the test material or an extract is applied directly to intact and abraded
sites on the skin of a rabbit. After a 24-hour exposure, the material is removed,
and the sites are scored for erythema and edema.
Mucous membrane irritation tests are recommended for devices that will have
externally communicating contact with intact natural channels or tissues. These
studies often use extracts rather than the material itself. Some common proce-
dures include vaginal, cheek pouch, and eye irritation studies.
Sensitization tests
Sensitization studies help to determine whether a material contains chemicals
that cause adverse local or systemic effects after repeated or prolonged exposure
(i.e., an allergic response). Sensitization is a delayed hypersensitivity reaction
(an immune response that takes a couple of days to develop) and is manifested in a
variety of clinical complications. Studies to determine sensitization potential may
be performed using either specific chemicals from the test material, the test mate-
rial itself, or, most often, extracts of the test material. Guinea pigs are especially
suitable for the evaluation of possible sensitizing properties of medical devices,
raw materials, or extracts.
Sensitization tests include but are not limited to the following:
116
Biocompatibility
Hemocompatibility tests
Hemocompatibility testing is required for any medical device or material that
comes into contact (directly or indirectly) with blood or blood components. In
practice, few materials have consistently shown good hemocompatibility. All
materials are to some degree incompatible with blood because they can either
disrupt the blood cells (hemolysis) or activate the coagulation pathways (throm-
bogenicity) and/or the complement system.
The ISO 10993-4 standard defines the categories of evaluations to be performed
for devices or components that come into contact with blood, and outlines which
types of medical devices need to have which test performed in Table 12.1. The
FDA, however, doesn’t agree with the chart but provides no guidance for testing.
The five categories of hemocompatibility testing outlined in ISO 10993-4 are throm-
bosis, coagulation, platelets, hematology, and complement system (immunology).
With the exception of thrombosis, which is in vivo, all of the other tests are
in vitro assays.
In the thrombogenicity (thrombosis) test, the test article is implanted into the
vasculature of an animal. After a given period of time, the implanted vessel is
removed, and the test article is observed for clot formations. Because thrombo-
genicity tests are usually difficult, controversial, and expensive, manufacturers
should contact the FDA to choose the proper model and test protocol.
117
Design controls for the medical device industry
The four remaining tests are carried out in test tubes and evaluate specific actions:
whether the test article has an effect on the blood’s ability to clot or coagulate,
can regulate an immune response, or can damage the cellular components of
the blood.
The hemolysis assay is recommended for all devices or device materials except
those that contact only intact skin or mucous membranes. This test measures the
damage to red blood cells when they are exposed by direct contact to materials or
their extracts and compares it to positive and negative controls. A hemolysis test
is a rather rapid test that requires simple equipment and provides easily interpre-
table quantitative results. The ASTM F-756 Standard Practice for Assessment of
Hemolytic Properties of Materials can be used to measure the hemolytic potential.
Coagulation assays measure the effect of the test article on human blood coag-
ulation time. They are recommended for all devices with blood contact. The
prothrombin time (PT) assay is a general screening test for the detection of coag-
ulation abnormalities in the extrinsic pathway. The partial thromboplastin time
(PTT) assay detects coagulation abnormalities in the intrinsic pathway.
Complement activation testing is recommended for implant devices that contact
circulatory blood. This in vitro assay measures complement activation in human
plasma as a result of exposure of the plasma to the test article or an extract. The
measure of complement actuation indicates whether a test article is capable of
inducing a complement-induced inflammatory immune response in humans.
The platelet test is performed to see how well platelets clump together and cause
blood clots. Using this method, a blood sample is obtained from an animal that
has been exposed to the intact material. The number of platelets per mm3 is
then determined.
Other blood compatibility tests (e.g., erythrocyte stability, protein absorption) and
specific in vivo studies may be required to complete the assessment of material–
blood interactions.
Implantation tests
Implantation tests are performed to determine the local and/or systemic effects of
implanted devices or materials. In implantation testing, the test material is surgi-
cally implanted or placed into the body or appropriate tissue of test animals. The
tissue chosen for implantation should be tissue that is most suitable for the test
article. When in doubt, do the muscle implant test.
The implantation study should reflect the intended clinical use and the intended
duration of contact with the body (e.g., short term or long term). Multiple time
points are conducted. For a permanent implant, a minimum short term of 1 to
4 weeks should be performed, and a long term should be conducted over 12 weeks.
