FAQ North American Biomedical Institute

START 5 FAQ North American Biomedical Institute
What is biocompatibility?

The concept of biocompatibility refers to the interaction between the tissues and the physiological systems of a patient treated with a medical device. The biocompatibility assessment is part of the overall device safety assessment.

 

Medical device biocompatibility assessment is actually carried out in order to ensure patient safety. When programming a biocompatibility test, manufacturers need to consider their compliance objectives and risks. In fact, medical device biocompatibility evaluation is a risk assessment study. All medical devices have a certain level of risk. Firms that design medical devices strive to maximize the benefits they provide to patients by minimizing risk.

 

The main standard in biocompatibility testing is the ISO 10993 standards. The first part of this standard is the test selection guide. The following sections cover specific test processes and other test related considerations.

 

Biocompatibility testing data is always required for devices with significant tissue contact. The ISO 10993-1 material biocompatibility matrix is used to determine whether a medical device requires a biocompatibility test. ISO 10993-1: 2018 through the Biological Evaluation Plan (BEP) allows to determine the potential risk based on the data provided by the Sponsor (information on raw materials, packaging, production conditions and previously performed studies). The next step is a series of studies proposed in the BEP to verify risk assessments, and finally in the Biological Evaluation Report (BER) risk assessment is summarized and explained what the potential sources of non-compliance could be.

 

The main purpose of the ISO standard is to verify that the device is suitable for the intended use. In this process, biological testing is the most important step in a biocompatibility assessment. The standard classifies devices by type of body contact and duration.

 

Biocompatibility is often associated with the necessity to perform a complete set of tests for new medical devices that are yet to be released on the market. But manufacturers of medical devices must remember that sometimes a seemingly small change in the production process of products already available on the market (for example: changing one of the materials, changing the production method, introducing new machines into the production line, or an apparently insignificant change in the sterilization method) is associated with another risk assessment and performing biocompatibility tests. Also manufacturers are required to collect safety data for all components and materials used in medical devices.

 

North American Biomedical Institute (NABI) works with European Biomedical Institute (EBI) that is Good Laboratory Practice (GLP) certified, ISO 17025 accredited, and US FDA 21CFR58 compliant. EBI institute also provides biocompatibility testing services in the field of certification services. Thanks to these services, enterprises are able to produce more efficient, high-performance and high-quality products in a safe, fast and uninterrupted manner.

 

For further information, please contact your sales representative team if you’re an existing customer or if you’re new to North American Biomedical Institute please reach us at  contact@nabi.bio

We look forward to helping you reach all of your evaluation goals and a successful submission!

 

We are here to support you!        

Why do you need ISO 17025 or GLP?

To ensure the highest quality services, our cooperating laboratories implemented and maintained internationally recognized quality standards. As North American Biomedical Institute (NABI) we cooperate with the European Biomedical Institute and we are a part of the Biomedical Institutes Group. European Biomedical Institute is:

 

GLP certified
Download GLP Certificate

ISO 17025 accredited
Download ISO Certificate

 

GLP

Quality system, that defines a set of rules and criteria for studies that are planned, performed and monitored, and their results are recorded, reported and archived. It is possible to trace the course of the study or its complete reconstruction.

 

ISO 17025

The quality management standard, implemented to standardize the technical requirements and requirements of the management system, intended for research laboratories in terms of testing and calibration. The objective of ISO 17025 is to promote the confidence in the operation of laboratories, to enable them to demonstrate they operate competently, and are able to generate valid results.

 

US FDA 21CFR58

Code of Federal Regulations of good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA.

 

According to the ISO 10993-1:2018, B.4.5.3 any testing to support a biological evaluation has to be conducted in appropriate quality systems. The quality systems controls applicable to biocompatibility testing are known as Good Laboratory Practices (GLP). GLP studies are carried out to define quality standards in laboratories that are accredited in line with an internationally implemented governmental scheme. Those studies have to be conducted under a laboratory quality system compliant to ISO/IEC 17025 or an equivalent standard (GLP).

 

Furthermore, European Biomedical Institute is inspected and subject to constant supervision of the following Bodies:

  • Veterinary Inspectorate
  • Ethic Committee
  • Pharmaceutical Inspectorate
  • Ministry of Science and Higher Education
  • European Commission

 

If you have any further questions in terms of quality, please contact with us at contact@nabi.bio

Biocompatibility must be addressed - but what does it exactly mean?

According to the ISO 10993 standards and FDA requirements, biocompatibility must be addressed for each medical device. It is really important, since a significant amount of 510k submissions are rejected because of biocompatibility chapters are left empty…                               

 

We need to keep in mind that addressing biocompatibility does not mean each medical device has to be tested for biocompatibility! For instance, testing of a medical device that has no direct and in-direct contact may be impractical and even impossible. To highlight it, we may ask a question: how to test a medical device software for biocompatibility? The answer is simple: such testing is not necessary.                           

 

Therefore, for such cases the best way is to prepare a rationale/justification why biocompatibility testing was not performed – and it is a must! Such appropriate rationale or justification meet the requirements of addressing biocompatibility.                           

 

Do you have a questions for your medical device testing? Feel free to ask us.

ISO 10993-1 Biocompatibility Matrix

An integral part of biological risk assessment, biocompatibility testing assesses the compatibility of medical devices with a biological system. It studies the interaction between the device and the various types of living tissues and cells that are exposed to the device when it comes into contact with patients.

 

Specific medical device safety evaluation programs follow ISO 10993 standards and the FDA guidance. EBI’s Biocompatibility Matrix is based on ISO 10993-1 Evaluation and Testing (2018), as well as the FDA Guidance (2020). While the matrix has been developed as a guideline for biocompatibility evaluation, it is essential that each device be evaluated based on its own unique characteristics.

