introduction, classification, regulatory approval process for medical devices (510k) premarket notification, pre market approval (PMA), investigational device exemption (IDE) and invitro diagnostics, quality system requirements 21 CFR PART 820, labeling requirements 21 CFR part 801, UDI

1. Unique device identification:
The Food and Drug Administration Amendments Act (FDAAA) of 2007 requires FDA to propose a
system for uniquely identifying medical devices using a unique device identifier (UDI). FDA has
worked for many years with the various stakeholders to create a proposed rule that is effective and is
compatible with systems that are in place for identifying medical devices for trade purposes and
Department of Defense (DOD) requirements.
FDA is establishing a unique device identification system to adequately identify medical devices
through their distribution and use. When fully implemented, the label of most devices will include a
unique device identifier (UDI) in human- and machine-readable form. Device labelers must also
submit certain information about each device to FDA’s Global Unique Device Identification Database
(GUDID). The public will be able to search and download information from the GUDID.
UDI BASICS: A UDI is a unique numeric or alphanumeric code that consists of two parts:
 A device identifier (DI), a mandatory, fixed portion of a UDI that identifies the labeler and the
specific version or model of a device,
 and a production identifier (PI), a conditional, variable portion of a UDI that identifies one or
more of the following when included on the label of a device:
• the lot or batch number within which a device was manufactured;
• the serial number of a specific device;
• the expiration date of a specific device;
• the date a specific device was manufactured;
• the distinct identification code required by §1271.290(c) for a human cell,
tissue, or cellular and tissue-based product (HCT/P) regulated as a device
FOUR STEPS TO A SUCCESSFUL UDI PROGRAM:
1. Develop a standardized system to create the UDI.
2. Place UDI on label or sometimes device
3. Create and maintain Global UDI database
4. Adoption and implementation by all stakeholders
Objectives of the Unique Device Identification Program:
FDA
Amendmen
ts Act of
2007
(FDAAA)
FDA
Safety &
Innovation
Act of
2012
UDI Final
rule SEP
24, 2013
UDI = DI + PI

2. IVDs and its classification:
Definition:
•In vitro diagnostic products are those reagents, instruments, and systems intended for use in
diagnosis of disease or other conditions, including a determination of the state of health, in order
to cure, mitigate, treat, or prevent disease or its sequelae.
•Such products are intended for use in the collection, preparation, and examination of specimens
taken from the human body.
•In the US, IVDs are defined under 21 CFR 809 and are regulated under guidelines similar to
medical devices.
How in Vitro Diagnostic’s are classified:
FDA classifies IVD products into Class I, II, or III according to the level of regulatory control
that is necessary to assure safety and effectiveness. The classification of an IVD (or other
medical device) determines the appropriate premarket process. It’s Classified As:
 Class I,
 Class II,
 Class III
The Code of Federal Regulations lists the classification of existing IVDs in 21 CFR 862, 21
CFR 864, and 21 CFR 866. 3 Classification Level of risk Con
 Facilitate the rapid and accurate identification of the
device.
 Enable access to important information concerning the
device.
 Allow more accurate reporting, reviewing and analyzing
of adverse events reports.
 Provide a standard and clear way to document a device
use in electronic health records
 Enable more effectively managed medical device
recalls.
“Establish a system
to adequately
identify devices
through distribution
and use”

3. De Novo Classification for IVD Devices
 Prior to the FDA Modernization Act of 1997 (FDAMA), all devices on the market as of
May 28, 1976 were classified according to their risk. Any device that was not classified
was automatically assigned to Class III, requiring a premarket approval (PMA)
application.
 A device could be moved out of Class III only through a cumbersome reclassification
process. FDAMA amended Section 513(f) to provide a new mechanism for classifying
new Class III devices for which there is no predicate device.
 It allows the recipient of an NSE (not substantially equivalent) letter to request a risk-
based classification determination to be made for the device.
 In some cases, this allows a manufacturer to use the De Novo process to submit a 510(k)
for a new IVD that would otherwise have to get to market via the PMA process.
Post marketing surveillance of medical devices: Postmarketing surveillance is overseen by
the Food and Drug Administration (FDA), which operates a system of passive surveillance
called Med Watch, to which doctors or the general public can voluntarily report adverse
reactions to drugs and medical devices. The FDA also conducts active surveillance of certain
regulated products. For example, the FDA may monitor safety and effectiveness of medical
devices through either a Post-Approval Study or through a 522 Post market Surveillance Study.