118
Biocompatibility
119
Design controls for the medical device industry
Supplemental testing
Supplemental testing involves reproductive toxicity testing and carcinogenicity
studies and degradation studies. These are all long-term tests that can prove to
be quite costly.
Carcinogenicity testing
Carcinogenicity testing is used to determine the tumorigenic potential of medical
devices, materials, and/or their extracts from either single or multiple exposures,
over a period consisting of the total life span of the test animal (e.g., 2 years for
rats, 18 months for mice, or 7 years for dogs).
Carcinogenicity testing of devices is expensive, and manufacturers should con-
duct such tests only if data from other sources suggest a tendency for tumor induc-
tion. Situations where the need for carcinogencity testing should be considered
include the following:
120
Biocompatibility
• Resorbable materials and devices for which the resorption time is greater
than 30 days, unless there are significant and adequate data on toxicoki-
netics or human use or exposure
• Materials and devices where positive results have been obtained in
genetic toxicity testing in both mammalian cells and in vivo
• Materials and devices introduced in the body and/or its cavities with a
permanent or cumulative contact of 30 days or longer, except when sig-
nificant and adequate human use history is available
Tests for carcinogenicity include the following:
• ISO 10993-3: Tests for Genotoxicity, Carcinogenicity, and Reproductive
Toxicity
• OECD 451: Carcinogenicity Studies
• OECD 453: Combined Chronic Toxicity/Carcinogenicity Studies
Biodegradation
Careful consideration of the potential for intended or unintended degradation of a
material is essential to the evaluation of the biological safety of a medical device.
121
Design controls for the medical device industry
Per Annex A of ISO 10993-9, degradation studies should be considered if the fol-
lowing is factual:
• The device is designed to be bioresorbable.
• The device is intended to be implanted for longer than 30 days.
• An informed consideration of the material(s) system indicates that toxic
substances may be released during body contact.
Biodegradation tests how much of the product or material is absorbed by the
body and follows the product or material through the body after it has been
absorbed to determine the effects over time. Degradation products can be gener-
ated in different ways, either mechanically, by fatigue loading, and/or by release
from the medical device due to interactions with the environment or combinations
thereof. The level of biological tolerability of degradation products depends on
their nature and concentration and should be primarily assessed through clinical
experience and focused studies.
Biodegradation testing includes the following:
• ISO 10993-9: Framework for Identification and Quantification of Potential
Degradation Products
• ISO 10993-13: Identification and Quantification of Degradation Products
from Polymeric Medical Devices
• ISO 10993-14: Identification and Quantification of Degradation Products
from Ceramics
• ISO 10993-15: Identification and Quantification of Degradation Products
from Metals and Alloys
• ISO 10993-16: Toxicokinetic Study Design for Degradation Products
and Leachables
122
Chapter 13 Design transfer
123
Design controls for the medical device industry
124
Design transfer
125
Design controls for the medical device industry
Canada Medical Device License, Europe CE Technical File), you are now ready
to release the product for distribution. An Approval for Sale Form is typically
completed prior to product launch to document the confirmation from all project
team members and management that all activities have been completed and the
device is ready for launch. An Approval for Sale Form template is provided in
Appendix K.
126
Chapter 14 Design change
127
Design controls for the medical device industry
128
Design change
129
Chapter 15 Design history file
131
Design controls for the medical device industry
Risk Analysis
Design Changes
Design Reviews
Design Validation
Design Inputs
DHF
Design Verification
Design Outputs
Design Plans
Note that DHFs are typically frozen after the final design transfer. When design
changes are made postproduction, addendums can be created or the supporting
documentation can be maintained in accordance with the firm’s change control
process. The original DHF should be the embodiment of the new product as it was
released for commercial distribution.
Many of the design output documents that form part of the DMR will come
directly from design and development activities. The remaining elements and
documents will be created using design output data and information. For exam-
ple, finished device test methods and data collecting forms may be derived from
design verification protocols.