 

Medical device categorized by Endpoints of biological evaluation
Nature of body contact Contact duration Physical and/or Chemical information Cytotoxicity Sensitization Irritation or Intracutneous reactivity Materiał mediated pyrogenicity Acute systemie toxicity Subacute toxicity Subchronic toxicity Chronić toxicity Implantation effects Hemocompatibility Genotoxicity Carcinogenicity Reproductive / develop mental toxicity Degradation
Category Contact

A – limited

(<24h)

B – prolonged

(> 24 h to 30 d)

C – long term

(> 30 d)
Surface medical device Intact skin A
B
C
Mucosal membrane A
B
C
Breached or compromised surface A
B
C
Externally communicating medical device Blood path, indirect A
B
C

Tissue

/

Bone

/

Dentin

 A
B
C

Circulating

blood

 A
B
C
Implant medical device

Tissue

/

Bone

 A
B
C
Blood A
B
C
means prerequisite information needed for a risk assessment
means endpoints to be evaluated in the risk assessment
additional FDA recommended endpoints for consideration
How many samples for biocompatibility tests?

According to the US Food and Drug Administration (FDA), it is recommended that a surface/volume (cm2/mL) ratio should be used for extraction.

BIOCOMPATIBILITY STUDY STANDARD SAMPLE REQUIREMENTS
< 0.5 mm thickness
ratio: 6 cm²/mL		 ≥ 0.5 mm thickness
ratio: 3 cm²/mL		 irregulary shaped solid devices
ratio: 0.2 g/mL		 irregulary shaped porous devices
ratio: 0.1 g/mL		 liquids
Biological Evaluation Plan ISO 10993-1 not applicable
Chemical Characterization Headspace GC-MS ISO 10993-18 1 sample
(min. 60 cm2)		 1 sample
(min. 30 cm2 )		 1 sample
(min. 2 g)		 1 sample
(min. 1 g)		 1 sample
(min. 10 mL)
GC-MS 3 samples
(min. 30 cm2 each)		 3 samples
(min. 15 cm2 each)		 3 samples
(min. 2 g each)		 3 samples
(min. 1 g each)		 3 samples
(min. 5 mL each)
LC-MS 3 samples
(min. 30 cm2 each)		 3 samples
(min. 15 cm2 each)		 3 samples
(min. 2 g each)		 3 samples
(min. 1 g each)		 3 samples
(min. 5 mL each)
ICP-MS 1 sample
(min. 90 cm2)		 1 sample
(min. 45 cm2)		 1 sample
(min. 3 g)		 1 sample
(min. 2 g)		 1 sample
(min. 15 mL)
Toxicological Evaluation ISO 10993-17 not applicable
Cytotoxicity MEM Elution ISO 10993-5 1 sample
(min. 60 cm2)		 1 sample
(min. 30 cm2)		 1 sample
(min. 2 g)		 1 sample
(min. 1 g)		 1 sample
(min. 10 mL)
Direct Contact to be individually determined
Agar Diffusion 1 sample
(min. 24 cm2)		 1 sample
(min. 12 cm2)		 1 sample
(min. 1 g)		 1 sample
(min. 1 g)		 1 sample
(min. 4 mL)
XTT 1 sample
(min. 60 cm2)		 1 sample
(min. 30 cm2)		 1 sample
(min. 2 g)		 1 sample
(min. 1 g)		 1 sample
(min. 10 mL)
MTT 1 sample
(min. 60 cm2)		 1 sample
(min. 30 cm2)		 1 sample
(min. 2 g)		 1 sample
(min. 1 g)		 1 sample
(min. 10 mL)
Sensitization GPMT ISO 10993-10 6 samples
(min. 240 cm2 each)		 6 samples
(min. 120 cm2 each)		 6 samples
(min. 8 g each)		 6 samples
(min. 4 g each)		 to be individually determined
LLNA 6 samples
(min. 120 cm2 each)		 6 samples
(min. 60 cm2 each)		 6 samples
(min. 4 g each)		 6 samples
(min. 2 g each)
Buehler 120 samples
(pieces of 2.5 cm x 2.5 cm patches each)		 to be individually determined
Irritation In Vitro Irritation ISO 10993-23 2 samples
(min. 60 cm2 each)		 2 samples
(min. 30 cm2 each)		 2 samples
(min. 2 g each)		 2 samples
(min. 1 g each)		 1 sample
(min. 10 mL)
Intracutaneous reactivity ISO 10993-10 2 samples
(min. 60 cm2 each)		 2 samples
(min. 30 cm2 each)		 2 samples
(min. 2 g each)		 2 samples
(min. 1 g each)		 to be individually determined
Animal Irritation Test to be individually determined
Material mediated pyrogenicity Material mediated pyrogenicity ISO 10993-11 1 sample
(min. 1200 cm2)		 1 sample
(min. 600 cm2)		 1 sample
(min. 40 g)		 1 sample
(min. 20 g)		 to be individually determined
Endotoxin LAL 1 sample
(min. 12 cm2)		 1 sample
(min. 6 cm2)		 1 sample
(min. 1 g)		 1 sample
(min. 1 g)		 1 sample
(min. 2 mL)
Toxicity Acute Systemic Toxicity ISO 10993-11 2 samples
(min. 120 cm2 each)		 2 samples
(min. 60 cm2 each)		 2 samples
(min. 4 g each)		 2 samples
(min. 2 g each)		 to be individually determined
Subacute Toxicity to be individually determined
Subchronic Toxicity to be individually determined
Chronic Toxicity to be individually determined
Implantation 4 week implantation ISO 10993-6 to be individually determined
13 week implantation to be individually determined
Hemocompatibility Hemolysis (direct & indirect) ISO 10993-4 6 samples
(min. 60 cm2 each)		 6 samples
(min. 30 cm2 each)		 6 samples
(min. 2 g each)		 6 samples
(min. 1 g each)		 6 samples
(min. 10 mL each)
Coagulation 3 samples
(min. 30 cm2 each)		 3 samples
(min. 18 cm2 each)		 3 samples
(min. 1 g each)		 3 samples
(min. 1 g each)		 3 samples
(min. 5 mL each)
Platelet Activation 3 samples
(min. 30 cm2 each)		 3 samples
(min. 18 cm2 each)		 3 samples
(min. 2 g each)		 3 samples
(min. 1 g each)		 3 samples
(min. 5 mL each)
Complement Activation 3 samples
(min. 12 cm2 each)		 3 samples
(min. 6 cm2 each)		 3 samples
(min. 1 g each)		 3 samples
(min. 1 g each)		 3 samples
(min. 2 mL each)
Hematology 3 samples
(min. 30 cm2 each)		 3 samples
(min. 18 cm2 each)		 3 samples
(min. 2 g each)		 3 samples
(min. 1 g each)		 3 samples
(min. 5 mL each)
Genotoxicity AMES ISO 10993-3 ISO 10993-33 3 samples
(min. 240 cm2 each)		 3 samples
(min. 120 cm2 each)		 3 samples
(min. 8 g each)		 3 samples
(min. 4 g each)		 1 sample
(min. 40 mL)
MLA 1 sample
(min. 480 cm2)		 1 sample
(min. 240 cm2)		 1 sample
(min. 16 g)		 1 sample
(min. 8 g)		 1 sample
(min. 80 mL)
Biological Evaluation Report ISO 10993-1 not applicable

