An introduction to Medical Devices and the ISO TC 194...

Harlan Laboratories Harlan Laboratories 1

An introduction to Medical Devices and the ISO TC 194 Evaluation Process

1

Harlan Laboratories

Dr. Albrecht Poth

Harlan Laboratories Harlan Laboratories

Some statistics

■ 310 billion US $ in 2010; 434 billion US $ in 2017 ■ Pharma: 290 billion; 370 billion US $ in 2017 ■ Annual growth rate 7% ■ MD industry is covering a wide spectrum of products ■ Life-time of the products is short and research and development is high

■ New Areas including Tissue-Engineering products, Advanced therapy medicinical products and Combination products

Global Medical Device Industry


Differences between Medical Devices and Drugs

Medical Devices

•  Physical objects: complex components and assemblies; generally based on mechanical and electrical features

•  Most act through physical interaction with body or body part

•  Tend to require significant user interaction

•  Heterogeneous group; range from pflasters to artificial organs

Drugs

•  Pure molecules: based on pharmacology and chemistry; now encompassing biotechnology, genetic engineering etc.

•  Administered via the mouth, skin, eyes, lungs, or by injection; act through metabolic, pharmacologic or immunological means

•  Generally little user interaction

•  Tend to differ only in molecular structure


Differences between Medical Devices and Drugs

Medical Devices

•  Duration and nature of exposure varies widely

•  Short market life (18-24 months) part

•  Small and medium sized enterprizes (more than 80%)

Drugs •  Typically short half-life in body

•  Long market life

•  Generally little user interaction


Instrument, apparatus, implement, machine, appliance, implant, in vitro reagent or calibrator, software, material or other similar or related article:

■ Intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the specific purposes of:

Ø Diagnosis, prevention, treatment or alleviation of disease or for an injury Ø Investigation, replacement, modification, or support of the anatomy or of a

physiological process Ø Supporting or sustaining life Ø Control of conception Ø Disinfection of medical devices Ø Providing information for medical or diagnostic purposes by means of in

vitro examination of specimens derived from the human body ■ and which does not achieve its primary intended action in or on the

human body by pharmacological, immunological or metabolic means, but which may be assisted in its intended function by such means

Definition of medical devices – Global Harmonization Task Force


Medical Device Approval US and EU

Kramer et. al. 2012, New England Journal of Medicine


Classification of Medical Devices


Regulatory requirements - EU


Regulatory requirements - US


Concerning safety and risk

■ Analyse and assess safety and risk ■ Minimise adverse effects ■ Ensure electrical and mechanical safety ■ Provide comprehensive information with the product ■ Avoid infection and contamination

Concerning performance and utilitiy

■ Ensure compliance with performance claims made by the manufacturer ■ Ensure suitability for intended purpose

Compliance with the Essential Requirements


Elaboration of the risk management process The risk management process has to be documented in the risk managment file and has to contain the following elements

■ Risk analysis ■ Risk evaluation ■ Risk control ■ Post production information

ISO 14971 – 2007 Application of risk management to Medical Devices


Identification of Hazards

ISO 14971 – 2007 Application of risk management to Medical Devices


Secretariat: DIN Secretary: Dipl.-Ing. Karl Wenzelewski Chairperson: Dr. Albrecht Poth until end 2015 ISO Central Secretariat contact: Mr. Stefan Marinkovic Creation date: 1988 ISO/TC 194/WG 1 Systematic approach to biological evaluation and terminology ISO/TC 194/WG 2 Degradation aspects related to biological testing x ISO/TC 194/WG 3 Animal protection aspects ISO/TC 194/WG 4 Clinical investigations of medical devices in humans x ISO/TC 194/WG 5 Cytotoxicity x ISO/TC 194/WG 6 Mutagenicity, carcinogenicity and reproductive toxicity x ISO/TC 194/WG 7 Systemic toxicity x ISO/TC 194/WG 8 Irritation, sensitization x ISO/TC 194/WG 9 Effects on blood x ISO/TC 194/WG 10 Implantation x ISO/TC 194/WG 11 Allowable limits for leachable substances x ISO/TC 194/WG 12 Sample preparation and reference materials ISO/TC 194/WG 13 Toxicokinetics x ISO/TC 194/WG 14 Material characterization x ISO/TC 194/WG 15 Strategic approach to biological assessment x ISO/TC 194/WG 16 Pyrogenicity ISO/TC 194/WG 17 Nanomaterials x

ISO/TC 194/SC 1 Tissue product safety

ISO TC 194 - Standards


Risik analysis for toxicological hazards is based on the following standards

■ ISO 10993-1, which describes the general principles of the biological evaluation of materials and medical devices

■ ISO 10993-18, which provide information for the quantitative and qualitative characterisation of materials and medical devices

■ ISO 10993-17, is giving guidance for the determination of the allowable limits for leachable substances.