The DMR includes or refers to the location of the following:
• Device specifications, including drawings, composition, formulation,
component specifications, and software specifications
• Production process specifications, including equipment specifications,
production methods, procedures, and environment specifications
132
Design history file
133
Chapter 16 The FDA inspection
technique
Oh no! The FDA investigator is here
So you’re about to be inspected or audited for compliance with the design control
requirements. What can you expect? First of all, if you’ve been doing everything
correctly, there is not much to worry about. An inspection or ISO audit will hap-
pen sooner or later. If things are running smoothly and you are complying with
the systems you put in place to meet the requirements, you should be fine.
The drawing in Figure 16.1 represents the process flow or FDA’s Quality System
Inspection Technique (QSIT) for inspecting the design control requirement.
The primary purpose of the FDA design controls subsystem inspection is to eval-
uate the process, the methods, and the procedures that a manufacturer has estab-
lished to implement the requirements for design controls. Although this diagram
outlines the FDA’s approach to auditing the design control requirements, it could
just as easily be applied to an ISO 9001 or ISO 13485 compliance audit.
In addition to the material mentioned previously, there are some questions that
may likely arise during an inspection or audit. These include, but are not limited
to, the following:
• General design control requirements:
• What initiates a design project?
• When does the actual design and development begin (e.g., design
controls)?
• Design and development planning:
• How is each design and development activity identified and
documented?
• How are responsibilities defined?
• Are design and development activities assigned to qualified personnel?
• Are plans updated as the design evolves?
• Are the organizational and technical interfaces between different
groups that input into the design process identified?
• Do procedures exist for the documentation, transmittal, and review
of interdepartmental data exchanges?
• Design input:
• Do design inputs include customer requirements?
• Do design inputs include applicable statutory and regulatory require-
ments for those countries in which you are intending to market?
135
820.30(f ), 820.30 (g)
136
820.30(g)
Confirm acceptance criteria were est-
Select a single design project Confirm that risk anlaysis was
ablished prior to the performance of
performed.
verification and validation activities.
Confirm design inputs were Confirm that unresolved discrepancies Verify that design reviews were
Design controls for the medical device industry
137
Design controls for the medical device industry
138
Appendix A—QARA Compliance
Connection, Inc.: Design
control procedure
DESIGN CONTROLS
SOP No. 820.30.DES Rev: A Effective Date: 01-01-2013 Page 1 of 13
RESTRICTED—DO NOT COPY
1.0. Purpose
This procedure defines the method to be used to control the design and develop-
ment of all QARA Compliance Connection products that are required to meet the
FDA’s Quality System Regulation requirements and/or ISO 13485 requirements
for design control.
The requirements to initiate a design control project may arise for a variety of
reasons, such as the identification of a new product, a marketing need to sat-
isfy a customer’s request or problem, a cost savings to the customer or company,
the potential for a process improvement, a change or modification in an exist-
ing device that significantly affects safety or effectiveness, or a change that is
imposed by external circumstances.
The decision of whether an individual change or the cumulative sum of changes
to an existing product requires the initiation of a new design control project versus
a Change Request Form shall be made by consulting the FDA’s 510(k) Device
Modifications Document “Deciding When to Submit a 510(k) for a Change to an
Existing Device.”
In all cases, the design control or change control process shall be carried out
under controlled conditions.
139
Appendix A—Standard operating procedure
2.0. Application/responsibility
This procedure applies to all products developed by QARA Compliance
Connection that bear the QARA Compliance Connection name as manufacturer
and are required to meet design control requirements. Responsibility for con-
trolled design and development applies to the generation of new products, as well
as to the significant redesign of existing products.
Project team members are responsible for acting as department liaisons in support
of project requirements.
Management has the responsibility to adhere to the requirements of this proce-
dure and to ensure that employees comply. Management is also responsible for
making decisions relating to the viability of a project.
The project leader is responsible for coordinating all aspects of the design con-
trol project.
3.0. Reference documents
F 820.30.DPCS Design Project Cover Sheet
F 820.30.PPS Product Performance Specification
F 820.30.DIO Design Input/Output Matrix
F 820.30.DRM Design Review Meeting Form
F 820.30.DC Design Change Form
F 820.30.DTCL Design Transfer Checklist
F 820.30.AFS Approval for Sale Form
SOP 820.30.RISK Risk Management Procedure
SOP 820.40.DOC Document and Change Control Procedure
SOP 801.LAB Labeling Generation and Approval Procedure
F 820.180.RCI Record Control Index
See also the FDA’s 510(k) Device Modifications Document “Deciding When to
Submit a 510(k) for a Change to an Existing Device.”