 

How many samples for other tests?
STUDY STANDARD SAMPLE REQUIREMENTS
<
0.5 mm thickness
ratio: 6 cm²/mL		 ≥
0.5 mm thickness
ratio: 3 cm²/mL		 irregulary shaped solid devices
ratio: 0.2 g/mL		 irregulary shaped porous devices
ratio: 0.1 g/mL		 liquids
Chemical
Characterization		 Exhaustive extraction pre-test ISO
10993-18		 1 sample/solvent
(min. 30 cm2 each)		 1 sample/solvent
(min. 15 cm2 each)		 1 sample/solvent
(min. 2 g each)		 1 sample/solvent
(min. 1 g each)		 1 sample/solvent
(min. 5 mL each)
Toxicological evaluation ISO 10993-17 not applicable
UV-VIS QMS 1 sample/solvent
(min. 30 cm2 each)		 1 sample/solvent
(min. 15 cm2 each)		 1 sample/solvent
(min. 2 g each)		 1 sample/solvent
(min. 1 g each)		 1 sample/solvent
(min. 5 mL each)
TOC 1 sample/solvent
(min. 30 cm2 each)		 1 sample/solvent
(min. 15 cm2 each)		 1 sample/solvent
(min. 2 g each)		 1 sample/solvent
(min. 1 g each)		 1 sample/solvent
(min. 5 mL each)
FT-IR 1 sample/solvent
(min. 30 cm2 each)		 1 sample/solvent
(min. 15 cm2 each)		 1 sample/solvent
(min. 2 g each)		 1 sample/solvent
(min. 1 g each)		 1 sample/solvent
(min. 5 mL each)
Other Sterility USP <71> depends on production batch volume
Bioburden validation USP <1227>
ISO 11737		 min. 3 samples (sterile)
Bioburden testing USP <61>
ISO 11737		 min. 3 samples (non-sterile)
Bacteriostasis &
Fungistasis		 USP <71>
ISO 11737		 min. 6 samples
Package valiadtion bubble emission ISO 11607 depends on production batch volume and Customer requirements
Package valiadtion dye
migration
Package valiadtion burst pressure
Package valiadtion seal strength
Package valiadtion
accelerated aging		 ASTM
F1980		 depends Customer requirements
Cleaning validation manual ISO 17664 5 samples
Cleaning validation
automated		 5 samples
Disinfection validation 7 samples
Steam sterilization
validation		 ISO 14937
ISO 17665-1		 5 samples
How long does biocompatibility testing take?
BIOCOMPATIBILTY STUDY STANDARD TOURNAROUND TIME [week]
Biological Evaluation Plan ISO 10993-1 4
Chemical characterization Headpace GC-MS ISO 10993-18 8
GC-MS
LC-MS
ICP-MS
Toxicological evaluation ISO 10993-17 4
Cytotoxicity MEM Elution ISO 10993-5 4
Direct Contact
Agar Diffusion
Filter Diffusion
MTT/XTT
Sensitization GPMT ISO 10993-10 12
LLNA 6
Buehler 12
Irritation In vitro irritation ISO 10993-23 8
Intracutaneous reactivity 4
Animal Irritation Test
Material mediated pyrogenicity Material mediated pyrogenicity ISO 10993-1 1 4
Endotoxin LAL
Toxicity Acute Systemic Toxicity ISO 10993-1 1 6
Subacute toxicity 12*
Subchronic toxicity 20*
Chronic toxicity 32*
Implantation 4 week implantation ISO 10993-6 12*
13 week implantation 21*
Hemocompatibility Hemolysis (direct & indirect) ISO 10993-4 6
Coagulation
Platelet Activation
Complement Activation
Hematology
Genotoxicity AMES ISO 10993-3 6
MLA ISO 10993-33 12
Biological Evaluation Report ISO 10993-1 4

* after Ethics Committee approval

We perform all biocompability studies in FAST TRACK mode !!! Please contact us to obtain more details.

 

