Medical Device Testing

Medical device

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

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

     Irritation

     Sensitization

     Hemocompatibility 

     Implantation 

     Genotoxicity; 

     Carcinogenicity

     And effects on reproduction, including developmental effects.

Hemocompatibility 

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 

     Hemolysis Test     

     Prothrombin Time (PT)

     Partial Thromboplastin Time (PTT / Inactive PTT)

     Complement Activation (C3a & SC5b-9)

     Platelet Aggregation / Activation

     Coagulation

     Thrombosis / Fibrinolysis

     Leukocyte Activation

Cytotoxicity Tests for Medical Devices

     Agar Overlay

     MEM Elution

     MTT Assay / XTT Assay

     Neutral Red Uptake

     Colony Formation

Systemic Toxicity Tests

     Acute

     Sub-acute

     Sub-chronic

     Chronic

Implant Tests

     Intramuscular

     Subcutaneous

     Bone

     Dental, Spine, Ocular and so on.

Genotoxicity Tests

     Bacterial Mutation (AMES) Test

     Mouse Iymphoma

     In vitro & In vivo micronucleus

     In vitro & In vivo chromosomal aberration

Irritation Tests

     Dermal Irritation

     Intracutaneous Reactivity

     Eye Irritation

     Mucosal Irritation (Oral, Rectal, Vaginal & Penile)

Sensitization Tests

     Buehler Sensitization Method

     Maximization (Magnus-Kligman)

     Local lymph Node Assay (LLNA)

Pyrogenicity Tests

     In vitro Bacterial Endotoxins

     Material Mediated Rabbit Pyrogen Test

Others

     Carcinogenicity

     Reproductive Toxicity

     Teratogenicity

     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  

          literature  

        –Have been previously evaluated

2. Manufacturing and processing information support no new biocompatibility 

    concerns.

CE Marking

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 

"Conformité Européene"

Regulatory Guidelines - Medical Devices

     ISO 10993

     ASTM

     US FDA

     AAMI

     Product Specific ISO Guidelines

     Pharmacopoeia (USP / BP / IP)

510K approval

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) 

     regulations. 

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       

    Part 820

    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 

                             welfare requirements

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                              

                             vitro cytotoxicity

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                              

                             sterilization residuals

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 

                             products        

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 

                             systemic toxicity

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 

                             medical devices

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 

                            leachables 

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 

                            devices [TS] 

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. 

Sensitization

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

Ref:  https://www.fda.gov/media/85865/download