Utilizing Chemical Characterization and Biological Risk ...

Utilizing Chemical Characterization and Biological Risk Assessment in Device Safety Evaluations | Confidential | 1

MEDICAL RESEARCH ORGANIZATION

Utilizing Chemical Characterization and Biological Risk Assessment in Device Safety EvaluationsZhaohui Li, PhD | Director of APAC Sales, NAMSA China | NAMSA

Mar 17, 2017


Biological Evaluation Program


Biocompatibility Today

ISO 10993-1 (2009/Cor1:2010)

Clause 4.1: “ The biological evaluation of any material or medical device intended for use in human shall form part of a structured biological evaluation programme within a riskmanagement process in accordance with ISO 14971”

Biological Risk Assessment


• ISO 14971 (2007) / EN ISO 14971 (2012)• Application of risk management to medical devices• Biological evaluation of a medical device is a

component of risk management• Conduct of a biological evaluation should aim to meet both the

requirements of ISO 10993-1 and ISO 14971

BiologicalRiskAssessment

- Risk Analysis- Risk Evaluation- Risk Control- Overall Risk Evaluation- Consideration of Production and

Post-Production Information


Utilizing Chemical Characterization and Biological Risk Assessment in Device Safety Evaluations | Confidential | 5CIMDR 2016Sept12

• ISO/TR 15499 (2012)• Biological evaluation of medical devices — Guidance

on the conduct of biological evaluation within a risk management process

Clause 4.2: “Simply planning to conduct testing against all of the

aspects of toxicology identified in Table A.1 of ISO 10993-1:2009

does not meet the requirements of ISO 14971 or ISO 10993-1”


Utilizing Chemical Characterization and Biological Risk Assessment in Device Safety Evaluations | Confidential | 6CIMDR 2016Sept12

US FDA guidance document

"Use of International Standard ISO 10993, ‘Biologicalevaluation of medical devices – Part 1: Evaluation and testing within a risk management process’”



Ø Recent History of ISO 10993 Part 1

• Section on selection of tests replaced by biological evaluation process- Based on chemical characterization (ISO 10993 Parts 18 and 19)- If characterization and biological risk assessment are inadequate then further

biological tests should be considered

• Tables that list tests to consider moved to informative annexes- Specifies that the tables are a framework for consideration and not a checklist.- Indicates that more or less testing may be warranted depending on the

situation

• Informative annex added to define the risk management process- References ISO 14971- Risk assessment emphasized



Table A.1(Annex A

ISO 10993-1)

Moved from the normative text intoan informative annex




General Principles- Provide guidance to use in an biological evaluation program

- Emphasize that with a thorough plan, testing is not the only outcome

- 8 principles that range from design stage of a device to re-evaluation if changes occur



Principle 1: Selection and evaluation of materials/device requires a structured plan of assessment – detailed plan

- Evaluation program based on ISO 14971

- Decisions by qualified individuals

- Weigh advantages/disadvantages of

• physical/chemical characteristics

• Historical data

• existing toxicological data

• test procedures considered

- Conclusion may indicate that additional testing is not required

1


• Principle 2: Selection of materials- Fitness for purpose- Chemical, toxicological, physical, mechanical properties

• Principle 3: Consider relevance of all potential factors in the biological evaluation- Manufacturing processes- Leachable substances- Degradation products- Material characterization shall precede biological testing – see

flowchart

2

3



• Principle 4: Consider chemical composition and exposure of device to the patient in the assessment- Degree of evaluation determined by the nature, degree, duration and

frequency of the exposure- Hazards may also vary depending on the composition

• Principle 5: All potential biological hazards identified should be evaluated- “…this does no imply that testing for all potential hazards will be

necessary or practical”- Both short term effects and long term effects to be evaluated as

appropriate- Various biological effects should be considered as appropriate for the

device in question

4

5



• Principle 6: Tests deemed necessary to be based on end use of device- GLP Guidance - Include in vitro studies where possible

• Principle 7: Re-evaluate as necessary- Examples

• Change in source of material• Change in processing• Change in sterilization

- Follow-up testing may be necessary and amount can vary

• Principle 8: Consider all information for thorough overall assessment- Vendor information on materials- Non-clinical tests- Post market experience