OTHER SERVICES STANDARD TOURNAROUD TIME
[week]
Consulting Services Consulting Internal QMS 1
Literature Screening 2
Microbiology and sterility testing Bioburden validation USP <1227>
ISO 11737		 4
Bioburden testing USP <61>
ISO 11737
Bacteriostasis & Fungistasis USP <71>
ISO 11737
Sterility
Chemical Characterization FT-IR USP <197> 8
UV-VIS
TOC USP <643>
THC USP <19227>
Customized chemical analysis Internal QMS
Package Validation Bubble emmision ISO 11607 4
Dye migration
Burst pressure
Seal strenght
Accelerated aging ASTM Fl 980 AA time + 2
Reprocessing Validation Automated cleaning ISO 1 7664 8
Manual cleaning
Disinfection
Steam sterilization ISO 14937
ISO 1 7665-1
Biocompatibility Dictionary
TERM DEFINITION
A absorb action of a non-endogenous (foreign) material or substance passing through or being assimilated by cells and/or tissue over time
absorb/absorption action of a non-endogenous (foreign) material or substance, or its decomposition products passing through or being assimilated by cells and/or tissue over time
absorption process by which a substance enters the blood and/or lymph system
accelerated extraction extraction that provides a measure of the leachable or extractable materials of the device or material, using conditionsthat shorten the timefor leaching of the substancesinto the extractionvehicle but do not result in a chemical change of the substances being extracted
accelerated extraction extraction whose duration is shorter than the duration of clinical use but whose conditions do not result in a chemical change to the substances being extracted
acute systemic toxicity adverse effects occurring at any time within 72 h after single, multiple or continuous exposures of a test sample for 24 h
agglomerate collection of weakly bound particles or aggregates or mixtures of the two where the resulting external surface area is similar to the sum of the surface areas of the individual components
aggregate particle comprising strongly bonded or fused particles where the resulting external surface area is significantly smaller than the sum of calculated surface areas of the individual components
allergen/sensitizer substance or material that is capable of inducing a specific hypersensitivity reaction upon repeated contact with that substance or materia
allowable limit (AL) largest amount of a leachable substance that is deemed acceptable on a daily basis, when taken into the body through exposure to a medical device
alloy material composed of a metallic element with one or more addition(s) of other metallic and/or non-metallic elements
analytical evaluation threshold (AET) threshold below which the analyst need not identify or quantify leachables or extractables or report them for potential toxicological assessment
analytical screening method method whose purpose is to discover, identify and semi-quantitatively estimate the concentration of all relevant analytes in a test sample above an established reporting threshold (such as the AET)
analytical targeting method method whose purpose is to quantify, with an appropriately high degree of accuracy and precision, specified analytes in a specified test sample over a specified concentration range
analytically expedient situation where an extraction vehicle can be directly evaluated with generally available analytical methods with the sensitivity and selectivity necessary to achieve a designated reporting threshold such as the AET
animal any live non-human vertebrate, excluding immature forms during the first half of gestation of incubation
animal test any use of an animal for scientific purposes
anticoagulant agent which prevents or delays blood coagulation
B benefit factor (BF) numerical factor that takes into account the health benefit from use of the medical device(s) containing the leachable substance in question
bioavailability extent of systemic absorption of specified substance
biocompatibility ability of a medical device or material to perform with an appropriate host response in a specific application
biodegradation degradation due to the biological environment
biological risk combination of the probability of harm to health occurring as a result of adverse reactions associated with medical device or material interactions, and the severity of that harm
biological safety freedom from unacceptable biological risk in the context of the intended use
biomaterial material or substance intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function of the body
bioresorbable medical device medical device intended for degradation and resorption in the biological environment of the body
bioresorption process by which a biomaterial is degraded in the physiological environment and the product(s) eliminated and/or absorbed
blank extraction vehicle not containing the test sample, retained in a vessel identical to that which holds the test sample and subjected to conditions identical to those to which the test sample is subjected during its extraction
blank disc noncoated circular plate made of the substrate material to be used in the finished device
blood/device interaction interaction between blood or a blood component and a device
breakdown potential (Ep) critical electrode potential above which localized or transpassive corrosion is found to occur
C carcinogenicity test test to determine the carcinogenic potential of medical devices, materials, and/or extracts using multiple exposures for a major portion of the life span of the test animal
ceramics typically crystallized materials that are physically nonmetallic and chemically inorganic
certified reference material (CRM) reference material, accompanied by a certificate, one or more of whose property values are certified by a procedure which establishes its traceability to an accurate realization of the unit in which the property values are expressed, and for which each certified value is accompanied by an uncertainty at a stated level of confidence
challenge / elicitation process following the induction phase, in which the immunological effects of subsequent exposures in an individual to the inducing material are examined
chemical characterization process of obtaining chemical information, accomplished either by information gathering or by information generation, for example, by literature review or chemical testing
chemical constituent any synthetic or natural substance that is used in a process for manufacturing materials and/ or medical devices, including the base material(s), additives (antioxidants, UV stabilizers, color additives, dyes, etc.), and processing aids (solvents, lubricants, antifoaming agents, etc.)
chemical information qualitative and quantitative, if applicable, knowledge related to the configuration, composition and production of the medical device and/or its materials of construction, thereby establishing the identities and amounts of constituents present in the materials and device
chronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a major part of the life span
clearance rate of removal of a specified substance from the body or parts of the body by metabolism and/or excretion
clinically established medical device, component, or material of construction which has been used extensively for specified and established clinical uses for which biocompatibility has been established
coagulation phenomenon that results from activation of the clotting (coagulation) factor cascade
colloidal osmotic pressure total influence of the proteins or other large molecular mass substances on the osmotic activity of plasma
competent authority body designated or recognized by a national government to take responsibility for overseeing, supervising or regulating animal tests, or the breeding and supply of purpose-bred animals for use on such tests, within the scope of this part of ISO 10993
complement system part of the innate immune system consisting of over 30 distinct plasma proteins, including enzymes, cofactors, and cellular receptors which may be involved in the promotion of thrombosis
component item which forms one part of a medical device, but is not itself a medical device
concomitant exposure factor (CEF) numerical factor that accounts for patient exposure to many medical devices containing the same leachable substance
constituent chemical that is present in a finished medical device or its materials of construction
convertor person or company who converts or fabricates a basic raw material into a semi-finished product (e.g. a former of lengths of rod, tubing, or plastic components)
corrosion attack on metallic materials by chemical or electrochemical reactions
culture vessels vessels appropriate for cell culture including glass petri dishes, plastic culture flasks or plastic multiwells and microtitre plates
D data set information, such as physical and/or chemical characterization, toxicity data, etc. from a variety of sources necessary to characterize the biological response to a medical device
debris particulate material produced by the degradation of a polymeric material
default value to be used, in the absence of data, for an uncertainty or other factor used in the calculation of the allowable limit
degradation decomposition of a material
degradation decomposition of a material
degradation product any intermediate or final by-product which results from the physical, metabolic, and/or chemical decomposition of a material or substance
degradation product any particle or chemical compound that is derived from the chemical breakdown of the original material
