Medical Device: A PRIMER BASED on Best Practices

Rommel Garcia
Medical Device: A PRIMER BASED on Best Practices

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DEDICATION:
This book is dedicated to my family who has given me the
drive and inspiration to write. They deserve a better life.
And the Lord who has given me all that I’m and all that I have.

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MEDICAL DEVICE: A Primer Based on Best Practices
A Compilation of best practices from relative experience in working in the Medical Device Industry

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Copyrights
(Initial Copyright Process has been started)

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Preface
You will have a certain purpose in mind as you browse through this book. Most likely you
are just inquisitive about the contents however, if you are serious about getting into the
medical device industry? You might have a need to increase your knowledge base. In
either case, this book is designed to provide relevant, teachable, and important
information.
In the years since I have become a professional in a highly regulated industry, it is
sometimes unbelievable to see how many of the companies I have been a part of
somehow struggle to find solutions to the ever changing world of regulations. In the
search of a plateau, many of them have “SOP’ed” themselves to death; meaning they
have created so many safeguards to try and quell a game of compliance. This has resulted
in a never-ending conundrum of “What are the Auditors going to see next?”
In the process of making it so, document after document pile up making it a challenge for
these companies to comply with their own processes and procedures, let alone complying
with the regulations and external standards. One of the companies that I used to work
with got rid of their quality system and started with a fresh one.
On the other end of the spectrum, are companies that have just started out (or have been
in business for a short while) and are trying to find a way to streamline their Quality
System to be compliant with the regulations set forth by regulatory agencies.
In my experience, companies that are always in danger are the ones that over create an
excessive number of documents that are sometimes non-defendable due to people that
come into this highly-regulated industry and begin creating documents and SOPs. Their
reasoning is usually that “This is the way we did it in the other industry and it worked”,
but guess what the Auditors in the medical device, IVD and pharmaceutical regulated
world say to them?
For example, I will use my experiences during my time in a company that I will call “A”. I
was called in to perform a remediation on Test Methods that they have in production. We
did the gap analysis and found out almost 100% of their methods that are used in

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manufacturing were not validated. I put a Validation Master Plan (VMP) together and
presented it to management. One of the requirements in the VMP is to have the
“Sampling Plans” be based on a good Statistical Foundation which is required in 21 CFR
820 Subpart O. Once I had made my initial protocol, my Manager and Lead said that they
wanted to use just 10 samples per protocol as executed. My Team and I knew that GR&R
itself on destructive test if done properly will cost a minimum of 30 samples for a matrix
of 10 x 3 x 3. We had numerous discussions, I found out throughout the course of these
discussions that my Manager was a Biologist and the lead had just started to understand
the regulations. I ended up leaving the company rather than sacrifice my integrity and
exposing myself to disbarment.
As a Quality Engineer, I have seen everything from very “SILOed” groupings to incredibly
unqualified or untrained engineers who had just entered this highly regulated industry.
As I have previously stated, the worst offenders are those who come from non-regulated
industries and are hired by companies due to their low cost who then bring their
“OPINIONS” along. Many of them are indeed very “OPINIONATED”. Without guidance,
they intentionally or unintentionally, disturb a system which is harmonized towards a
non-copasetic situation.
I guess I would say that I am lucky; I came from another industry and the way I was
exposed to the regulations (ISO 13485) in 1997 was in a rather unorthodox fashion. ISO
13485 was implemented a year earlier in 1996 and during those times, there were no
Subject Matters Experts except the Notified Bodies. I was working in a Japanese company
in Asia and I was put in charge of a program that aimed to make the company compliant
with these new regulations, and it was definitely a challenge that I gained much valuable
experience from. However, through many mentoring and training with TUV, my team and
I was able to get the company compliant within a year.
This book is meant to be a guide to all who want to learn about a highly regulated industry.
My approach is to give you, the reader, an example of a fictitious device and we will take
it from a conceptual idea all the way to launch and beyond. My intention is to incorporate
the best experiences that I and other contributors have had into this book and convert
them into layman’s terms for those who are in need. These experiences can, and will be