6

7

8



Evaluating the biological safety of a medical device requires a written and detailed plan of assessment

• Risks must be defined• Evaluation must mitigate the risks• Test plan to provide assurance that the final product will

perform as intended and be safe for human use• Evaluation provides predictive evidence of biological safety• Performed by qualified individuals

General Principles of Biological Risk Assessments


1. Risk Analysis§ Nature, degree, duration and frequency of exposure§ Patient versus user (if different)§ Need to consider potential cumulative use

§ Raw materials§ Fitness for purpose§ Chemical, toxicological, structural/physical, mechanical

properties§ Potential leachables (plasticizers, crosslinkers, catalysts,

lubricants, solvents, etc.)§ Degradation products

§ Manufacturing processes§ Intended additives, process contaminants and residues



> 30 days

< 24h

Implant

Indirect contact

Heart / Brain

Healthy skin Biological Risks

Biological Risks



Local tolerance, Degradation profile Hemocompatibility= Toxicological hazards

Ÿ Surface stateŸ PorosityŸ Aspect (solid, gel, liquid)Ÿ Geometry Ÿ …

Structural / physical properties

Ø Raw Materials



Biocompatibility is not a property of a raw material but a characteristic of a material-tissue interaction

BIOCOMPATIBLE MEDICAL DEVICE !≠

Ÿ USP Class VIŸ ISO / ASTM certificationŸ “Medical grade”Ÿ MAF



Ÿ Machining (assembly, casting, welding, gluing, polishing, coloration, anodization, ink marking, laser marking, …)

Ÿ Cleaning/disinfection (chemical agents)

Ÿ Packaging (interaction with container/content)

Ÿ Sterilization (EtO residuals, …)

Ø Manufacturing Processes



2. Risk Evaluation§ Existing raw material certification(s)?§ Existing toxicological data in the literature?§ Existing preclinical data from raw material suppliers or on the

device itself?§ Other types of preclinical data available?§ Existing clinical/post-market surveillance data available from

the device or a similar/predicate device?



Biological Evaluation ProgramFlow chart 2009

ISO 10993-1: 2009 / Corr 1: 2010 Perform toxicological risk assessment (Annex B)

© COPYRIGHT 2014, NORTH AMERICAN SCIENCE ASSOCIATES, INC. ALL RIGHTS RESERVED


3. Risk Control

Following the logic of ISO 14971, if the risk evaluation concludes from existing data that the identified risks are acceptable, no further testing is needed!

Otherwise, additional information required:

Written justification

Chemical characterization / Biological testing



Biological Evaluation Process

Describes two items to consider in this order- Material characterization

- Biological evaluation

Material characterization- Extent depends on nature and duration of patient contact and known

toxicological data

- Device extractables and leachables shall be evaluated

- May establish that further biological evaluation is not needed

Biological Evaluation Tests- Based on all data collected, determine any missing data needed to address

biological safety based on the following table

- Indicates additional animal testing is unethical if there is existing data


Chemical Characterization of Materials


• EN ISO 10993-18• Biological Evaluation of Medical Devices, Part 18:

- Chemical Characterization of Materials• ANSI/AAMI BE83:2006 – Biological Evaluation of Medical

Devices – Part 18: Chemical Characterization of materials.

Chemical Characterization of Materials


ISO 10993-18: Chemical Characterization of Materials

• Scope–Presents a framework for the identification of a material and the

identification and quantification of its chemical constituents–As part of an assessment of the overall biological safety of a medical

device–Judging equivalence of material or devices –Screening of potential new materials–Part 18 is intended for suppliers of materials and manufacturers of

medical devices


General Principles

• Identify the material and general constituents of the material

• Identify any additives and/or processing aids

• Identify bioavailable chemicals

The better we know the species that migrate, the better we can mitigate the risks associated with them


Why Characterize Materials and Medical Devices?

• Materials Characterization is a dynamic ongoing process to be used throughout the lifetime of a medical device.

• MC helps monitor material quality, manufacturing processes and sterilization procedures.

• When used properly will eliminate the need to repeat expensive and time consuming biological testing to qualify new lots or vendors.