degradation product chemical compound derived from the breakdown of the polymeric material, including any compound produced by consecutive chemical reactions
degrade to physically, metabolically, and/or chemically decompose a material or substance
device component one of the different parts of which a device is composed
digestion process of completely solubilizing a medical device, one or more of its components or one or more of its materials of construction by breaking it down into its fundamental structural units, including its elemental constituents or monomeric units
direct blood contact term used when the device or device material comes into physical contact with blood or blood constituents
direct contact medical device or medical device component that comes into physical contact with body tissue
dissolution process of completely solubilizing a medical device, one or more of its components or one or more of its materials of construction, generally preserving the molecular structures of its constituents
distribution process by which an absorbed substance and/or its metabolites circulate and partition within the body
dose / dosage amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area
dose-effect relationship between the dosage and the magnitude of a defined biological effect either in an individual or in a population sample
dose-response relationship of dosage to the spectrum of effects related to the exposure
E electrolyte medium in which electric current is transported by ions
embolization process whereby a blood thrombus, or foreign object, is carried in the bloodstream and which may become lodged and cause obstructed blood flow downstream
energy-depositing medical device device intended to exert its therapeutic or diagnostic effect by the delivery of electromagnetic radiation, ionising radiation or ultrasound
engineered nanomaterial nanomaterial designed for a specific purpose or function
erythema reddening of the skin or mucous membrane
eschar scab or discoloured slough of skin
estimated quantitative analysis analytical approach which estimates an analyte’s concentration by using the response from a surrogate substance chosen without specifically addressing or considering the relative responses of the analyte and the surrogate
euthanasia humane killing of an animal by a method causing a minimum of physical and mental suffering
ex vivo test system term applied to a test system that shunts blood directly from a human subject or test animal into a test chamber located outside the body
exaggerated extraction extraction that is intended to result in a greater number or amount of chemical constituents being released as compared to the amount generated under the clinical conditions of use
excretion process by which an absorbed substance and/or its metabolites are removed from the body
exhaustive extraction extraction until the amount of EO or ECH in a subsequent extraction is less than 10 % of that detected in the first extraction, or until there is no analytically significant increase in the cumulative residue levels detected
exhaustive extraction extraction conducted until the amount of extractable material in a subsequent extraction is less than 10 % by gravimetric analysis of that detected in the initial extraction
exhaustive extraction multi-step extraction conducted until the amount of material extracted in a subsequent extraction step is less than 10 % by gravimetric analysis (or achieved by other means) of that determined in the initial extraction step
experimental control substance with well-characterized responses, which is used in a specific test system to assist in evaluating if the test system has responded in a reproducible and appropriate manner
externally communicating medical device medical device or medical device component that is partially or wholly located outside the body but has either direct or indirect contact with the internal body fluids and/or tissues
extract liquid or suspension that results from exposing a test or control material to a solvent under controlled conditions
extractable substance that is released from a medical device or material of construction when the medical device or material is extracted using laboratory extraction conditions and vehicles
extractables substances that canbereleased from amedical deviceor materialusingextractionsolvents and/or extraction conditions that are expected to be at least as aggressive as the conditions of clinical use
extraction power ability of an extraction vehicle to extract (or leach) substances from a medical device, component or material of construction
extraction vehicle medium (solution or solvent) which is used to extract (or leach) a test article for the purpose of establishing the test article’s extractables or leachables profile
F filtrate solution which passes through the filter paper
final product medical device or medical device component that has been subjected to all manufacturing processes for the “to be marketed” medical device including packaging and if applicable, sterilization
G genotoxicity test test using mammalian or non-mammalian cells, bacteria, yeasts, fungi or whole animals to determine whether gene mutations, changes in chromosome structure, or other DNA or gene changes are caused by the test samples
geometry / device configuration shape and relative arrangement of the parts of the medical device
H haematocrit ratio of the volume of erythrocytes to that of whole blood in a given sample
haematology study of blood that includes quantification of cellular and plasma components of the blood
haemocompatible device able to come into contact with blood without any appreciable clinicallysignificant adverse reactions such as thrombosis, haemolysis, platelet, leukocyte, and complement activation, and/or other blood-associated adverse event occurring
haemolysis liberation of haemoglobin from erythrocytes, either by destruction or through a partially damaged but intact cell membrane
half-life time for the concentration of a specified substance to decrease to 50 % of its initial value in the same body fluid or tissue
harm to health physical injury and/or damage to health
health benefit likelihood of maintaining or improving health
health hazard potential source of harm to health
health risk combination of the likelihood of occurrence of harm to health and the severity of that harm
health risk analysis use of available information to identify health hazards and to estimate health risk
homogeneous condition of being of uniform structure or composition with respect to the biological endpoint under study
humane endpoints pre-determined, specific criteria and measures to be implemented to minimize or terminate pain, suffering or distress caused by animal tests as soon as the scientific objectives have been met, or when it is realized they cannot be met, or when the animal welfare problems being encountered are greater than can be justified by the importance, potential benefits, objectives and nature of the study
hydrolytic degradation scission of chemical bonds in a polymer by the attack of water
I identification process of assigning a molecular structure and chemical name to an organic compound or assigningconstituent elements or molecular structure as appropriate, and a chemical name to an inorganic compound
immunogenic able to stimulate cells of the immune system resulting in an antigen specific immune response
immunotoxicology study of the adverse health effects that result, directly or indirectly, from the interaction of xenobiotics with the immune system
implant medical device which is intended to be totally introduced into the human body or to replace an epithelial surface or the surface of the eye by means of clinical intervention and which is intended to remain in place after the procedure
incidental nanomaterial nanomaterial generated as an unintentional by-product of a process
indirect blood contact nature of devices that contact the patient’s blood path at one point and serve as a conduit for entry into the vascular system
indirect contact medical device or medical device component through which a fluid or gas passes, prior to the fluid or gas coming into physical contact with body tissue (in this case the medical device or medical device component itself does not physically contact body tissue)
induction process that leads to the de novo generation of an enhanced state of immunological activity in an individual, to a specific material
information gathering process of collecting existing chemical information, including available test results, that is relevant to chemical characterization
information generation process of producing chemical information via laboratory testing
irritant agent that produces irritation
irritation localized non-specific inflammatory response to single, repeated or continuous application of a substance/material
L leachable extractable component from a material that is not a product of degradation
leachable chemical that can migrate from a device or component under storage conditions or conditions of use
leachable substance that is released from a medical device or material during its clinical use
leachable substance chemical removed from a device or material by the action of water or other liquids related to the use of the device
leachable substance chemical removed from a medical device by the action of water or other liquids related to the use of the device
legally-marketed comparator device (LMCD) approved, or cleared long-established, and recognized-to-be-safe medical device used as a reference control in an in vitro or in vivo safety evaluation of a test device of similar design, material(s), and clinical use