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indispensable to beginners and professionals alike who are trying their hand in the
Medical Device Industry, and to those who have not been out of their silo to help see how
each of the systems relate to each as a whole.
However, it should be noted that the contents of this book should be taken only as
information and is not intended to demonstrate how companies can be in compliance. In
some instances, there are multiple ways to go through the maze of regulations that are
documented and made by agencies because the regulations are pretty much made and
designed to be flexible and high level so that companies can adopt their systems which is
solely designed for their purpose.
Therefore, this book will try to avoid complicated words, and less complex technical
details of engineering and statistics. This book will strive to be an embodiment of the
honest to goodness, everyday experiences, and issues that folks experience while working
in the Medical Device Industry.
Safety is not an intellectual exercise to keep us in work. It is a matter of
life and death. It is the sum of our contributions to safety management
that determines whether the people we work with live or die.
~ Sir Brian Appleton, Safety Assessor

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Acknowledgements
(This is where Contributors, Peer Reviewer, Technical Advisers will be identified)
Kim Niles - is a distinguished professional in the Medical Device Industry who
has worked in many high profile companies.
Elizabeth Libarnes - a distinguished professor in the top university in Asia. A graduate
of Summa Cum Laude.

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Table of Contents
CHAPTER 1 ..................................................................................................................................................12
1. The Medical Device.........................................................................................................................13
1.1. Let us begin with fictitious Medical Device: ...........................................................................13
1.2. Medical Device:.......................................................................................................................14
1.3. Medical Device Industry..........................................................................................................14
1.4. In the Company of Medical Device .........................................................................................15
1.5. CHAPTER 1 - SUMMARY..........................................................................................................16
CHAPTER 2 ..................................................................................................................................................17
2. Regulatory Study and Agencies.......................................................................................................18
2.1. FDA Submissions.....................................................................................................................18
2.2. Medical Device Directive (MDD) Submissions........................................................................29
CHAPTER 3 ..................................................................................................... Error! Bookmark not defined.
3. 21 CFR 820 & ISO-13485 – Quality System Regulations .................... Error! Bookmark not defined.
3.1. What are they ............................................................................ Error! Bookmark not defined.
3.2. Same or Different....................................................................... Error! Bookmark not defined.
3.3. CFR – Code for Federal Regulation Title 21 ............................... Error! Bookmark not defined.
3.4. ISO 13485 2016 E - Medical Devices — Quality Management System.....Error! Bookmark not
defined.
3.5. Japan PMDA – JPAL.................................................................... Error! Bookmark not defined.
3.6. Chapter 3 – Summary ................................................................ Error! Bookmark not defined.
4. Medical Device Designing Program ................................................... Error! Bookmark not defined.
4.1. Basic Phases ............................................................................... Error! Bookmark not defined.
4.2. Chapter 4 – Summary ................................................................ Error! Bookmark not defined.
5. Exploration of the Phases .................................................................. Error! Bookmark not defined.
5.1. Concept Phase............................................................................ Error! Bookmark not defined.
5.2. Feasibility Phase......................................................................... Error! Bookmark not defined.

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5.3. Development Phase................................................................... Error! Bookmark not defined.
5.4. Verification and Validation Phase.............................................. Error! Bookmark not defined.
6. Design Transfer .................................................................................. Error! Bookmark not defined.
6.1. Potential Challenges................................................................... Error! Bookmark not defined.
7. Product Launch Phase........................................................................ Error! Bookmark not defined.
7.1. LAUNCHING A NEW PRODUCT................................................... Error! Bookmark not defined.
7.2. A Successful Launch .................................................................. Error! Bookmark not defined.
7.3. CHAPTER 6 SUMMARY............................................................... Error! Bookmark not defined.
8. POST LAUNCH ACTIVITIES.................................................................. Error! Bookmark not defined.
8.1. ABOUT POST MARKET SURVEILANCE: ....................................... Error! Bookmark not defined.
8.2. Complaint Handling.................................................................... Error! Bookmark not defined.
8.3. Medical Device Reporting (MDR)............................................... Error! Bookmark not defined.
8.4. Continuous Risk Assessment...................................................... Error! Bookmark not defined.
8.5. CORRECTIVE ACTION and PREVENTIVE ACTION ........................ Error! Bookmark not defined.
9. EPILOGUE........................................................................................... Error! Bookmark not defined.