• Polymers- Plastics (PE, PP, PET, PU, PMMA)- Elastomers (Silicone, Rubber)

• Metals & Alloys- Titanium- Stainless Steel

• Ceramics- Hydroxyapatite, Calcium Phosphates, TCP

• Natural Macromolecules- Gelatin, Collagen, Chitosan, Processed Bone



Ÿ To screen potential new materialsŸ To establish baseline testing (benchmark) Ÿ To monitor material quality, manufacturing processŸ To judge equivalence of:

- Materials to qualify new lots or vendors (change control)- “New” device versus predicates- Prototype used in testing versus the final medical device- A medical device after changes



Ÿ Close collaboration of chemists and toxicologists: interpretation of chemistry results through Toxicological Risk Assessment (ISO 10993-17) to calculate the Margin of Safety (MOS)

Ÿ When used properly, chemical characterization can reduce or even eliminate some expensive and time consuming biological testing

Ÿ However, depending on the results, complementary biological testing program may be required



Leachables vs. Extractables

• Leachables: Chemicals that migrate spontaneously from materials under recommended conditions of use (simulated physiological conditions)

• Often a subset of extractables

• Extractables: Chemical additives and by products extracted from device or material using exaggerated temperature and time conditions in organic solvents, water or buffers – what may be released from the product to the patient

• Useful in predicting potential leachables and in selecting the most appropriate materials


• Purified Water: Extraction vehicle allowing for solubilization of polar chemicals and ions

• Isopropyl alcohol / ethanol: More aggressive extraction vehicle used to evaluate less polar molecules => Often leading to more extracted substances than purified water

• Hexane / dichloromethane: Even more aggressive solvents for extraction of non-polar compounds => Often giving the higher quantity of extracted molecules

Extractions


• Physicochemical testing (USP <661>)- Non-Volatile Residue - Residue on Ignition- Heavy Metals - Buffering Capacity (pH)- UV absorbance- Turbidity

Collectively, these tests provide insight into the general chemical nature and amount of extracted substances

Routine Testing


• Physicochemical testing (USP <661>)

Routine Testing


Fourier Transform Infrared spectroscopy (FTIR)

= Identification of non-volatile organic compounds

= Fingerprint of a material

By matching the infrared spectrum of an unknown compound with that of a known material, proof of identity is established

Routine Testing


• HPLC/MS: Identification and quantification of non-volatile organic compounds

• GC/MS: Identification and quantification of semi-volatile organic compounds

• Head-Space/GC/MS : Identification and quantification of volatile organic compounds

• ICP: Identification and quantification of metals and some other elements of the periodic table with a very low limit of detection (ppb)

Routine Testing


Situation: You have selected a raw material but you do not have its exact chemical composition (confidential) and the supplier did neither perform chemistry nor biological testing

= Use a subset of chemical testing to identify and quantify the chemical components of this raw material to evaluate whether leachables / extractables may raise toxicological concerns if used in your medical device？

Key roles of the chemical characterization

To qualify a material Ê


Situation: You have selected and qualified a raw material supplier but how can you be sure that no changes have occurred over time in the composition of the material ? Supplier must notify customers of any change but not always the case, not reliable.


To control material quality and qualify new lots / batches of materials

Ê

= Use a subset of chemical testing as quality control measures to detect and evaluate known or suspected changes in raw materials


To qualify new material / new supplierÊ

Situation: Your raw material supplier informs your Company that he will stop the production of the material used in your device launched to the market for 10 years = you have to qualify a new material from a new supplier= Use a subset of chemical testing to demonstrate the toxicological equivalency in the level/nature of leachables /extractables between the actual and the proposed material

ISO 10993-18 Annex C: Principles for Judging Toxicological Equivalency



Biological Evaluations: Constraints & Limitations

Expertise

ISO 10993-1 (Clause 4.1): “The biological evaluation shall be planned, carried out and documented by knowledgeable and experienced professionals”ISO/TR 15499 (Clause 4.2): “ The biological evaluation plan should be drawn up by a knowledgeable experienced team”

ISO 14971 (Clause 3.3): “ Persons performing risk management tasks shall have the knowledge and experience appropriate to the tasks assigned to them”


Chemical Data

Biological Evaluations: Constraints & Limitations

Ÿ What about mixtures (additivity, antagonism, potentiation, synergism) ?