limit test use of a single group treated at a suitable dosage of test sample in order to delineate the presence or absence of a toxic hazard
lowest observed adverse effect level (LOAEL) lowest concentration or amount of a substance found by experiment or observation which causes detectable adverse alteration of morphology, functional capacity, growth, development or life span of the target organism under defined conditions of exposure
M manufactured nanomaterial nanomaterial intentionally produced to have selected properties or composition
manufacturer natural or legal person who manufactures or fully refurbishes a medical device, or has a device designed, manufactured, or fully refurbished, and markets that medical device under its name or trademark
material synthetic or natural polymer, metal or alloy, ceramic, or composite, including tissue rendered nonviable, used as a medical device or any part thereof
material characterization broad and general process of collecting existing information about a material’s chemistry, structure and other properties, and if appropriate, new data, to facilitate the evaluation of these properties
material composition listing of the constituents that are contained in a material (qualitative) and the amount of each substance in the material (quantitative)
material of construction individual raw material that is used to produce a component
maximum tolerated dose (MTD) maximum dose that a test animal can tolerate without any adverse effects
mean residence time statistical moment related to half-life which provides a quantitative estimate of the persistence of a specified substance in the body
medical device any instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software, material or other similar or related article, intended by the manufacturer to be used, alone or in combination, for human beings
medical device configuration listing of a medical device’s components (qualitative), including a listing of the component’s materials of construction (qualitative) and the proportion of each material in each component (quantitative)
metabolism process by which an absorbed substance is structurally changed within the body by enzymatic and/or nonenzymatic reactions
minimally irritating level (MIL) amount of a leachable substance that is minimally irritating to the patient
modifying factor (MF) mathematical product of uncertainty factors UF1, UF2 and UF3
morphological relating to the shape, contours and microstructural organization (of materials)
multiple exposure more than one exposure of the same patient to devices containing the same leachable substance, simultaneously or at different times
N nano-object discrete piece of material with one, two or three external dimensions in the nanoscale
nanofibre nano-object with two similar external dimensions in the nanoscale and the third dimension significantly larger
nanomaterial material with any external dimension in the nanoscale or having internal structure or surface structure in the nanoscale
nanomaterial material with any external dimension in the nanoscale or having internal structure or surface structure in the nanoscale
nanoparticle nano-object with all external dimensions at the nanoscale where the length of the longest and the shortest axes of the nano-object do not differ significantly
nanoplate nano-object with one external dimension in the nanoscale and the two other external dimensions significantly larger
nanorod solid nanofibre
nanoscale length range approximately from 1 nm to 100 nm
nanoscale phenomenon effect attributable to the presence of nano-objects or nanoscale regions
nanoscale property characteristic of a nano-object or nanoscale region
nanoscience study, discovery and understanding of matter, where size- and structure-dependent properties and phenomena manifest, predominantly in the nanoscale, distinct from those associated with individual atoms or molecules, or extrapolation from larger sizes of the same material
nanostructure composition of inter-related constituent parts in which one or more of those parts is a nanoscale region
nanostructured material material having internal nanostructure or surface nanostructure
nanotechnology application of scientific knowledge to manipulate and control matter predominantly in the nanoscale to make use of size- and structure-dependent properties and phenomena distinct from those associated with individual atoms or molecules, or extrapolation from larger sizes of the same material
nanotube hollow nanofibre
necrosis cell death as a direct result of irreversible changes caused by injury or disease
negative control any well-characterized material or substance that, when tested by a specific procedure, demonstrates the suitability of the procedure to yield a reproducible, appropriately negative, non-reactive or minimal response in the test system
negative control material material which, when tested in accordance with this part of ISO 10993, does not produce a cytotoxic response
no observed adverse effect level (NOAEL) greatest concentration or amount of a substance found by experiment or observation which causes no detectable adverse alteration of morphology, functional capacity, growth, development or life span of the target organism under defined conditions of exposure
non-blood-contact nature of the device or material contact with the patient’s body where the device or potentially extracted material does not have direct or indirect contact with blood
non-contacting indicates that the medical device or medical device component has neither direct nor indirect contact with body tissues
non-irritating level (NIL) largest amount of a leachable substance that is not irritating to the patient
O oedema swelling due to abnormal infiltration of fluid into the tissues
open-circuit potential potential of an electrode measured with respect to a reference electrode or another electrode when no current flows to or from it
oxidative degradation scission of chemical bonds in a polymer by the attack of one or more oxidizing agents
P passive limit potential (Ea) electrode potential of the positive limit of the passive range
physical and chemical information knowledge regarding formulation, manufacturing processes, geometric and physical properties and type of body contact and clinical use that is used to determine whether any additional biological or material characterization testing is needed
physico-chemical relating to the physical chemistry (of materials)
physiologically based pharmacokinetic modelling (PBPK modelling) system of modelling biological effects taking into account metabolic and pharmacokinetic differences among species of animal
platelet adherent device having the tendency to allow or promote platelets to attach to its surface
platelets anuclear, cellular bodies that are present in blood and contribute to the process of thrombosis by adhering to surfaces, releasing factors, and/or aggregating to form a haemostatic plug
polymeric material materials consisting of long-chain and/or crosslinked molecules composed of units called monomers
positive control any well-characterized material or substance that, when evaluated by a specific test method, demonstrates the suitability of the test system to yield a reproducible, appropriately positive or reactive response in the test system
positive control material material which, when tested in accordance with this part of ISO 10993, provides a reproducible cytotoxic response
potentially affected individual person having direct or indirect body contact with the medical device
potentiodynamic test test in which the electrode potential is varied at a preprogrammed rate and the relationship between current density and electrode potential is recorded
potentiostatic test test in which the electrode potential is maintained constant and the current is recorded as a function of time
procedural training prior training and acclimatizing of animals to the interventions to be performed during an animal test, with a view to minimizing stress to the animal when animal tests are conducted
proportional exposure factor (PEF) numerical factor for patient exposure to a leachable substance that accounts for the fact that a medical device is not typically utilized every day during the entire exposure category of interest
protocol documentation prepared in advance of animal tests being undertaken setting out the justification, rationale and test method (including scientific and humane endpoints) for the animal tests
purpose-bred animal any animal bred with the intention that it be used in animal tests or for other experimental or scientific purposes
Q qualification process of establishing that an analytical method is suitable for its intended use
qualitative analysis analytical approach which estimates an analyte’s concentration by using the response from a surrogate substance (or substances) chosen without specifically addressing or considering the relative responses of the analyte and the surrogate(s)
quantification process of assigning a concentration to an analyte present in a sample
quantitative analysis analytical approach which establishes the most accurate estimate of an analyte’s concentration by using a response function (calibration curve) generated specifically for the analyte via the use of a reference standard
reduction reducing to the essential minimum the number of animals used in an animal test to meet a defined scientific objective