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An Introduction
I was once watching a show on television about Charles Lindbergh. I know the man as a revered aviation hero.
He made the first solo nonstop flight across the Atlantic Ocean on May 20-21, 1927. Other pilots had crossed
the Atlantic before him. But Charles Lindbergh was the first person to do it alone nonstop.
1He studied engineering briefly at the University of Wisconsin, but became disillusioned with "the limits" of
formal engineering education and left school. In other words, he did not finish his engineering degree but
never the less his informal background was in engineering.
In 1929, his sister-in-law was diagnosed with rheumatic heart
disease, a disease that carried with it a poor prognosis due
primarily to an inability to perform surgical procedures on a
beating heart.
Lindbergh learned that the lack of the surgeon’s ability to
provide artificial mechanical means of circulating oxygenated
blood prevented a cure. At that point he made up his mind to
design a pump capable of circulating blood through the body
while the heart was being repaired. Armed with his ideas, an
innovative mind, and spirit of adventure, Lindbergh pursued
his goal of designing and building a mechanical heart/lung
machine. For more than 100 years, physiologists had tried to
maintain organs alive outside the body with no real success.
I was amazed by the story that a mere engineer without a real exposure to human physiology could invent
and artificial device for helping originate blood.
My first exposure to the medical device industry was with a company that manufactures a beating heart
medical device suite. The device was so amazing for me since they can operate on the heart while it is beating.
From there I became so interested and fascinated in many the mechanics in the medical device industry.
In working in the Medical Device Industry, I have worked in several capacities from an R&D Engineer, Test
Development Engineer, Project Manager, Principal Design Quality Engineer, and it is still not history. I hope
with this book I could help shed a little light to those who are in need of information.
Remember:
“If it is not documented, it does not exist” or “In God we trust, all else document”
CAVEAT:
I will constantly be reiterating this thought in this book: “The activities and documentation requirements can
vary from company to company depending on how their intrinsic QSR is structured.” The activities and
documents in this book are based on best practices experiences from a lot of companies, interviews with
SMEs from different institutions and all the readings that I have done on all available reference materials.
1
http://americanhistory.si.edu/blog/2013/08/what-we-dont-remember-charles-lindbergh-for-the-perfusion-pump.html - Picture of Charles Lindbergh

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CHAPTER 1
The Medical Device
2
2
http://www.crystalinks.com/romemedicine.html

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1. The Medical Device
1.1. Let us begin with fictitious Medical Device:
In the introductory page of this book, I have discussed about a Medical Device product
that Charles Lindbergh has created. Although crude by today’s standards, never the
less, it is an attempt to create a novel cure for a person who is in need. He progressed
in his quest and developed the device. And device turned out to be not only helpful for
a single patient but to a lot more who were suffering with same disease. The device
could very well be the grandfather of the modern machines that we have today. That
same concept has been improved so much and those grandson machines in the market
have helped and are still helping countless of patients everywhere.
At the same token, if the same attempt was to be performed today, Charles Lindbergh
would have to contend with a whole host of regulations, scrutiny, and approval before
he can use his device on a single human being.
Those regulations are results of the Regulatory bodies and agencies attempt to protect
consumers, end users and patients from products that can be harmful or at worst, if
used, would result in dire or catastrophic consequence.
In this book, it is my quest to show informative, best practices and useful tools that one
can use to get more “educated and compliant” in the Medical Device, In-vitro Medical
Devices (IVD) or Pharmaceutical Industry. I will also use a fictitious device as a model. I
will name the fictitious device as a “Romascalpel”3
.
I have designed this book in a way that I will be setting examples as if in as a case study
of a product… “What it is”, “What to do” and “What to say” in getting a device from
cradle to its natural manufacturing.
4
3
https://www.youtube.com/watch?v=_Ki5jK4xShA
4
http://www.crystalinks.com/romemedicine.html
Romascalpel