Ÿ No toxicological data available to calculate the MOS ?Ÿ MOS < 1 ?Ÿ Is not intended to replace all biocompatibility testsŸ Will never replace a local tolerance / thromboresistance testing,

which also takes into account surface features, geometry, etc.


Case Study


Case Study I – Nitinol implant (Stent)1) Hazard Identification:

Nitinol composition = alloy of nickel and titanium Concern for nickel release into the body. Nickel may be

absorbed as the soluble nickel ion (Ni+2).Nickel is known to bind to specific proteins and/or amino acids in the blood serum Nickel is an essential element, but can also be toxic: dermatitis, cancer subsequent to inhalation, toxic effect on cellular reproduction.

Toxicological Risk Assessment



Case Study I – Nitinol implant (Stent)2) Dose-Response (Hazard) Assessment:

Literature search revealed the recommended safe level of exposure in IV fluids is a maximum of 35 mg/day. This is our allowable limit.

TI = 35 mg/day70 kg (adult)

= 0.5 mg/kg/day



Case Study I – Nitinol implant (Stent)3) Exposure Assessment: Measure concentration of nickel

release for nitinol.

1 cm2 sample of nitinol extracted in saline for 28 days and nickel concentration measured by ICP at various time points. Corrosion or leaching of nickel peaked at day 7, then declined steadily thereafter.

Results: 12.8 mg/day/cm2.



Case Study I – Nitinol implant (Stent)4) Risk Characterization:

Comparison of available dose with the allowablelimit shows that there is an ample safetymargin. Considering quality of data, the safety margin is sufficient to justify using nitinol invascular implants. Safety Margin = RfD = 35 mg/day

Exposure 12.8 mg/day= 2.7



Case Study II– Polyurethane

1) Hazard Identification:Polyurethane for manufacturing a permanent implant device

(spinal disc replacement).BD (1,4-Butanediol) listed as starting monomer

Concern for BD release into the body from implant. • Neurotoxic effect – depression of CNS• Competitive inhibitor of alcohol dehydrogenase - >alcohol effect.



HO – CH2 – CH2 – CH2 – C – OH Gamma-hydroxybutyrate (GHB)



Gamma Hydroxybutyrate (GHB)• GHB has been used historically as a general anesthetic, to treat

conditions such as insomnia, clinical depression, narcolepsy, and alcoholism

• It is also used illegally under the street names Juice, Liquid Ecstasy, Fantasy, "Georgia Homeboy", and simply G, either as an intoxicant or as a date rape drug.



Case Study II– Polyurethane Material2) Dose-Response (Hazard) Assessment:

Literature search revealed rat IP LD50 = 1.33 g/kg. The NOAEL for BD (repeated oral dose) = 100 mg/kg/day. Repeated IP administration induced narcotic effect at more than 500 mg/kg/day.



Case Study II– Polyurethane Material3) Exposure Assessment: Measure concentration of BD release form

polyurethane. 19.9g was extracted in 100 mL Hexane at 50oC for 24 hours and

BD concentration measured by GC/MS. Extraction was repeated one more time and no BD detected.Results: 10.23 mg/mL 10.23 mg/mL x 100 mL = 1,230mg (1.02 mg)



Case Study II– Polyurethane Material4) Risk Characterization:

TI = NOAEL mg/kg/day(mg/kg/day) Uncertainty Factor

(10,100,1000)= 100 mg/kg/day = 0.1mg/kg/day

1000*Safety Margin = TI = 0.1 mg/kg/day

Exposure 1.02 mg/70 kg/day= 6.86

* Uncertainty FactorUF1 = 10 for human variabilityUF2 = 10 for animal to human UF3 = 10 for use of oral NOAEL and quality of data.


We are driven to make a scientific contribution to every medical device in the world


Thank you!!

Zhaohui Li, PhD | Director of APAC Sales, NAMSA China | NAMSAMobile: +86 18221071796 | Office: +86 (21) 57545015

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