4.0. Definitions
Design control project
A self-contained program of work initiated either to introduce a new product or
process or to make a change to an existing product or process that may require
redevelopment of that product or process.
Design history file: A file containing the complete history of the product’s design
process, providing historical traceability of design control. The file contains or
140
Appendix A—Standard operating procedure
141
Appendix A—Standard operating procedure
Clinical data: These are the safety and/or performance information that is gener-
ated from the use of a device. Clinical data are sourced from the following:
• Clinical investigation(s) of the device concerned
• Clinical investigation(s) or other studies reported in the scientific litera-
ture of a similar device for which equivalence to the device in question
can be demonstrated
• Published and/or unpublished reports on other clinical experience of
either the device in question or a similar device for which equivalence to
the device in question can be demonstrated
Clinical evaluation: This is the assessment and analysis of clinical data pertain-
ing to a medical device in order to verify the clinical safety and performance of
the device when used as intended by the manufacturer.
Marketing evaluation: This is a study in which a marketed or nonmarketed test
article is not used on humans but rather gathers input from humans to assess
physical and chemical characteristics of the test article, or a study in which a mar-
keted test article is used on humans, but no individual medical data are collected
(e.g., questionnaire or survey).
Preliminary evaluation: This is work done to establish the basic merit of an idea.
Design phases: The number of phases for a design project is dependent on the
complexity of the project and will be determined by the project team. At a mini-
mum, each design project will contain the following phases (e.g., formal design
review meeting):
• Design and development phase: This phase marks the onset of formal
design control. All critical functional and design specifications for the
device design should be defined at this point. Design inputs shall be for-
mally documented and approved, and the design and development phase
will begin. Upon formal approval of the design inputs, changes to the
product’s design shall be controlled.
• Design transfer phase: This phase involves the process of translating the
product design into production specifications and procedures to ensure
accurate manufacture of the approved design. This phase shall include a
review of all design and development activities, final validation results,
a final risk analysis, and confirmation that all process validation and
associated training has been completed.
• Design release phase: This phase ensures that all project team members
and executive management agree on the relevance and suitability of the
verification and validation results and that all documents and data nec-
essary to ensure that the product is ready for distribution are in place.
142
Appendix A—Standard operating procedure
143
Appendix A—Standard operating procedure
• Biocompatibility
• Electromagnetic interference
• Compatibility with accessories/auxiliary devices
• Compatibility with the environment of intended use
• Human factors
• Clinical reports
• Physical/chemical characteristics
• Labeling and packaging
• Statutory and regulatory requirements
• Past design history files
• Manufacturability
• Cleaning, disinfection, and maintenance requirements
• Registration and patents, trademarks, and licensing agreements
• Medical reimbursement considerations
5.2.2. The PPS shall be reviewed and approved by the project team at the ini-
tial design review meeting. Approval shall be indicated on the Design Review
Meeting Form. Any changes needing to be made to the PPS shall be identified on
the Design Review Meeting Form. The PPS shall be revised as needed, approved,
and controlled moving forward using the Design Change Form. The PPS is a
revision controlled document and shall be maintained as an element of the Design
History File.
144
Appendix A—Standard operating procedure
5.4. Risk analysis
5.4.1. An initial risk analysis for the design shall also be conducted either prior to
or at the initial design review meeting to assess the risks and hazards associated
with use of the product in accordance with the Risk Management Procedure. The
outputs from the risk assessment should serve as inputs to the PPS, as applicable.
The Risk Analysis Master Record (RAMR), or alternative method, shall be used
to document the risk assessment process. The RAMR shall be approved by all
project team members as part of the initial design review meeting, and initial
approval shall be documented on the Design Review Meeting Form.
5.4.2. The RAMR shall be reviewed and revised, as needed, at each subsequent
formal design review meeting. Any changes needing to be made to the RAMR
shall be identified on the Design Review Meeting Form. The RAMR shall be
revised as needed and controlled (i.e., approved) using the Design Change Form.
The RAMR is a revision-controlled document and shall be maintained as an ele-
ment of the Design History File.