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FIGURE 1
1.2. Medical Device:
What is a Medical Device? FDA has described a medical device5
as "an instrument,
apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or
related article, including a component part”, or accessory which is:
 Recognized in the official National Formulary, or the United States
Pharmacopoeia, or any supplement to them,
 Intended for use in the diagnosis of disease or other conditions, or in the
cure, mitigation, treatment, or prevention of disease, in man or other
animals, or
 Intended to affect the structure or any function of the body of man or other
animals, and which does not achieve any of its primary intended purposes
through chemical action within or on the body of man or other animals and
which is not dependent upon being metabolized for the achievement of any
of its primary intended purposes."
In general, a medical device is something that is used to help medical professionals or
users to remediate6
medical conditions of patients.
Let us then journey into the world of Medical Device… let us begin to invent, develop,
launch and sell a “Romascalpel”.
1.3. Medical Device Industry
As this book is being conceived, there are thousands of medical device companies in
the world and hundreds more are being born.
All these companies always abide by the
laws, rules and regulations that are
generated by numerous regulatory
agencies around the world.
The biggest competing markets are the
Americas, Europe, and Asia Region. In
other words, if a company intends to sell
market or distribute in a certain country
or region, the medical device must be approved by the regulatory agency local to the
market (See Appendix J for list of Agencies worldwide).
For example, in the US, it is FDA, in Europe it is MDD, in Japan it is Japan PMDEA and
the list7
goes on (See Appendix J for a list of agencies worldwide). It is important to know
from the marketing folks where and what is the target market.
5
See FDA - http://www.fda.gov/AboutFDA/Transparency/Basics/ucm211822.htm
6
Remediate – diagnoses, cures, lessens, treats prevents, affect the function of human physiology
7
https://www.pda.org/scientific-and-regulatory-affairs/regulatory-resources/global-regulatory-authority-websites#Asia

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For the general purpose of this book, we are going to discuss mostly important subject
pertaining to the world of FDA (21 CFR 820) and MDD (ISO-13485).
Let us say that the “Romascalpel” will be marketed in the US and later in the European
Union and Japan Market. So initially, the device will be subject to the FDA regulations
which are in the 21 CFR 820. There will be more discussions on this in Chapter 2.
1.4. In the Company of Medical Device
In my career in the Medical Device / IVD / Combination Pharmaceutical Industry, I have
been with many big, small, start-up companies, and companies that manufactures
different kinds, types, and classes of devices.
The common theme for all the companies is the establishment of their own quality
system which embodies the requirements and adherence to Current Good
Manufacturing Practices (cGMP)8
and to other pertinent regulations. “It is Compliance
to the laws!”
Current Good Manufacturing Practices (cGMP) requirements for devices are embodied
in 21 CFR Part 820 and ISO 13495.
Because9
the regulation must apply to so many different types of devices, the
regulation does not prescribe in detail how a
manufacturer shall comply with the regulation.
Rather, the regulation provides the framework that all
manufacturers must follow by requiring the
manufacturers to develop and follow procedures and
fill in the details as appropriate to a given device
according to the current state-of-the-art
manufacturing that are device specific.
Within this flexibility, it becomes the responsibility of each manufacturer to establish
requirements for each type or family of devices. Those internal requirements shall
result in device products that are safe and effective.
These companies must establish methods and procedures to design, produce,
distribute, etc. devices that meet their quality system requirements (QSR).
In this book, we will talk a lot about the “A to Z” of designing a device while discussing
the governing laws that are required in the background.
On the historical end, in the early 90s; FDA has recognized the need to control the
framework and requirements of how the industry produces devices. So they started
revising the major and important components the cGMP and one of the major results
was they have added “Design Controls” which I would call the most important pillar in
the development of modern medical devices.
FDA’s approach is to harmonize the medical device industry (in terms of cGMP
regulation) to be consistent with the requirements for quality systems contained in
8 http://www.fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/qualitysystemsregulations/ - FDA QSR

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applicable International Standards, primarily, the International Organization for
Standards (ISO 13485). Although the attempt is to harmonize, the system still has
differences which we will discuss in the succeeding chapters.
Now for our Example:
As I have discussed starting from Section 1.1., our device, “Romascalpel” will be
designed, developed, manufactured, marketed, and sold by “Rogargear Systems”.
1.5. CHAPTER 1 - SUMMARY
We10
have just described what a medical device is in the
eyes of FDA (and other agencies) or perhaps it is for us to
think that a medical device is an important part of our
history and to remember those who try to help alleviate
difficulties involving ailments in the human anatomy.
The EXAMPLE:
Device Name - ROMASCALPEL
Manufacturer - RogarGear Systems
Company Location - San Jose, California
Intended Market - U.S.A., European Union, Japan
Agencies - FDA, MDD & PMDA
10
http://1080.plus/TOP_5_NON-COPYRIGHTED_DUBSTEP_SONGS_2015_by_TheQuagShow/a5wjSOOnAho.video

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CHAPTER 2
The Regulatory Agencies

