Medical Device Testing. Andrew Makin, MSc, ERT, MRSB Scientific Director CiToxLAB Scantox, Denmark

Transcription

1 Medical Device Testing Andrew Makin, MSc, ERT, MRSB Scientific Director CiToxLAB Scantox, Denmark

2 Medical device Risk evaluation Efficacy Biocompatibility Clinical testing Pharmaceutical product Preclinical studies Genetic Toxicology Toxicology Safety Pharmacology Phase I Clinical studies Preclinical studies Toxicology Reproductive Toxicology DMPK Phase II Clinical studies Marketing Preclinical studies Toxicology Reproductive Toxicology Carcinogenicity Marketing

3 Overview What does biocompatibility mean? Biocompatibility issues associated with sterilization. How to evaluate if the material is biocompatible. How to examine for unwanted biological responses? hazard identification

4 What is biocompatibility? Is the product safe for people? with respect to biological effects. Are there any unwanted biological effects? - Local effects, e.g. irritation, cell death - Systemic effects, e.g. sensitisation, toxicity, genotoxicity, pyrogenicity, reproductive toxicity

5 Identified biological hazards! Biological evaluation studies are performed to identify potential hazards. Results of biological studies should be interpreted with respect to relevance for man. Use the information in the risk management process

6 Toxicity of a substance Amount Route of administration Absorption Distribution Metabolism Excretion

7 Risk management of biological risks Biological hazards identified Estimate the biological risks Evaluate the biological risks Reduce and/or control the risks Monitor the effectiveness of the control

8 Biocompatibility of a device Is the product safe for people? with respect to biological effects. Are there any unwanted biological effects? - Local effects, e.g. irritation, cell death - Systemic effects, e.g. sensitisation, toxicity, genotoxicity, pyrogenicity, reproductive toxicity

9 Biocompatibility issues associated with sterilization What does the sterilization process do to the material? Does it affect the polymer? Does it affect the other chemicals? Does it produce new chemical structures (degradation products)? Does it change the surface structure? High load of inactivated bacteria may still cause pyrogenicity

10 Changes in the sterilization method can be critical Change in temperature from one sterilization process to another Differences in radiation dosage Creation of degradation products Sterility

11 1. Good knowledge of the intended use 2. Material characterisation Including additives, processing aids, coatings, effect of sterilization process etc. 3. Chemical (and physical) characterisation. Known chemicals, toxic chemicals, unknown chemicals 4. Calculation of allowable limits of certain chemicals 5. Extraction test to identify levels of exposure to toxic substances 6. Literature study 7. Clinical data of identical exposure 8. Biological tests Biological evaluation ISO

12 Risk management ISO Risk analysis Use and purpose determination Hazard identification Risk estimation ISO series can be used for identification of relevant biological hazards

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14 Cytotoxicity test This in vitro test evaluates the potential of leachable substances from the device to cause damage to cells in culture. Evaluation: Cell viability after 48 hours of exposure, on a scale of 0-4. Pass if the score is 2 or less

15 Sensitisation test (GPMT) Procedure Intradermal injection Dermal application Dermal challenge Evaluation: Erythema at the test sites 48 hours after challenge exposure Positive: 30 % of animals sensitised

16 Local lymph node assay (LLNA) Procedure Three topical applications on the ears with extracts Intraveneous injection of radioactivity (thymidine) Collection of lymph nodes Measurement of incorporated radioactivity Evaluation: Proliferation of lymphocytes in test group compared with the control group. Stimulation index

17 Irritation Toxicity of chemicals and materials Leachablility of toxic compounds Shape and size Environment

18 Skin irritation tests These in vivo tests evaluate the potential of leachable substances either in extracts of the device or directly from the device to cause irritation on different parts of the body. Evaluation: Erythema and oedema 24, 48 and 72 hours after exposure. Negative control may be included.

19 Systemic toxicity tests These in vivo tests evaluate the potential of leachable substances either in extracts of the device or directly from the device to cause systemic toxicity either acute, subchronic or chronic.

20 Acute systemic toxicity tests Clinical behaviour Body weight 3 days after treatment

21 Long term systemic toxicity tests Clinical behaviour Body weight Ophthalmoscopy ECG Food and water intake Haematology Clinical chemistry Urine analysis Organ weight Organ tissue

22 Pyrogenicity test Material Mediated Pyrogenicity The pyrogen test is an in vivo test which evaluates the potential of leachable substances in extracts of the device to cause increased body temperature in rabbits. Endotoxin Pyrogenicity The LAL test is an in vitro test which evaluates the presence of bacterial endotoxins

23 Genotoxicity Ames test in bacteria (OECD 471) Detects point mutations In vitro Mammalian Cell Gene Mutation Test in mouse lymphoma cells (OECD 476) Detects mutations and aberrations In vitro Mammalian Chromosome Aberration Test in human lymphocytes (OECD 473) Detects visible aberrations

24 Implantation test This in vivo test evaluates the potential of the device to cause tissue damage after implantation either intramuscularly, subcutaneously or any other relevant route. Evaluation: macroscopic and microscopic exanimation of tissue damage. Negative control included.

25 Haemocompatibility These tests evaluate the potential of the device and of leachable substances from the device to cause effects on blood. Hemolysis Thrombosis Coagulation Platelets Haematology Complement activation

26 Perform literature review. Ethical considerations Perform extraction tests with chemical analysis where possible. Perform in vitro studies prior to in vivo studies. Justification of in vivo studies. Maximise amount of information obtained from in vivo studies. Only perform relevant in vivo studies.

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