R reference material (RM) material or substance one or more of whose property values are sufficiently homogeneous and well established to be used for the calibration of an apparatus, the assessment of a measurement method, or for assigning values to materials
reference method thoroughly investigated test method that clearly and exactly describes the necessary conditions and procedures for the evaluation of a specific biological endpoint, has been shown to have accuracy and precision commensurate with its intended use and can, therefore, be used to characterize a RM
refinement sum total of measures taken to safeguard the welfare of the test animals by minimizing any resulting pain, suffering, distress, or lasting harm to the animals that are used
repeated use use of the same device by the same patient more than once without reprocessing
replacement any scientifically valid and reasonably and practically available test method that either completely or partially replaces the use of living vertebrate animals with test methods that have not the potential to cause pain or distress to animals
representative test material (RTM) material, which is sufficiently homogenous and stable with respect to one or more specified properties, and is implicitly assumed to be fit for its intended use in the development of measurement and test methods that target properties other than those for which homogeneity and stability have been demonstrated
reproductive and developmental toxicity test test to evaluate the potential effects of test samples on reproductive function, embryonic morphology (teratogenicity), and prenatal and early postnatal development
residual monomer unreacted chemical compound(s) used to build the polymeric chains, which is still present in the final polymeric material
retentate undissolved solids remaining in the filter paper after filtration
risk analysis systematic use of available information to identify hazards and to estimate the risk
risk assessment overall process comprising a risk analysis and a risk evaluation
risk evaluation process of comparing the estimated risk against given risk criteria to determine the acceptability of the risk
risk management systematic application of management policies, procedures and practices to the tasks of analysing, evaluating, controlling and monitoring risk
S safety freedom from unacceptable health risk
safety concern threshold (SCT) threshold below which a leachable (or an extractable as a probable leachable) has a dose so low that it presents a negligible safety concern from carcinogenic and non-carcinogenic toxic effects
semi-quantitative analysis analytical approach which provides an analyte’s concentration by using the response from a surrogate substance (or substances), specifically accounting for the relative responses of the analyte and the surrogate
service environment anatomical location for the intended use of the device including surrounding fluids, tissues and biomolecules
simulated-use extraction extraction to demonstrate compliance with the requirements of this part of ISO 10993, by evaluating residue levels available to the patient or user from devices during the routine use of a device with water extraction to simulate product use
simulated-use extraction extraction using a method that simulates clinical use
simultaneous use use of more than one device by the same patient at the same time
skin corrosion production of irreversible damage to the skin, manifested as visible necrosis through the epidermis and into the dermis, following application of a test sample
skin sensitization / allergic contact dermatitis immunologically mediated cutaneous reaction to a substance
solubilisation action or process of using a vehicle to dissolve part or all of a test article
sponsor individual or organization that plans, commissions, and takes responsibility for testing of a medical device
stability ability of a material, when stored under specified conditions, to maintain a specific stated biological response, within specified limits, for a specific period of time
stalbility of property values ability of a material, when stored under specified conditions, to maintain the stated biological response, within specified limits, for a specific period of time
subacute systemic toxicity adverse effects occurring after multiple or continuous exposure between 24 h and 28 d
subchronic systemic toxicity adverse effects occurring after the repeated or continuous administration of a test sample for a part of the lifespan
subconfluency approximately 80 % confluency, i.e. the end of the logarithmic phase of growth
substance single chemical element or compound, or a complex structure of compounds
supplier person or company who manufactures or provides the materials of construction or components to be used in the manufacture of a medical device
systemic toxicity toxicity that is not limited to adverse effects at the site of contact between the body and the device
T TCL modifying factor (MF TCL) mathematical product of uncertainty factors UF4, UF5 and UF6
test animal any animal used in in vivo animal tests, or used to provide tissue for ex vivo or in vitro tests
test material material, device, device portion or component thereof that is sampled for biological or chemical testing
test sample material, device, device portion, component, extract or portion thereof that is subjected to biological or chemical testing or evaluation
test sample material, device, device portion, component, extract or portion thereof that is subjected to biological or chemical testing or evaluation
test sample material, device, device portion, component, extract or portion thereof that is subjected to biological or chemical testing or evaluation
test sample medical device, component or material (or a representative sample thereof, manufactured and processed by equivalentmethods), or an extract or portion thereof that is subjected to biological or chemical testing or evaluation
test sample preparation residual, extractables, leachables or biodegradable device materials that are resuspended in a vehicle compatible with the test system
threshold of toxicological concern (TTC) level of exposure for constituents, below which there would be no appreciable risk to human health
thrombin generating device due to its surface properties, having the tendency to promote or show increased thrombin formation
thromboembolization process where a dislodged thrombus is carried downstream, where it may cause subsequent vascular blockage or occlusion
thrombogenic device due to its surface properties, having the tendency to form or promote thrombus formation
thrombosis formation of a thrombus under in vivo, ex vivo, or in vitro simulated conditions, caused by activation of the coagulation system and platelets in flowing whole blood
thrombus coagulated mixture of red blood cells, aggregated platelets, fibrin and other cellular elements
tolerable contact level (TCL) tolerable contact exposure to a leachable substance resulting from contact with a medical device
tolerable exposure (TE) product of the tolerable intake, the body mass and the utilization factor
tolerable intake (TI) estimate of the average daily intake of a substance over a specified time period, on the basis of body mass, that is considered to be without appreciable harm to health
tolerable risk risk which is accepted in a given context based upon the current values of society
topographical relating to the features of the surface (of materials)
toxic capable of causing an adverse biological response
toxicological hazard potential for a chemical substance or material to cause an adverse biological reaction, taking into account the nature of the reaction and the dose required to elicit it
toxicological risk probability of a specified degree of an adverse reaction occurring in response to a specified level of exposure
toxicological risk assessment act of determining the potential of a chemical to elicit an adverse effect based on a specified level of exposure
toxicological threshold limit, such as a tolerable intake (TI), tolerable exposure (TE), allowable limit (AL) value, or Threshold of Toxicological Concern (TTC) below which adverse effects are not expected for relevant biological endpoints
transitory contact medical device or medical device component that has a very brief duration of contact with body tissue
U ulceration open sore representing loss of superficial tissue
uncertainty factor (UF) factor intended to account for the uncertainties inherent in estimating potential effects of a chemical on humans from results obtained in human populations or surrogate species
utilization factor (UTF) numerical factor used to take into account the utilization of the device in terms of frequency of use and utilization in conjunction with other medical devices that can be reasonably anticipated to contain the same leachable substance
V validation formal process by which the reliability and relevance of a test method is established for a particular purpose
vehicle liquid used to moisten, dilute, suspend, extract or dissolve the test substance/material
vehicle control extraction vehicle not containing the test material , retained in a vessel identical to that which holds the test material and subjected to identical conditions to which the test material is subjected during its extraction
volume of distribution parameter for a single-compartment model describing the apparent volume which would contain the amount of test substance in the body if it were uniformly distributed
W whole blood unfractionated blood drawn from a human donor or test animal
X xenobiotic substance foreign to the human body or living organisms
Animal Facility