145
Appendix A—Standard operating procedure
146
Appendix A—Standard operating procedure
• Bills of materials
• Product and design specifications
• Component and material specifications
• Equipment calibration requirements
• Equipment maintenance requirements
• Quality specifications
• Manufacturing assembly procedures
• Inspection and test methods
• Standard purchasing agreements
• Packaging procedures and specifications
• Labeling procedures and specifications
• Verification and validation protocols
5.6.6. Design outputs will be reviewed and approved (i.e., transferred) as needed
during the design and development process using the Design Change Form.
5.7. Design verification
5.7.1. As the design progresses through the development phase, various meth-
ods of verification shall be used to determine whether the design outputs meet
functional and operational requirements (e.g., design inputs). Verification and
acceptance criteria should be unambiguous, objective, and quantifiable. Design
verification will be performed on prototypes.
5.7.2. Verification may be accomplished using a variety of methods, including
inspection and testing under simulated used conditions, that is, performing bench
testing, biocompatibility testing, and/or package integrity tests; performing alter-
native calculations; comparing the new design with a similar proven design, if
available; reviewing data and results at design reviews, tests, and demonstrations;
and so on. Verification activities should take into account worst-case operating
conditions, where practical. Verification documentation will identify the design
project, verification method, date, results, and individual performing the verifica-
tion. Verification documentation is maintained as part of the Design History File.
5.7.3. Verification results are reviewed and discussed at design review meetings.
As such, results may require changes to design inputs, outputs, or product require-
ments. Any needed changes are identified on the Design Review Meeting Form,
and documents are revised as needed. The project plan may also be updated to
account for the changes.
5.7.4. Any risks and/or hazards exposed during the design and development phase
should be identified and addressed at the subsequent formal design review meet-
ing. The RAMR should be revised as needed to address any potential new or
unexpected risks and approved using the Design Change Form.
147
Appendix A—Standard operating procedure
5.7.5. The project leader may call project team meetings as necessary as the proj-
ect moves forward through the design and development phase to review project
status, update schedule time lines, review and approve outputs, and so on. An
agenda will be issued to identify the topics of discussion and project team mem-
bers required in attendance.
5.7.6. All project team meetings shall be documented by the project leader or
designee. If the Design Review Meeting Form is used to document the minutes
of the meeting, indication should be made that the meeting is not a formal design
review meeting. Any changes or decisions to be made should be documented and
controlled using the Design Change Form and reviewed and approved at the sub-
sequent formal design review meeting.
5.7.7. After the development and verification of prototypes, the project leader will
call a formal design review meeting to include all project team members, plus the
addition of one objective reviewer not directly responsible for the design phase
being reviewed. The purpose of the design review meeting will be to ensure veri-
fication and any preliminary validation results confirm that outputs meet input
requirements prior to commencing manufacture of production runs under simu-
lated use conditions.
5.7.8. The results of the design review meeting and any changes that need to be
implemented shall be documented on the Design Review Meeting Form. Approval
of the Design Review Meeting Form will signify readiness to commence manu-
facture of initial production runs. Outputs shall be revised as needed, and approval
of these changes shall be documented on the Design Change Form.
5.8. Process validation
5.8.1. Process validation (IQ, OQ, PQ) may be initiated during the design control
process and finished after transfer of the design of manufacture. Process validations
shall be documented and performed, as needed, to validate production processes.
Validation documentation will include the design project, method or procedure,
date, and individual(s) conducting the validation.
5.9. Design validation
5.9.1. Design validation shall be performed to ensure that the resulting product
is suitable for its intended use and meets the user’s needs. Validations will be
performed under defined operating conditions on initial production lots that have
been produced under the same production and quality system methods, proce-
dures, and equipment that will be used for routine production. These final valida-
tion studies will involve test systems and environments representative of true end
use conditions. Design validation activities may include the following:
148
Appendix A—Standard operating procedure
149
Appendix A—Standard operating procedure
6.0. Record retention
6.1.
A Design History File shall be created for each new product and shall contain or
refer to the location of the records generated by this procedure.
6.2.
The project leader or designee will have responsibility for maintaining the Design
History File.
150
Appendix A—Standard operating procedure
6.3.
The completed Design History File will be retained in accordance with the
Record Control Index.