4.  After a device is approved in the US, companies must maintain quality manufacturing
control systems. They must also report to the US Food and Drug Administration (FDA)
adverse events brought to their attention by their employees or user facilities, providing
patient demographic data, clinical information, and procedure details. Reports are collected
in a publicly searchable database, though with variable content and quality. For example,
most reports originate from manufacturer representatives, while health care providers have
no mandate to report adverse events, and rarely do so.
 The FDA may require manufacturers to conduct PS studies in two ways. First, “post-
approval studies” may be appended to the approval of devices evaluated through the
premarket approval (PMA) or Humanitarian Device Exemption (HDE) pathways, which
include high-risk devices or those serving patients with rare diseases, where premarket
testing may be especially limited. Second, so-called “522 studies” for select devices
(including those medium- or lower-risk devices cleared through the 510(k) pathway based
on risk or other criteria) may also be required. FDA posts the status of post-approval
studies and 522 studies on public websites.
 When PS points to potential device problems, the FDA issues safety communications to
inform patients and clinicians. Actual patient harms trigger safety alerts from the FDA,
manufacturers, or distributors; for example, a 2012 safety alert described a defective
component in an automated external defibrillator that led to unexpected failure to deliver
high-voltage therapy.
 A recall reflects systemic concerns with a device. A manufacturer may conduct a recall on
its own, or in response to an FDA request, and is responsible for developing the strategy for
managing the recall process. More serious recalls, such as those issued for metal-on-metal
designs for hip prostheses, invoke stricter FDA oversight, including follow-up and auditing
of communication to providers or end-users. Publicly searchable databases track safety
alert and recall information.
 Recently, the FDA proposed adding a unique device identifier (UDI) system to its PS
activities. UDIs allow linkage of specific devices to clinical information that can enhance
the context of adverse event reports. UDIs might facilitate rapid notification of devices' use
and performance characteristics, support more accurate and timely aggreggation of adverse
event data, and enable better coordiation of recalls.
PMA and about its process:
Premarket approval is the scientific review process designed by the FDA for the safety and
effectiveness evaluation of medical devices. All the Class III devices must go through PMA
considering associated high risks.

5. Also, several Class II devices need to go through PMA. There are two scenarios where PMA is
mandatory for a Class II device.
1. If a manufacturer thinks that their device is not substantially equivalent and
cannot find suitable predicate; and
2. Manufacturer applies for 510(k) submission with the predicate, but it gets
rejected by FDA stating that the device is not substantially equivalent.
Premarket approval is a tough requirement where the applicant must get an approval for PMA
application before starting any marketing activities. Whether to approve the PMA or not,
depends on the provided scientific evidence assuring that the device is safe and effective for the
proposed use specified in the application.
According to the regulation, it should take 180 days to approve or reject the PMA application,
but in reality, it takes longer most of the time.
Once the applicant (an individual, organization or organizational unit, association, private or
government establishment or any other kind of legal entity) submits the PMA, the FDA will send
the application to the appropriate advisory committee for review at a public meeting. The
committee will provide the recommendation and facts supporting whether to approve or reject
the application.
Once the FDA determines the submission, they notify the applicant that their application has
been approved or rejected. And then FDA publishes a notice on their website with the aims of
1. Announcing the data on which the decision is based, and
2. Providing interested persons an opportunity to petition FDA within 30 days for
reconsideration of their decision.
On completion of a successful PMA process, an approval in the form of a private license
granting the applicant a permission to market the device is released.

6. labeling requirements of MD as per 21CFR part 801:
PART 801 LABELING
Subpart A--General Labeling Provisions
§ 801.1 - Medical devices; name and place of business of manufacturer, packer or
distributor.
§ 801.3 - Definitions.
§ 801.4 - Meaning of intended uses.
§ 801.5 - Medical devices; adequate directions for use.
§ 801.6 - Medical devices; misleading statements.
§ 801.15 - Medical devices; prominence of required label statements; use of symbols in
labeling.
§ 801.16 - Medical devices; Spanish-language version of certain required statements.
§ 801.18 - Format of dates provided on a medical device label.
Subpart B--Labeling Requirements for Unique Device Identification
§ 801.20 - Label to bear a unique device identifier.
§ 801.30 - General exceptions from the requirement for the label of a device to bear a
unique device identifier.
§ 801.35 - Voluntary labeling of a device with a unique device identifier.
§ 801.40 - Form of a unique device identifier.
§ 801.45 - Devices that must be directly marked with a unique device identifier.
§ 801.50 - Labeling requirements for stand-alone software.
§ 801.55 - Request for an exception from or alternative to a unique device identifier
requirement.
§ 801.57 - Discontinuation of legacy FDA identification numbers assigned to devices.
Subpart C--Labeling Requirements for Over-the-Counter Devices
§ 801.60 - Principal display panel.
§ 801.61 - Statement of identity.
§ 801.62 - Declaration of net quantity of contents.
§ 801.63 - Medical devices; warning statements for devices containing or manufactured
with chlorofluorocarbons and other class I ozone-depleting substances.
Subpart D--Exemptions From Adequate Directions for Use
§ 801.109 - Prescription devices.
§ 801.110 - Retail exemption for prescription devices.
§ 801.116 - Medical devices having commonly known directions.
§ 801.119 - In vitro diagnostic products.
§ 801.122 - Medical devices for processing, repacking, or manufacturing.
§ 801.125 - Medical devices for use in teaching, law enforcement, research, and analysis.
§ 801.127 - Medical devices; expiration of exemptions.
§ 801.128 - Exceptions or alternatives to labeling requirements for medical devices held by
the Strategic National Stockpile.
Subpart E--Other Exemptions
§ 801.150 - Medical devices; processing, labeling, or repacking.

