medical device - a primer based on experience 2.21 part 1

Rommel Garcia

Medical Device: A PRIMER BASED on Best Practices


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.


MEDICAL DEVICE: A Primer Based on Best Practices

A Compilation of best practices from relative experience in working in the Medical Device Industry


Copyrights

(Initial Copyright Process has been started)


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


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


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


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.


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.


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.


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


CHAPTER 1

The Medical Device

2

2 http://www.crystalinks.com/romemedicine.html


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


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


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


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


CHAPTER 2

The Regulatory Agencies


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/

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/#step5


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


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


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).


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.


FIGURE 4

FIGURE 5


FIGURE 6

Active Devices are mostly Electrical or Electronic Equipment used

in surgery such as lasers, ultrasound, X-rays and others.

FIGURE 7


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:


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/


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)


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

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm232269.htm

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHTransparency/ucm232269.htm

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/ucm462775.htm

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/ucm462775.htm


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


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,


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


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

medical device - a primer based on experience 2.21 part 1

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