Revision history
Rev Effective Date ECO/CR Number Description of Change
01 01-01-13 CR13-001 New procedure
151
Appendix B—QARA Compliance
Connection, Inc.: Product
performance specification
Project Leader:____________________________________________________
Product Name: ____________________________________________________
General description of device or system:
Performance definitions
Distinction should be made between desirable attributes (e.g., “want to haves”)
and essential requirements (e.g., “have to haves”). Layman terms should be used.
Customer expectations, safety, and satisfaction must be taken into consideration.
If certain requirements are unique for a market, then it should be indicated as
such within the appropriate section. Additional description areas may be added
as needed.
A. Performance characteristics
1. Indications for Use of Device (e.g., purpose):
Can the patient affect its use (e.g., limitations in hearing, sight, strength, etc.)?
153
Appendix B—Product performance specification
2. Clinical Procedure for Use (e.g., directions for use including assembly,
cleaning, disinfection, sterilization, inspection, and test):
B. Product characteristics
1. Functional Characteristics (dimensional: limits and tolerances, measur-
ing accuracy, color, shape, size, mobile or portable, etc.):
154
Appendix B—Product performance specification
155
Appendix B—Product performance specification
C. Marketing requirements
1. Intended Marketplace (e.g., customer requirements, countries, key
markets/groups):
4. GMDN Code:
156
Appendix B—Product performance specification
E. Financial requirements
1. Potential Market/Volumes (market the product/device is to perform in and
size):
2. Cost Projection:
4. Proposed Forecast/Profit:
7. Total Opportunity:
9. Medicare/Reimbursement:
Revision history
Rev Revision Description/Reason for Change ECO Date
157
Appendix C—QARA
Compliance Connection, Inc.:
CE product claims sheet
Product/Product Family
Intended Use(s):
Product Claims: Supporting Data:
Warnings/Cautions:
Contraindications:
Title/Function Date
Title/Function Date
Title/Function Date
Revision record
Rev Number Date ECO Number Description
159
Appendix D—QARA Compliance
Connection, Inc.: Design inputs
and associated outputs matrix
Product/Project____________________________________________________
Output(s)
Input (e.g., procedure, drawing, test method,
(Requirement/Specification) validation protocol, labeling, etc.)
161
Appendix E—QARA
Compliance Connection, Inc.:
Project approval form
Project Team:
Name: Title and Responsibility:
Independent:
163
Appendix F—Design
review meeting record
Project:
Date/Location:
Date:
Time:
Location:
Agenda:
Objective(s):
Attendees:
165
Appendix F—Design review meeting record
Meeting Minutes:
Results/Review
Outcome
(Ver./Val.) Proposed Changes
Inputs Outputs Inputs = Outputs Conflicts/Comments
Decisions:
Issues/Action Items:
Approvals:
Signature confirms agreement that (a) this meeting as documented herein
occurred, (b) the listed attendees attended, (c) Project Decisions recorded herein
have been taken, and (d) the Action Items recorded herein in have been properly
dispositioned in writing and recorded in the DHF.
166
Appendix G—QARA
Compliance Connection, Inc.:
Risk management plan
Product Name/Family:
Product Description:
Revision History
Revision Description/Reason for Change ECO/PDCF No. Evaluation Date
167
Appendix G—Risk management plan
Heading:
Product Name/Family: Identify the product name or product family to which the
risk analysis pertains.
Product Description: Provide a brief description of the product.
Intended Use(s): Identify the intended use(s) of the product.
Revision history:
Maintain the revision history for the risk analysis inclusive of a description of any
revision and/or the reason for revision (e.g., annual review, customer complaint(s),
nonconformance(s), literature search, field data, service data, etc.).
Record the Engineering Change Order (ECO) number or Product Development
Change Form (PDCF) number associated with the revision and the date of the review.
168
Risk Assessment ◻ Design ◻ Production ◻ Post-Production
Characteristics That Possible Hazard
Could Affect Safety Associated with Probability Risk Risk Probability Residual
(potential or Characteristic Probable of Potential Estimate Control of Potential Risk
real problems) (i.e., effect) Cause Occurrence Severity (L, M, H) Measure(s) Occurrence Severity (L, M, H)
169
Appendix G—Risk management plan
Appendix G—Risk management plan
Risk assessment: Identify the scope (i.e., life-cycle phase) of the assessment—
e.g., design, production, post-production.