7. Subparts F-G [Reserved]
Subpart H--Special Requirements for Specific Devices
§ 801.405 - Labeling of articles intended for lay use in the repairing and/or refitting of
dentures.
§ 801.410 - Use of impact-resistant lenses in eyeglasses and sunglasses.
§ 801.415 - Maximum acceptable level of ozone.
§ 801.417 - Chlorofluorocarbon propellants.
§ 801.420 - Hearing aid devices; professional and patient labeling.
§ 801.421 - Hearing aid devices; conditions for sale.
§ 801.430 - User labeling for menstrual tampons.
§ 801.433 - Warning statements for prescription and restricted device products containing
or manufactured with chlorofluorocarbons or other ozone-depleting substances.
§ 801.435 - User labeling for latex condoms.
§ 801.437 - User labeling for devices that contain natural rubber.
IDE and its procedure for marketing authorization of MD:
Investigational Device Exemption (IDE) is a provision that allows manufacturers to collect
device-specific safety and effectiveness data for the proposed device before commercialization,
which can be used to support premarket approval application or in some cases for premarket
notification submission.
Safety and effectiveness data are collected by monitoring a provisioned device for the intended
use. Apparently, IDE is mandatory for devices which are unable to get marketing clearance using
510(k) notification and PMA applications.
There are several base-line requirements to proceed with IDE. It includes:
 an investigational plan approved by an IRB – institutional review board (in case
if the study involves a significant risk device, the IDE must also be approved
by FDA);
 informed consent from all patients;
 labeling stating that the device is for investigational use only;
 monitoring of the study and;

8.  all the records and reports.
For 510(k) notification, FDA needs clinical data to provide marketing clearance in very limited
cases. An approved IDE application provides rights to lawfully ship the devices for investigation
purpose without forcing other FDA needs that are required for device commercialization.
A manufacturer must submit complete IDE application to FDA. Although, it does not have a pre-
determined format, but they are bound to imply certain information in the form, such as sponsor
investigator information, clinical plan overview, investigational plan method and controls
information.
Procedures for market authorization:
Legislation concerning medical devices is governed by the Medical Device Amendments of May
28, 1976, to the Federal Food Drug and Cosmetic Act (FD&C Act). For general medical devices,
this Act is implemented by regulations Title 21 Code of Federal Regulations (21 CFR) Parts 800-
1299. The definition of a medical device, classification, conformity assessment and registration
requirements are described in these Parts.
Once the classification for the new product is known, the correct market submission procedure
can be followed. There are two main procedures for market submission requiring FDA
involvement: Pre-market Notification or 510(k) and Pre-market Approval (PMA). In general, the
following rules apply:
 Most Class I devices are exempt from 510(k)
 Most Class II devices require 510(k)
 Most Class III devices require PMA
The most stringent form of market submission is the PMA procedure, for which the
manufacturer has to submit an extensive set of documents to the FDA. For the 510(k) procedure,
the manufacturer has to show that his device is RIVM Letter report 2015-0001 Page 17 of 56
substantially equivalent to another, already marketed device. It should be noted that the route of

