A medical device is any apparatus, appliance, software, material, or other article-whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application—intended by the manufacturer to be used for human beings for the purpose of:
a) Diagnosis, prevention, monitoring, treatment, or alleviation of disease
b )Diagnosis, monitoring, treatment, alleviation, or compensation for an injury or handicap;Investigation, replacement, or modification of the anatomy or of a physiological process
c)Control of conception; and which does not achieve its principal intended action in or on the human body by pharmacological, immunological, or metabolic means, but which may be assisted in its function by such means.
Medical device Classification as per FDA
The FDA generally classifies medical devices based on the risks associated with the device and by evaluating the amount of regulation that provides a reasonable assurance of the device's safety and effectiveness.
Class I (Low Risk) - Clearance/approval (not required)
Class II (Moderate Risk) - Clearance/approval (510(k))
Class III (High Risk) - Clearance/approval (PMA, Pre-market Approval)
Class I Medical Devices
Examples of medical devices include surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lenses, and orthopedic pins. A longer list of examples of medical devices is in the FDA Information Sheet Guidance, “Significant Risk vs. Non-Significant Risk Devices.”
Class II Medical Devices
Examples of Class II devices include powered wheelchairs and some pregnancy test kits. 43% of medical devices fall under this category.
Class III Medical Devices.
These devices usually sustain or support life, are implanted, or present potential unreasonable risk of illness or injury. They represent 10% of medical devices regulated by the FDA. Examples of Class III devices include implantable pacemakers and breast implants.
Biocompatibility means, a biomaterial, device or construct can be brought into direct contact with living tissue without causing a harmful tissue reaction (pain, swelling or necrosis) that could compromise function, causing a systemic toxic reaction or having tumorigenic potential.
In general, the biocompatibility endpoints to be considered include:
In vitro cytotoxicity
Acute, subchronic and chronic toxicity
And effects on reproduction, including developmental effects.
Hemocompatibility is a measure of the thrombotic response induced by a material or device in contact with blood that will lead to the activation of the blood coagulation cascade, including platelet response, complement activation, and coagulation cascade initiation.
Extraction conditions (In vivo testing)
Extraction conditions based on common practices are as follows (see also C.5):
a) (37 ± 1) °C for (24 ± 2) h
b) (37 ± 1) °C for (72 ± 2) h
c) (50 ± 2) °C for (72 ± 2) h
d) (70 ± 2) °C for (24 ± 2) h
e) (121 ± 2) °C for (1 ± 0,1) h.
Examples of extraction media
a) Polar medium: water, physiological saline; culture media without serum
b) Non-polar medium: freshly refined vegetable oil (e.g. cottonseed or sesame oil) of quality defined in various pharmacopoeia
c) Additional media: ethanol/water, ethanol/saline, polyethylene glycol 400 (diluted to a physiological osmotic pressure), dimethyl sulfoxide and culture media with serum.
Hemocompatibility Tests for Medical Devices
Prothrombin Time (PT)
Partial Thromboplastin Time (PTT / Inactive PTT)
Complement Activation (C3a & SC5b-9)
Platelet Aggregation / Activation
Thrombosis / Fibrinolysis
Cytotoxicity Tests for Medical Devices
MTT Assay / XTT Assay
Neutral Red Uptake
Systemic Toxicity Tests
Dental, Spine, Ocular and so on.
Bacterial Mutation (AMES) Test
In vitro & In vivo micronucleus
In vitro & In vivo chromosomal aberration
Mucosal Irritation (Oral, Rectal, Vaginal & Penile)
Buehler Sensitization Method
Local lymph Node Assay (LLNA)
In vitro Bacterial Endotoxins
Material Mediated Rabbit Pyrogen Test
Immunotoxicity / Immunogenicity
New biocompatibility testing may not be needed if both:
1. The device is made of materials that:
–Have been well characterized chemically and physically in the published
–Have been previously evaluated
2. Manufacturing and processing information support no new biocompatibility
CE marking is the medical device manufacturer's claim that a product meets the essential requirements of all relevant European Medical Device Directives. The Directives outline the saftey and performance requirements for medical devices in the European Union (EU).
The letters "CE" are the abbreviation of French phrase
Regulatory Guidelines - Medical Devices
Product Specific ISO Guidelines
Pharmacopoeia (USP / BP / IP)
A 510(K) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR §807.92(a)(3)) that is not subject to premarket approval.
Premarket approval (PMA)
Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. The applicant must receive FDA approval of its PMA application prior to marketing the device.
ISO 10993-1 seven general principles
1. The selection of material(s) to be used in device manufacture and its
biocompatibility evaluation should initially take into account the likelihood of
direct or indirect tissue contact and any available information for the
materials of manufacture.
2. The material(s) of manufacture, the device in its final finished form, and
possible leachable chemicals or degradation products should be considered
for their relevance to the overall biocompatibility evaluation of the device.
3. Endpoints relevant to the biocompatibility evaluation should take into account
the nature, degree, frequency, duration, and conditions of exposure of the
device materials to the body.
4. Any in vitro or in vivo biological safety experiments or tests should be
conducted in accordance with recognized Good Laboratory Practice (GLP)
5. When test data are provided, complete experimental data, complete to the
extent that an independent conclusion could be made, should be submitted
to the reviewing authority.