We have our own animal facility (vivarium)!

 

All activities related to the maintenance and use of laboratory animals are required by national and international standards and regulations. In our work, we operate in accordance with applicable legal regulations and the latest guidelines of non-governmental organizations.

  • All procedures are carried out at European Biomedical Institute Animal Facility with the prior approval of the Local Ethics Committee.
  • European Biomedical Institute Animal Facility is in the register of users of laboratory animals under the number 0054.
  • Animal Facility is under the supervision of the Veterinary Inspectorate and National Ethical Committee for Animal Experiments.
  • Personnel involved in the care of animals and carrying out procedures have the appropriate education, training and experience.
  • At the European Biomedical Institute, the Animal Welfare Advisory Team is appointed for this purpose to ensure animal welfare.

 

Our unit is equipped with an innovative animal keeping system (IVC – individual ventilated cage). The living space for each individual complies with the requirements of national and international directives and standards. The ventilation system is equipped with devices that maintain constant temperature and humidity, and ensure a constant number of air changes. With the animals well-being in mind, each cage is equipped with elements to enrich the environment.

 

„3R” :Replacement, Reduction, Refinement

 

In our work, we use the principles of improvement and ethical use of laboratory animals described as “3R: Replacement, Reduction, Refirement”.

 

Whenever possible, we use the Replace method. The tests are then carried out by the European Biomedical Institute In Vitro Research Team. However, when it is not possible, we limit the number of animals used in experiments as much as possible and try to use methods that reduce animal suffering and improve animal welfare.

 

The vivarium consists of:

  • Air-conditioned room to keep the rats
  • Air-conditioned room to keep the mice
  • Air-conditioned room to keep the guinea pigs
  • Air-conditioned room to keep the rabbits
  • Quarantine room
  • Surgery room
  • Preparation room
  • Autopsy room
  • Cage washing room
  • Storage room
  • Utility room
  • Water Purification Station

 

About North American Biomedical Institute

As North American Biomedical Institute (NABI) we are a part of the Biomedical Institutes Group, together with European Biomedical Institute (EBI). EBI is an independent Contract Research Organization (CRO) mainly focused on providing comprehensive biocompatibility and chemistry testing for medical devices according to the ISO 10993, in-house.

Together with our partner, that is ISO 17025 accredited, Good Laboratory Practice (GLP) certified, and US FDA 21CFR58 compliant, we are allowed to meet the most restricted requirements of Competent Authorities (e.g. FDA, MHLW, MFDS, ANVISA) and Notified Bodies.

We are specialized in comprehensive in vitro, in vivo and in silico preclinical medical device testing institute. Furthermore, we constantly develop our laboratories, therefore our services also include, but are not limited to:

  • physical and chemical characterization, extractable and leachable (E&L)
  • complete ISO 10993 biocompatibility
  • microbiology and sterility
  • cleaning, disinfection and sterilization validations
  • package validation
  • toxicology
  • Biological Evaluation Plan (BEP), Biological Evaluation Report (BER), Biological Risk Assessment (BRA)
  • Biological reactivity of elastomerics, plastics and other polymeric materials USP 87, USP 88

Over 20 years’ experience allows us to reduce spendings of our Customers on unnecessary testing.

With ambitious people and most modern laboratories in Europe we service professional advice and competitive offers.

If you would like to know more about European Biomedical Institute please visit: https://ebi.bio/

 

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