9. substantial equivalence is only valid for eligible devices (mostly Class II) and not for any device
for which a substantially equivalent device is available.
Pre-market Approval (PMA):
A PMA is the assessment process of FDA for the safety and effectiveness of most Class III
medical devices. Because of the high risks associated with these devices, FDA has determined
that special controls (as described for 510(k) approval) alone are not sufficient to guarantee
safety and effectiveness of the product. Therefore, a PMA is required for these devices.
The PMA documentation, that has to be submitted by the manufacturer, includes both
administrative elements and scientific evidence sections. Although the scientific part is the main
part of the document, an application will not be assessed if the document lacks certain
administrative elements. If certain clinical data or scientific arguments are lacking, the
assessment process will be delayed. It is therefore recommended to manufacturers to have their
applications reviewed before submission to FDA.
There are two scientific evidence sections in a PMA application:
 Non-clinical research: This section contains information on, among others, the
microbiology, toxicology, immunology, biocompatibility, wear and shelf life of the
product. Non-clinical research has to be performed in accordance with certain
regulations, defined in 21 CFR Part 58.
 Clinical research: This section has to contain at least study protocols, safety and
effectiveness data, adverse reactions and complications, patient information and results.
A Class III medical device with a denied PMA is considered to be adulterated, and is not
allowed to be marketed.
This procedure for market authorization is used for about one percent of all devices allowed onto
the USA market.

10. Pre-market Notification (510(k)): A 510(k) is a pre-market notification to FDA in which it is
shown that the device to be marketed is at least as safe and effective as a similar device which is
already legally marketed in the USA. This approach is valid for most Class II devices. This
comparison with an existing similar device is called showing substantial equivalence, and the
existing device that is used for comparison is called the predicate.
A device is substantially equivalent if in comparison with the predicate:
 ‐ it has the same intended use, and the same technological characteristics, or
 ‐ it has the same intended use, and has different technological characteristics, but the
information submitted to FDA:
o Doesn’t raise new questions on safety and effectiveness, and
o Demonstrates that the device is at least as safe and effective as the legally
marketed predicate.
For devices for which a 510(k) procedure is applicable, 510(k) must be submitted to FDA when:
1. A device is commercially distributed for the first time, and was not marketed by the firm
before May 28, 1976 (pre-amendment device).
2. A different intended use is proposed for a device which the firm already has in
commercial distribution.
3. A change or modification of a legally marketed device is made, which could significantly
affect its safety or effectiveness. It is recommended to record the justification for
submitting or not submitting a new 510(k) in the change control records.
The mandatory elements of a 510(k) include (amongst others):

11. 1. A sufficiently detailed description of the device, allowing the determination of substantial
equivalence.
2. An identification of the predicate device, to which substantial equivalence is claimed.
3. An explanation of the intended use of the device. When these explanations differ from
the predicate, an additional explanation must be provided, describing why these
differences will not have influence on the safety and effectiveness of the device.
4. If the device has the same technological characteristics as the predicate, a summary must
be provided in which the technological characteristics of the new device are compared to
the predicate. If the device has different technological characteristics, a summary must be
provided in which it is explained in what way the technological characteristics are similar
to the predicate’s characteristics.
FDA will answer to the 510(k) submission by sending a letter, indicating whether FDA agrees on
substantial equivalence. If this is so, the device is declared substantially equivalent (SE), and can
be marketed in the USA.
If FDA determines the device is not SE, the device would automatically become a Class III
device. The submitter can:
 submit another 510(k) with new data;
 request for a revision of classification to a Class I or II device for which a 510(k) is not
required (this is known as the de novo procedure, see underneath);
 submit a PMA application.
For Class II devices, regulatory requirements referred to as special controls apply. FDA classifies
devices in Class II for which general controls alone are insufficient to provide reasonable
assurance of the safety and effectiveness of the device, and for which there is sufficient
information to establish special controls to provide such assurance. Special controls are usually
device specific and include:

12. Performance standards
 Post-market surveillance (PMS)
 Patient registries
 Special labeling requirements
 Pre-market data requirements
 Guidelines
In some cases, Class III devices can obtain market authorisation using the 510(K) procedure. An
example is a metal-on-metal hip implant, as these are pre-amendment devices.
Pre-amendment devices only require a PMA if the FDA has published a decision to that effect.

13. The regulatory approval process for Medical Devices:
The US FDA medical device approval process explained
Step-1
Determine the classification of your device by searching the FDA classification database using
relevant search terms, or by identifying another device with the same intended use and
technology. Pay special attention to the three letter Product Code and seven digit Regulation
Number associated with the predicate devices you identify. If the classification cannot be
determined, use 513(g) to request classification from the FDA.
Step-2
Most Class I devices have to comply with the QSR (GMPs), except for Part 820. For Class II and
III devices, implement Quality Management System (QMS) which meets the FDA Quality
System Regulation (QSR)found in 21 CFR Part 820.
Step-3
Innovative Class II, and all Class III, devices will likely require clinical studies. Get “Pre-
Submission (Pre-Sub)” feedback from the FDA.
Step-4
If clinical studies will be required, apply for an Investigational Device Exemption (IDE).
Develop clinical trial protocol and conduct studies.* Non-significant risk studies may be
performed with IRB approval.