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2. Regulatory Study and Agencies
2.1. FDA Submissions
As discussed in the previous section, the medical device companies11 are subject to the
regulatory controls from the countries where the devices are manufactured, packaged,
labeled sterilized and sold.
There are numerous requirements that apply to medical devices before they are
marketed (Premarket Requirements), and other applies to medical devices after they
are marketed (Post Market Requirements). In the US, the medical device must follow
the FDA’s requirements as follows:
2.1.1. Premarket Requirement Steps:
 Step One: Classify Your Device
 Step Two: Choose the Correct Premarket Submission
 Step Three: Prepare the Appropriate Information for your Premarket
Submission to the FDA
 Step Four: Send your Premarket Submission to the FDA and Interact with
FDA Staff during Review
 Step Five: Complete the Establishment Registration and Device Listing
 STEP 1: Classifications
If we are to classify our Concept Device (Romascalpel), one should ask
questions like:
 “What kind of design will the Medical Device be?”
 “Will the concept of the device be used external or internal to
the body?
 “Will the device be minimally invasive?”
 “Will it be something that will be interfacing directly with the
blood path?”
 “Will it be something that will be imbedded inside the human
physiology as an implant device?”
These are very important questions because the amount of regulation
applied to the device will depend a lot on the manner that device
interfaces with the human body and the risk that it presents during use
or even after use in some cases (i.e. Implantable Devices, Combination
Devices, etc.).
11
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/

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With these questions in mind, let us begin with some history of the
American Regulatory Body and then we will proceed with how the
classification of the Medical Device will be defined or determined, in a
narrative format.
In 1976 the government enacted the “Medical Device Amendments of
1976” which gave FDA authority to ensure the safety and effectiveness
of a range of life-saving medical devices while also protecting the public
from fraudulent devices. The Amendments are:
 Define the Medical Device,
 Established three device classes (I, II, and III)
 Identified pathways to market,
 Established Advisory Panels, and
 Set clinical investigation requirements.
Numerous changes in the regulation from then on have been
implemented but the Classification of the Medical Device has been the
same for FDA.
How do we go about knowing what the classification of our device is?
In every company, there is a group of individuals who are Subject
Matter Experts (SME) in determining the Regulatory Pathways for a
particular medical device. Normally, they are called Regulatory Affair
Specialists. These individuals are the primary conduit to the Regulatory
Agencies. The company depends on these individuals to guide them in
regulatory assessments like classification of medical device.
With regards to the Classification, the US, Europe, Canada, and Japan
regulatory agencies classifies Medical Devices a little different from one
another which is why a complete understanding by the Regulatory
Specialist of the intricacies of the Regulatory Pathways is necessary.
 In the United States
FDA classifies medical devices based on the risks associated with
the device which are as follows:
 Class 1 - devices present a low risk of harm to the user and
are subject to general controls that are sufficient to protect
the user. Most are exempt from the regulatory process.
Examples: non-powered breast pumps, elastic bandages,
tongue depressors, examination gloves, most hearing aids,
arm slings, microbial analyzers
 Class 2 - devices are more complicated and require special
controls for labeling, guidance, tracking, design,
performance standards, and post-market monitoring. Most
require Premarket Notification 510(k). Examples: powered

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wheelchairs, CT scanners, contact lens care products,
endoscopes
 Class 3 - devices usually sustain or support life, are
implanted, or present potential unreasonable risk of illness
or injury. They have the toughest regulatory controls. Most
of these devices require Premarket Approval because
general and special controls alone cannot reasonably
assure their safety and effectiveness. Examples:
pacemakers, implanted weight loss devices, non-invasive
glucose testing devices, medical imaging analyzers, breast
implants, heart pumps.
 In the EUROPEAN UNION / CANADA
European Medical Device Directive
(MDD) and the Canadian MDR
(Canadian Medical Devices Conformity
Assessment System - CMDCAS) has
similar classification of medical device in
which applies a four-tier classification
system to the
medical devices according to the risk of the
device to the human body. Class I
representing the lowest risk to the human
body and Class IV representing the highest
risk. The flow below shows the path for
which the medical device is classified for the EU Region12
:
12
Based on http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_4_1_rev_9_classification_en.pdf - GUIDELINES RELATING TO THE APPLICATION OF THE COUNCIL
DIRECTIVE 93/42/EEC ON MEDICAL DEVICES