Characteristics that could affect product, patient, and/or user safety:
i.e., problems
List all of those characteristics that could affect the device’s safety. Characteristics
should consider the following as applicable:
• Intended use or application of the device (e.g., intended user knowledge,
intended contact, duration/frequency of use, patient condition, con-
ditions for use, potential use error) improper use, re-use of single use
device, improper cleaning.
• Materials/Components used and/or accessories to the device (e.g., com-
patibility of materials, degradation of materials, toxicity, biological
safety of materials, physical and chemical characteristics).
• Risks from manufacture/assembly (e.g., contamination, residuals, incor-
rect assembly, incompatible accessory/substance, risk of substances
leaking from the device).
• Environmental factors (i.e., during transport, storage and use) (e.g., ESD,
EMC, temp, humidity, pressure, vibration, noise, fluorescent lighting,
risk of unintentional ingress from substances into device).
• Packaging (single or multi-use device, sterile or non-sterile) (e.g., pack-
age integrity, shelf life, useful life).
A non-encompassing list that may be used as a guide to identify characteristics is
provided in Appendix I of the Risk Management procedure.
Possible hazards associated with characteristics: (i.e., effect)
A hazard is a potential source of harm, resulting from a characteristic which
could affect safety. Compile a list of potential hazards (i.e., what happens if the
characteristic occurs) associated with the device in both normal and fault condi-
tions. A non-encompassing list of possible hazards and contributing factors is
given in Appendix II of the Risk Management procedure. For example; product
failure.
Probable cause:
Indicate the likely or probable cause of the problem.
Evaluation of risk:
Consider the probability of each hazard occurring and the associated implica-
tions (i.e., potential consequence/severity). For each possible hazard, estimate and
document the probability (e.g., 1,2,3,4,5), severity (e.g., A,B,C,D,E) and associ-
ated risk (e.g., Low, Medium, High) under both normal and fault conditions. Refer
to the Risk Assessment Matrix below and the Risk Management procedure for
assignment of risk.
170
Appendix G—Risk management plan
171
Appendix H—QARA
Compliance Connection, Inc.:
Clinical evaluation report form
Intended Application of Device (State the purpose of the device, duration of use, degree of
invasiveness, application.):
Intended Therapeutic and/or Diagnostic Indications and Claims (State the medical conditions to be
treated, outline any specific safety or performance claims.):
173
Appendix H—Clinical evaluation report form
Context of the Evaluation and Choice of Clinical Data Types (Is device based on a new
technology, a new clinical application of an existing technology, an existing technology, or an
incremental change of an existing technology. Is evaluation based on existing device data or an
equivalent device? Does device require the evaluation of any essential requirements related to
special performance or safety concerns?):
Summary of the Clinical Data and Appraisal (Identify clinical data used, appraisal process, and
relevance of data with regard to device performance and/or safety.):
Safety Data Analysis (Describe the total experience with the device inclusive of device-related
adverse events and any user training requirements.):
Product Literature and Instructions for Use (Is product labeling consistent with clinical data
results? Address any hazards or other clinically relevant information.):
Conclusions (Provide conclusions reached about safety and performance, determination of whether
identified risks have been addressed to acceptable levels as evidenced by the clinical data,
statement of conformity with essential requirements.):
174
Appendix I—QARA Compliance
Connection, Inc.: Design
transfer checklist
Product/Project: Date:
Yes No NA
Is design verification testing complete and acceptable? ◻ ◻ ◻
Is design validation complete and acceptable? ◻ ◻ ◻
Is the risk analysis complete and up to date? ◻ ◻ ◻
Is the device master record (DMR) complete and include, as applicable: ◻ ◻ ◻
DMR index ◻ ◻ ◻
Bill of materials ◻ ◻ ◻
Component, material, subassembly, and finished product specifications ◻ ◻ ◻
Assembly drawings ◻ ◻ ◻
Manufacturing assembly/process procedures and specification ◻ ◻ ◻
Incoming inspection procedures ◻ ◻ ◻
Manufacturing in-process inspection and test procedures ◻ ◻ ◻
Finished product test and inspection procedures ◻ ◻ ◻