14. Step-5
For Class II devices, prepare and submit 510(k) Premarket Notification application and pay
related fee. For Class III devices, prepare* and submit Premarket Approval (PMA) application.
Pay PMA submission fee.
Step-6
For Class III devices, FDA conducts facility inspections of all major suppliers involved in the
design and production of your device. All parties must be compliant with FDA QSR.
Step-7
For Class II devices, the FDA issues 510(k) clearance letter and posts it online. For Class III
devices, the FDA issues PMA approval letter and posts it online.

15. Step-8
At this time, you must be in full compliance with QSRs. The FDA will not inspect Class I or II
device manufacturers for compliance prior to device registration but does conduct random
inspections and can issue a Form 483 for non-compliance.
Step-9
If you have no local presence in the US, appoint an FDA US Agent representative as a local
point of contact with the FDA..
Step-10
List your device and register your company using FURLS system on the FDA website in
accordance with 21 CFR Part 807. Pay fees for Establishment Registration and Listing which
must be renewed each year.
Step-11
You are now able to sell your device in the US. Your company and device registration status will
be listed on the FDA website. Your authorization does not expire as long as no changes are made
to the device design, intended use, etc
The Quality system requirements for Medical Devices as per 21CFR part-820:
Subpart B—Quality System Requirements
§820.20 Management responsibility.
(a) Quality policy. Management with executive responsibility shall establish its policy and
objectives for, and commitment to, quality. Management with executive responsibility shall
ensure that the quality policy is understood, implemented, and maintained at all levels of the
organization.
(b) Organization. Each manufacturer shall establish and maintain an adequate
organizational structure to ensure that devices are designed and produced in accordance with the
requirements of this part.
(1) Responsibility and authority. Each manufacturer shall establish the appropriate
responsibility, authority, and interrelation of all personnel who manage, perform, and assess
work affecting quality, and provide the independence and authority necessary to perform these
tasks.
(2) Resources. Each manufacturer shall provide adequate resources, including the
assignment of trained personnel, for management, performance of work, and assessment
activities, including internal quality audits, to meet the requirements of this part.
(3) Management representative. Management with executive responsibility shall appoint,
and document such appointment of, a member of management who, irrespective of other
responsibilities, shall have established authority over and responsibility for:
(i) Ensuring that quality system requirements are effectively established and effectively
maintained in accordance with this part; and

16. (ii) Reporting on the performance of the quality system to management with executive
responsibility for review.
(c) Management review. Management with executive responsibility shall review the
suitability and effectiveness of the quality system at defined intervals and with sufficient
frequency according to established procedures to ensure that the quality system satisfies the
requirements of this part and the manufacturer's established quality policy and objectives. The
dates and results of quality system reviews shall be documented.
(d) Quality planning. Each manufacturer shall establish a quality plan which defines the
quality practices, resources, and activities relevant to devices that are designed and
manufactured. The manufacturer shall establish how the requirements for quality will be met.
(e) Quality system procedures. Each manufacturer shall establish quality system procedures
and instructions. An outline of the structure of the documentation used in the quality system shall
be established where appropriate.
§820.22 Quality audit.
Each manufacturer shall establish procedures for quality audits and conduct such audits to
assure that the quality system is in compliance with the established quality system requirements
and to determine the effectiveness of the quality system. Quality audits shall be conducted by
individuals who do not have direct responsibility for the matters being audited. Corrective
action(s), including a reaudit of deficient matters, shall be taken when necessary. A report of the
results of each quality audit, and reaudit(s) where taken, shall be made and such reports shall be
reviewed by management having responsibility for the matters audited. The dates and results of
quality audits and reaudits shall be documented.
§820.25 Personnel.
(a) General. Each manufacturer shall have sufficient personnel with the necessary
education, background, training, and experience to assure that all activities required by this part
are correctly performed.
(b) Training. Each manufacturer shall establish procedures for identifying training needs
and ensure that all personnel are trained to adequately perform their assigned responsibilities.
Training shall be documented.
(1) As part of their training, personnel shall be made aware of device defects which may
occur from the improper performance of their specific jobs.
(2) Personnel who perform verification and validation activities shall be made aware of
defects and errors that may be encountered as part of their job functions.