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FIGURE 2
In Figure 2, there are 4 rulings that define the state of the
classification for the medical device but one would notice the
“NON Invasive Devices”. So let us look closer, in general, Medical
Devices are categorized in 2 major groups and they are: Non-
Invasive and Invasive devices.
Non-Invasive devices as defined are devices that are used in
procedures that does not require or involve break-in to the skin
and there is no contact with mucous membrane or internal body
cavity. In terms of FDA are Class I devices like gloves, stethoscopes
and others which falls in RULE 1.
RULES 2, and 4 are all still non-invasive devices but the intent of
device use goes a little further than those in RULE 1, which may
involve getting in contact with bodily liquids like blood therefore
can be further classified as Class II.
RULE 3 is still non-invasive goes down as Class II because the
intended use is for example removing undesirable substance out
of the blood as it is out of the body and back into the body (i.e.
Dialysis Devices).

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FIGURE 3
FIGURES 3 to 6 are all Invasive Devices but they all differ in the
duration of use internal to the patient. I know the question to be
asked now is “What do they mean by duration?” … The following
are the descriptions:
 Transient - Normally intended for continuous use for
less than 60 minutes.
 Short term - Normally intended for continuous use for
not more than 30 days.
 Long term - Normally intended for continuous use for
more than 30 days.

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FIGURE 4
FIGURE 5

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FIGURE 6
Active Devices are mostly Electrical or Electronic Equipment used
in surgery such as lasers, ultrasound, X-rays and others.
FIGURE 7

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Special Rules covers medical devices such as those which are
combined with medicinal substances for helping the functionality
of the device (i.e. Combination Devices).
It is also important to remember that Canada, European Union,
and the Japan use Notified Bodies (NB) to help in the assessment
of the classification.
The lists of agencies below are some the known NBs that are
operating with those countries:
 BSI Group America, Inc.
 DQS GmbH
 Intertek Testing Services
 Kema Quality BV
 LGA InterCert Gmbh
 Lloyd’s Register Quality Assurance, Inc.
 National Standards Authority of Ireland
 Office of Manufacturing Quality, TGA
 RWTUV Systems GmbH
 SAI Global Certification Services Pty Ltd.
 SGS United Kingdom Ltd.
 TUV Rhineland of North America
 TUV SUD America, Inc.
 TUV USA, Inc.
 Underwriters Laboratories, Inc
NOTE:
Only Health Canada-
recognized third parties
(also called registrars) are
eligible to certify
manufacturers that intend
to sell or advertise products for sale in Canada.
 Japan Ministry of Health Labour and Welfare (MHLW) /
Pharmaceuticals and Medical Devices Agency (PMDA)
The Japanese Regulatory Agency categorizes the also a little
different. They have four classifications but they are also Risk
based (For more information about the submission, please See
Section 3.5:

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FIGURE 813
Class I - Devices with extremely low risk to the human body in case
of problems. Examples: In vitro diagnostic devices, steel made
small devices (including a scalpel, tweezers), X-ray film, devices for
dental technique
Class II - Devices with relatively low risk to the human body in case
of problems. Examples: MRI devices, electronic endoscope,
catheter for digestive organs, ultrasonic devices, dental alloy
Class III - Devices with relatively high risk to the human body in
case of problems. Examples: Dialyzer, bone prosthesis,
mechanical ventilation
Class IV - Devices highly invasive to patients and with life-
threatening risk in case of problems. Example: Pacemaker,
artificial cardiac valve, stent graft
The Table 1 - below describes the approval pathways for
submission.
13
https://www.pmda.go.jp/english/