Labeling and packaging specifications and procedures, and acceptance criteria ◻ ◻ ◻
Device History Record (i.e., batch record) forms ◻ ◻ ◻
Copies of labeling (carton, product, instructions for use) ◻ ◻ ◻
Are supplier evaluations and approvals complete? ◻ ◻ ◻
Have equipment calibration and maintenance requirements been determined? ◻ ◻ ◻
Have personnel been trained? ◻ ◻ ◻
Have regulatory approvals been received? ◻ ◻ ◻
Has a change request been generated to release the product to production? ◻ ◻ ◻
Is the CE Technical File complete and include, as applicable: ◻ ◻ ◻
Essential Requirements Checklist (inclusive of Canada requirements) ◻ ◻ ◻
Technical Documentation Checklist ◻ ◻ ◻
Clinical Evaluation ◻ ◻ ◻
Product Claims Sheet ◻ ◻ ◻
Declaration of Conformity ◻ ◻ ◻
Product Classification Justification ◻ ◻ ◻
175
Appendix H—Design transfer checklist
Approvals:
Engineering Date
QA/RA Date
Marketing/Sales Date
Operations/Manufacturing Date
Other Date
176
Appendix J—QARA
Compliance Connection, Inc.:
Design change form
Product/Project Name:_____________________________________________
Date of Change:___________________________________________________
Proposed Changes:________________________________________________
Approvals:
Engineering Date
QA/RA Date
Marketing Date
Operations Date
Other Date
177
Appendix K—QARA
Compliance Connection, Inc.:
Approval for sale
Product/Project Name:_____________________________________________
Project Team Leader:______________________________________________
Product Number(s):_______________________________________________
ECO Number:____________________________________________________
The activities detailed within this project are to be completed prior to obtaining
release for sale. If an activity has not been completed, and/or is not applicable, an
explanation in the form of a memo will be attached to the Approval for Sale Form.
Engineering
QA/RA
Marketing/Sales
Operations/MFG
Purchasing/Planning
COO/CEO
Other
Other
THE APPROVAL OF THIS DOCUMENT INDICATES THAT THE PRODUCT(S) DETAILED ABOVE HAS BEEN
APPROVED FOR SALE AND IS AVAILABLE FOR CUSTOMER PURCHASE.
179
References
181
References
Nobel, J.L. “Medical Device Failures and Adverse Effects,” Pediatric Emergency Care 7 (1991):
120–23.
Saliterman, Steven S. “Biocompatibility, FDA and ISO 10993.” Department of Biomedical
Engineering, University of Minnesota. n.d.
Sawyer, Dick. “Do It by Design: An Intro to Human Factors in Medical Devices.” FDA, December
1996.
Stark, Nancy J., and Dan McLain. “Medical Device Biocompatibility.” Clinical Device Group,
May 2011.
Teixeira, Marie B. Design Controls Training Module. Odessa: QARA Compliance Connection, 2011.
Teixeira, Marie, and Richard Bradley. Design Controls for the Medical Device Industry. New
York: Marcel Dekker, 2003.
US Department of Health and Human Services, Food and Drug Administration, Center for
Devices and Radiological Health, Division of Device User Programs and Systems
Analysis, Office of Health and Industry Programs. “Medical Device Use-Safety:
Incorporating Human Factors Engineering into Risk Management.” July 18, 2000.
Use of International Standard ISO 10993. “Biological Evaluation of Medical Devices Part 1:
Evaluation and Testing.” Blue Book Memorandum G95-1. May 1, 1995.
182
Biomedical Engineering
Design Controls
For the
MEDICAL DEVICE
InDustry
sECOnD EDItIOn
the second edition of a bestseller, Design Controls for the Medical Device
Industry provides a comprehensive review of the latest design control
requirements, as well as proven tools and techniques to ensure your
company’s design control program evolves in accordance with current
industry practice. the text assists in the development of an effective design
control program that not only satisfies the us FDA Quality system regulation
(Qsr) and IsO 9001 and 13485 standards, but also meets today’s third-party
auditor/investigator expectations and saves you valuable time and money.
the author’s continual participation in FDA Qsr inspections and notified Body
IsO audits is reflected in updates to all chapters and appendices of the book,
now bursting at the seams with
the book addresses design control elements such as design planning, input,
output, review, verification, validation, change, transfer, and history, as well
as risk management inclusive of human factors and usability, biocompatibility,
the FDA Quality system Inspection technique (QsIt) for design controls, and
medical device regulations and classes in the us, Canada, and Europe.
K14470
ISBN: 978-1-4665-0354-0
90000
9 781466 503540