Important standards for the biological evaluation and risk analysis


Annex B describes

■ Identification of biological hazards of the device

■ Estimation, evaluation and control of risks ■ Control of the efficacy of the control measures

ISO 10993 – 1 2009: Evaluation and Testing within a risk management process


Considerations for the biological evaluation

■ Materials/Chemicals for processing of the device ■ Additives, Impurities and residues ■ Leachable components ■ Degradation products ■ Physical properties: Porosity, particle size, form and surface morphology

ISO 10993-1 2009: Evaluation and Testing within a risk management process


Systematic Approach

ISO 10993-1 2009: Evaluation and Testing within a risk management process


Pre-requisits for the selection of biocompatibility tests

■ Degree, duration and frequency of application ■ Chemical and physical properties of the final product ■ Toxicological relevant chemicals in the device composition

■ Biocompatibility studies may not be necessary if leachable components can be excluded or if the leachable components have a known and accepted toxicity profile (ISO 10993-17) ■ Ratio of the surface of the medical device to the body mass of the patient

■ Inclusion of available literature or of already available non-clinical testing and/or clinical

experience



Toxicological endpoints for consideration in the biological evaluation



Importance for the biological evaluation process

■ Information on the release of chemicals will lead to the selection of the necessary toxicological studies

■ Data will be used for the risk characterisation –

Establisment of a TI-value according to 10993-17

Material Characterisation


Effects based on the manufacturing process

■ Processes which can lead to changes of the surface of the devices e.g. by surface treatment or welding

■ Additives: colour pigments, lubricants, inks ■ Contaminations by cleaning-, desinfection- and sterilising agents ■ Degradation by manufacturing, clinical use or storage



Consideration on the change of material properties

■ Material abrasion und Material ageing especially for materials used in prothesis, which

can lead to the generation of particles and degradation products

■ Friction which can lead to irritation – Application of catheters

■ Heat e.g. thermal degradation or other material changes ■ Interactions with the physiological environment e.g. endocopes (gastric fluid), dressing materials

(sweat), UV-light, detergents, process of sterilisation



Procedure of the characterisation

■ Step-wise procedure including 5 steps ■ Analytical procedures have to be selected in order

to get a robust assessment of the toxicological evaluation

■ Development of adequate analytical methods ■ Validation of the analytical methods including

precision, specificity etc.

ISO 10993 – 18 2005: Chemical characterisation of materials


Flow-Chart of the step-wise procedure

ISO 10993 – 18 2005: Chemical characterisation of medicial devices


Scope

■ Specification of methods for determination of allowable limits for leachable components in medical devices

■ Description of a systematic process where the risk of hazardous compounds can be estimated quantitatively

ISO 10993-17 2009: Establishment of allowable limits for leachable substances


Principles

■ Evaluation of the biological risk of a leachable substance by collecting data and identifying critical health endpoints, by determining the tolerable intake levels specific for the route of entry and duration of exposure and by determining tolerable contact levels if irritation is an endpoint ■ Determination of the tolerable exposure of the patient to the leachable substance under consideration of the patient body mass and the application of utilisation and safety factors ■ Consideration of various routes of exposure: absorption via skin, oral or inhalative uptake, or direct systemic application ■ Inclusion of a risk/benefit analysis

ISO 10993-17 2009: Establishment of allowable limits for leachable substances


Flowchart for determination of allowable limits

ISO 10993 – 17 2009: Establishment of allowable limits for leachable substances


Biological Safety Evaluation – Re-Evaluation

■ Changes in manufacturing process (sterilisatiion, cleansing, surface treatment, primary packaging) ■ Change of supplier

■ Changes in the material specification ■ Changes in the formulation of the device (e.g

. new additives) ■ Changes in material storage (prolongation of

durability) ■ Changes in the biological environment

■ Changes in the clinical application

Conducting a Biological Evaluation


Biological Safety Evaluation – Report

■ General descripton of the medical device ■ Quantitative information on the composition of all

components in contact with the patient ■ Evaluation of the available information on toxicity

for every relevant material or chemical ■ Results of biological testing ■ Evaluation of all data and a final conclusion

Conducting a Biological Evaluation


Practical approach

■ In general the approach is dependent on the materials and devices (polymers, metals, composite materials, biodegradable materials)

■ Is dependent on the toxicological endpoints (e.g. non-carcinogenic and carcinogenic endpoints, respectively)

■ Screening tests can help in the selection of material components ■ Search for already available biocompatibility studies

■ Characterisation of the composition of the device

Biological Evaluation


Practical Approach - Continuation

■ Comparison of the new medical device with an already marketed device – toxicological

equivalence ■ In case toxicological components are inclued in

the device the amount should be determined (worst-case assumption or determination of the amount with extraction testing)

■ Determination of the maximal exposure levels (consideration of cancer and non-cancer endpoints) ■ Biological evaluation and Safety Evaluation

■ In case the data seem not to be sufficient to do an adequate evalution of safety, for certain toxicological endpoints biocompatibility studies are conducted



Practical Approach – Continuation

■ Step-wise performance of biocompatibility studies (in vitro/in vivo) ■ Biological evaluation and safety assessment of the

medical device unter consideration of the results of the biocompatibility tests



■ Request for testing procedures which are established in international or national guidelines and standards ■ Internal laboratory validation necessary for new adopted or established methods

Validation in the medical device area – ISO 17025


■ Validation is needed for: New methods not included in normative documents Methods where guidelines are already available but which are used outside of their intended scope Modification of standard methods to confirm that the methods are fit for the intended use

Validation of new methods – ISO 17025


■ Use of reference materials

■ Comparion of results achieved with other methods

■ Interlaboratory comparison

■ Systematic assessment of the factors influencing the results ■ Assessment of the uncertainty of the results based on scientific understanding of the theoretical principles of the method and practical experience

Determination of the performance of a method – ISO 17025


■ Uncertainty of results

■ Limit of detection

■ Selectivity of the method (Sensitivity/Specificity)

■ Linearity of the method ■ Reproducibility of the method

■ Robustness of the method

Range and accuracy of values obtainable from validated methods – ISO 17025


Thank your for your attention

Harlan Laboratories

An introduction to Medical Devices and the ISO TC 194...

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