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TABLE 1
 STEP 2: Correct Premarket Submission
After the Concept Device has been correctly classified, then the premarket
submission type must be selected. The types of premarket submissions
include:
 510K (Premarket Notification)
 PMA (Premarket Approval)
 De Novo (Evaluation of Automatic Class III Designation)
 HDE (Humanitarian Device Exemption)
510 K Submissions
510K are premarket submissions in which the devices to marketed
is safe and effective and substantially equivalent to a legally
marketed device (21 CFR 807.92(a) (3)) which are not subjected to
Pre-Market Approval (PMA). In other words, the device that you
are developing should have predicate. The following are the types
of 510K submissions:
 Traditional 510K - for a modification to a previously cleared
device under 510K
 Special 510K - for device modifications and utilizes the
design controls aspects
 Abbreviated 510K – is used when:
o a guidance documents exists
o a special control has been established
o FDA has recognized a relevant consensus standard
NOTE:
Some Class I and Class II devices are exempt from 510K if they do not
exceed the limitations of exemption stated in 21CFR 862-892. Example: an
elastic bandage
A Premarket Approval (PMA Submission)
Traditionally, these are Class III devices. High Risk like implantable
devices requires a Premarket Approval. A PMA has the most
stringent type of premarket submission. Before the FDA approves
Classification
Class I
Class II
Class III
Class IV
Type of Regulation
Approval/certification not required
(Notification/self declaration)
Certification by third party
certification (limited to devices
for designated controlled
Medical Device, complying with
certified standards)
Approval by the
Minister of Health,
Labor and Welfare
(reviewed by PMDA)
Approval by the Minister of Health, Labor and Welfare
(reviewed by PMDA)

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a PMA, the Regulatory Affairs must provide valid scientific evidence
demonstrating reasonable assurance of safety and effectiveness
for the device’s intended use. In other words, “What are the Risks
and with those Risks, is it safe?”
De Novo
De Novo provides a pathway for a new device, without a valid
predicate, to be classified into Class I or II if it meets certain criteria.
The criteria are provided in the following sites:
 FD&C Act, section 513(f)(2)
 Evaluation of Automatic Class III Designation (De Novo
Process) Summaries
 Evaluation of Automatic Class III Designation (De Novo
Process)
Humanitarian Device Exception (HDE)
HDE provides a regulatory path for Class III devices that are
intended to benefit patients with rare diseases or conditions.
 STEP 3: Appropriate Information for the Premarket Submission
After selecting the correct premarket submission type, the fun begins; you
must prepare the appropriate information that will be needed. Information
that is needed to be considered are but not limited to:
 Design Control – all Class II and III must be designed in accordance to
21 CFR 820.30 Design Controls
 Nonclinical Testing: Nonclinical testing performed in support of a
premarket submission for a medical device must comply with the
Good Laboratory Practices (GLPs).
 Clinical Evidence: Prior to initiating a clinical study, the study sponsor
may need to obtain approval of an Investigational Device Exemption
(IDE) by the FDA. The study will also must be approved by the
appropriate Institutional Review Board (IRB). Clinical studies must
comply with all applicable IDE regulations and Good Clinical Practices
(GCPs).
 Labeling: The labeling for a device must be written according to
labeling regulations and included in your premarket submission.
Most of the time, in the regulatory world, biocompatibility is reserved and should be
performed on device Class II and III. We will also discuss what biocompatibility is in later
sections of this book.
 STEP 4: Submit to the Regulatory Body
After all the necessary documents has been fulfilled for the Premarket
Submission, all the supporting documents will be sent to the FDA. The

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Regulatory folks must interface with the FDA during review not only for the
defense of the submission but also for hearing suggestions from the folks who
are the most important people who can reject or approve all the
documentations.
 STEP 5: Complete Establishment Registration and Device Listing
The device facility must register its establishment and list its devices with the
FDA.
2.1.2. Investigational Device Exemption (IDE) - Institutional
Review Board (IRB) Processes. 14
In the Investigational Device Exemption (IDE) pathway can allow an
investigational device to be used in a clinical study to collect the safety and
effectiveness data required for a Premarket Approval (PMA) or a Premarket
Notification (510(k) submission to FDA.
Clinical studies with devices of significant or high risk must be approved by
both FDA and an Institutional Review Board (IRB) before the study can begin.
Studies with devices posing non-significant risk to patient must be approved
by an IRB before the study can begin.
FDA concentrates its review of all relevant data provided on showing great
deal of safety and benefits of the device as it is used in humans. FDA also
focuses on the scientific validity of the proposed clinical trial.
2.2. Medical Device Directive (MDD) Submissions
Although MDD is a little different in terms protocols for submission, the basic elements
are pretty much the equivalent. As in directives, the FDA follows the 21 CFR 820, while
the MDD follows the directives of ISO 13485.
There are five (5)15
key elements when it comes to submission in MDD and they are:
1. CE Technical File or Design Dossier – The Technical File or Design Dossier as
explained in are set of documentations that makes up many information about
the device for submission. The amount of information in your application will
depend so much on the complexity of your device and its classification. As you
might have guessed, a Class I, IIa and IIb have somewhat relaxed or lower
amount of risks compared to a Class III device which has a higher risk.
Technical File / Design Dossier
As we go through this book, we will encounter much directive and one of
them is Design Control. The output of Design Control as a directive goes
14
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm203018.htm
15
https://www.stratos.com/blog/5-key-elements-required-medical-devices-prior-regulatory-submission-eu