6. Any change in chemical composition, manufacturing process, physical
configuration (e.g., size, geometry, surface properties) or intended use of the
device should be evaluated with respect to possible changes in
biocompatibility and the need for additional biocompatibility testing.
7. The biocompatibility evaluation performed in accordance with this guidance
should be considered in conjunction with information obtained from other
nonclinical tests, clinical studies, and postmarket experiences for a safety
assessment that incorporates all available relevant information.
Ref: https://www.fda.gov/media/85865/download(accessed on 01.07.2019)
What is IDE?
Investigational Device Exemption (IDE) is a provision that allows manufacturers to collect device specific safety and effectiveness data of proposed device before commercialization, which can be used to support premarket approval application or in some cases for premarket notification submission.
What are the regulations that manufacturer must comply in the United States?
Center for Devices and Radiological Health regulates the firms involved in manufacturing, repackaging, labelling or importing of medical devices in the United States.
Below are the basic regulatory requirements that distributors must comply with in order to get an approval from FDA:
Establishment Registration – 21 CFR Part 807
Medical Device Listing – 21CFR Part 807
Premarket Notification 510(k) – 21 CFR Part 807 Subpart E
Premarket Approval (PMA) – 21 CFR Part 814
Investigational Device Exemption (IDE) – 21CFR Part 812
Quality System Regulation (QS)/Good Manufacturing Practices (GMP) – 21 CFR
Labeling – 21 CFR Part 801
Medical Device Reporting – 21 CFR Part 803
ISO 10993 Guidelines
ISO 10993-1 Biological evaluation of medical devices -Part 1: Evaluation
and testing within a risk management process
ISO 10993-2 Biological evaluation of medical devices - Part 2: Animal
ISO 10993-3 Biological evaluation of medical devices - Part 3: Tests for
genotoxicity, carcinogenicity and reproductive toxicity
ISO 10993-4 Biological evaluation of medical devices - Part 4: Selection of
tests for interactions with blood
ISO 10993-5 Biological evaluation of medical devices -- Part 5: Tests for in
ISO 10993-6 Biological evaluation of medical devices - Part 6: Tests for local
effects after implantation
ISO 10993-7 Biological evaluation of medical devices -- Part 7: Ethylene oxide
ISO 10993-8 Biological evaluation of medical devices -- Part 8: Selection and
qualification of reference materials for biological tests
ISO 10993-9 Biological evaluation of medical devices -- Part 9: Framework for
identification and quantification of potential degradation
ISO 10993-10 Biological evaluation of medical devices -- Part 10: Tests for
irritation and skin sensitization
ISO 10993-11 Biological evaluation of medical devices -- Part 11: Tests for
ISO 10993-12 Biological evaluation of medical devices -- Part 12: Sample
preparation and reference materials
ISO 10993-13 Biological evaluation of medical devices -- Part 13: Identification
and quantification of degradation products from polymeric
ISO 10993-14 Biological evaluation of medical devices -- Part 14: Identification
and quantification of degradation products from ceramics
ISO 10993-15 Identification and quantification of degradation products from
metals and alloys
ISO 10993-16 Toxicokinetic study design for degradation products and
ISO 10993-17 Establishment of allowable limits for leachable substances
ISO 10993-18 Chemical characterization of materials
ISO 10993-19 Physico-chemical, morphological and topographical
characterization of materials [TS]
ISO 10993-20 Principles and methods for immunotoxicology testing of medical
Points to be considered
Permanent or absorbable implants
For permanent or absorbable implants, FDA may request data from exhaustive extraction studies (per ISO 10993-12) and surface characterization information to support use of the representative test articles.
Multiple Components or Materials in a Single Test Article
For devices that include components with different lengths of contact (e.g., categorized as limited, prolonged, or permanent), FDA recommend that any extract-based biocompatibility testing be conducted separately. If the components are combined into a single test article, this will dilute the amount of component materials being presented to the test system and may not accurately identify potentially toxic agents that would have been found if the components were tested separately. For example, FDA recommend testing implants separately from delivery systems or other kit components.
For devices or device components that contain multiple materials with differing surface areas or differing exposure to the body, if one or more materials is new (i.e., not used before in devices with the same type and duration of contact), it may also be necessary to test the new material component(s) separately as well, to further understand the potential toxicity of this component. For example, for a catheter-based delivery system that contains a new balloon material, tests of the delivery system separate from the balloon may be necessary to ensure adequate assessment of each of the materials.
There are two types of sensitization tests that are generally submitted in support of IDE and marketing applications: the Guinea Pig Maximization Test and the Local Lymph Node Assay. In addition, the Buehler method can be used for topical devices only (i.e., those in contact with skin), per ISO 10993-10.
FDA intends to evaluate use of LLNA tests for medical devices on a case-by-case basis for medical device extract/residuals that are composed of chemical mixtures. LLNA:2-Bromodeoxyuridine-Enzyme Linked Immunosorbent Assay (BrdU-ELISA) test or the LLNA: Daicel Adenosine Triphosphate (DA) test
Biocompatibility Evaluation Endpoints are given in the following tables
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