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into the Design History File (DHF). One of these outputs is called DMR
(Device Master Record). However, in the MDD world, similar to DMR with
some other elements of the DHF such as Risk Management and Clinical
Data are generally the elements of a Technical File (TF) and Design Dossier
(DD). The difference between a TF and a DD, a Technical File are reserved
for MDD Compliant products for Class I and IIa and IIb, while the Design
Dossier are reserved for Class III MDD devices. And the basic element that
supports those files includes:
 Company’s Declaration of Conformity
 General Information / Product Description / EC Authorized
Representative
 Classification Determination (Annex IX, Rule [select applicable
rule])
 Essential Requirements (Annex I)
 Risk Analysis
 Labeling
 Product Specifications
 Design Control
 Clinical Evaluation (Annex X; literature review, et al.)
 System Test Reports
- Functional Bench Testing
- Lab Testing (cytotox, hemolysis, sensitization,
carcinogenicity, other biocompatibility testing)
- Sterilization Validation (or AAMI TIR 28 Analysis)
 Packaging Qualifications
 Manufacturing
 Sterilization
 Conclusion
 Declaration of Conformity (Annex II, V, VII)
 Appendix (further supporting information / details on the
above).
2. Essential Requirements – Providing proof of Conformity to the essential
requirements means the manufacturer of the device must provide objective
evidence that substantiates compliance to Annex I of the Medical Device
Directive which is a very long write up of word that is hard to understand. But
to sum it all up, the documents that demonstrate compliance includes:
 Standard Operating Procedures (SOPs)
 Risk Analysis
 Design Specifications
 Design Verification and Validation test results
3. Post-Market Surveillance – In ISO 13485 Directive 8 – Measurement, Analysis
and Improvement describes the requirements for manufacturers to record,

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evaluate and provide any incidents of adverse events. This is the same as what
FDA requires the manufacturer for Post Market Requirements.
4. EC Declaration of Conformity – the Declaration of Conformity is a special
document which is signed by the proper company representative(s) that the
“declaration shall be in respect of all Community acts applicable to the product
containing all information required for the identification of Community
harmonization legislation to which the declaration relates16
”. In other words,
the product shall be compliant with any or all applicable directives and
standards as it applies to.
5. Competent Authority Notification – the manufacturer shall notify each
country’s competent authority where the company is registered that the
device is being marketed or sold within their authority. The Competent
Authority may ask the manufacturer to provide supplemental information
(including but not limited to labeling and Information for Use IFU or any
product information) about the medical device.
NOTE:
As stated, there are differences and complexities about the EU submissions compared to
the FDA submission. That is the reason why the need for competent Regulatory Affairs
person is a must in the company to guide or properly steer the submission towards
compliance and acceptance.
2.2.1. Chapter 2 – Summary
The device Example:
 Let us say at this point that the
“Romascalpel” can be used to cut deep
into a human tissue and interfaces with
human blood flow or path. It can then be
classified as a Class II in the FDA
standard in which would require Premarket Notification 510(k).
 In the European Union or Canada, the device is an invasive device
which penetrates inside the body through the surface of the body,
with the aid of or in the context of a surgical operation so it should be
Class IIa.
 In the Japan, it could be a Class II or Class III depending on more
development for the device.
16
http://www.shbode.com/Upload/ueditor/files/2016-03-09/ISO%2013485-2016-547d1f58-f6f7-4f37-8c6e-f1fb7a9651a1.pdf

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 Application on the which regulatory agency will still be the
responsibility of the Regulatory Affairs group with input coming from
Development and Marketing Group.
The EXAMPLE:
 Device Name - ROMASCALPEL
 Manufacturer - RogarGear Systems
 Company Location - San Jose, California
 Intended Market - U.S.A., European Union, Japan
 Agencies - FDA, MDD & PMDA
Device Classification will be determined during Concept Phase

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