Sterilization

 Sterility is a state of being free from viable microorganisms

Medical devices are produced as per medical device quality requirements are also may have low number of microorganisms prior to sterilisation .These products are called nonsterile products.

Products are sterilized to inactivate the microorganisms to transform nonsterile products to sterile products. Sterile products are free from viable microorganisms.

A strategy for sterilization or disinfection of inanimate objects and surfaces based on the degree of risk involved in their use.

EH Spaulding provided a strategy for sterilization or disinfection of the device based on their intended use .

Classification	Type of contact	Sterilization/Disinfection
Critical	Sterile tissue or the vascular system	Sterilization
Semi‐critical	Contact mucous membranes or non‐intact skin	High‐level disinfection
Non‐critical	Contact intact skin but not mucous membranes	Low‐level disinfection

 

Medica devices are either terminally sterilized or aseptic processing

S.No	Terminal sterilization	Aseptic processing
1	it is a condition of a medical device which has been exposed to a sterilization process in a packaged or assembled form that maintains the sterility of the medical device or a defined portion thereof.	Medical device components are sterilized individually and then assembled in clean room
2	Risk of contamination is low because product is fully sealed	Risk of contamination is high
3	State of sterility for terminally sterilized medical devices is defined  using sterility assurance level (SAL) of 10−6 or less (e.g. 10−7) .Probability of there being a viable microorganisms present on/in the device shall be equal to or less 10−6	Difficult to achieve the SAL f 10−6 or less (e.g. 10−7) as accidental contamination caused by inadequate technique cannot be reliably eliminated
4	Physical methods: --Steam,dry heat --Radiation Chemical methods: Ethylene oxide, Hydrogen perioxise	Filtration

.

References:

https://sterigenics.com/industry-insights/comparing-terminal-sterilization-and-aseptic-processing-of-pharmaceutical-products/

https://basicmedicalkey.com/sterilization-in-practice/

BSI whitepaper Sterilization – Regulatory requirements and supporting standards

Biocompatibility

 Biocompatibility is defined as “ability of a medical device or material to perform with an appropriate host response in a specific application”.

The following information shall be considered for evaluating the overall biological evaluation of the medical device:

• a) Direct and indirect tissue contacting materials
• b) Additives, process contaminants and residues
• c) Packaging materials
• d) Leachable substances
• e) Degradation products
• f) Performance and physical characteristics of the final product

 Biological evaluation is determined based on nature, degree, frequency and duration of the exposure and the hazards identified for the medical device or material.

 Step 1: Identify the category of medical devices.

This helps for selection of appropriate tests relevant for medical devices. 

Categorization by nature of body contact	Categorization by duration of contact
Non-contacting medical devices Surface-contacting medical devices Skin,Mucosal membrane ,Breached or compromised surfaces Externally communicating medical devices Blood path, indirect, Tissue/bone/dentin, Circulating blood Implant medical devices Tissue/bone, Blood	Limited exposure (A) – duration of contact is up to 24 h.   Prolonged exposure (B) – contact time is likely to exceed 24 h but not exceed 30 days.   Long-term exposure (C) –contact time exceeds 30 days

 

• Transitory-contacting medical devices have limited exposure (A) and these devices does not require testing to address biocompatibility. But for products made with materials such as coatings or lubricants needs testing.
• Medical devices with multiple contact duration categories require more rigorous testing and/or evaluation considerations shall apply.

 

Step 2: Conduct a physical and/or chemical characterization per ISO 10993-18.

 If the materials, chemicals and processes has an established history of safe use in

the intended application and physical properties have not changed, then no further testing required and rationale shall be documented.

 further testing need not be required if the device extractables and leachables have sufficient toxicological data relevant to the expected exposure (quantity, route and frequency)

 Step 3: Conduct the biological testing (source ISO 10993:2018)

 

S.No	Testing	Type of Devices to be tested	Categorization by nature of body contact	Categorization by duration of contact
1	Physical and/or chemical information	All medical device categories	all types of contact	all durations of contact
2	Irritation or intracutaneous reactivity	externally communicating medical devices	indirect blood path contact	long term duration
3	Material mediated pyrogenicity and acute systemic toxicity	medical devices with breached or compromised surface contact		all durations of contact
4	Material mediated pyrogenicity	externally communicating medical devices and implant medical devices	all types of contact	all durations of contact
5	Acute systemic toxicity	surface medical devices	mucosal membrane contact	prolonged or long-term contact
		externally communicating medical devices	tissue/ bone/dentin contact	limited duration
		implant medical devices	tissue/bone contact	limited duration
6	Subacute toxicity	all medical device types		prolonged and long term contact
7	Subchronic and chronic toxicity	all medical device types		long term contact
8	Implantation effects	surface medical devices	mucosal membrane contact	prolonged or long term contact
		surface medical devices	breached or compromised surface contact	prolonged or long term contact
		externally communicating medical devices	indirect blood path contact	long term duration
9	Genotoxicity	externally communicating medical devices	circulating blood contact	limited duration
10		implant medical devices	blood contact	limited duration
11	Carcinogenicity	surface medical devices	breached or compromised surface contact	long term duration
12		externally communicating medical devices	all types of contact	long term duration
13		implant medical devices	all types of contact	long term duration

 

For US FDA regulatory submission please use the US FDA guidance document “Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"

MDSAP(Medical device single audit program)

International Medical Device Regulators Forum (IMDRF) developed a MDSAP program to conduct regulatory audits of quality management systems (QMS) of manufacturers of medical devices.

MDSAP program covers the below quality management systems requiremenrts.

• Medical devices - Quality management systems - Requirements for regulatory purposes (ISO 13485:2016)
• Quality Management System requirements of the Conformity Assessment Procedures of the Australian Therapeutic Goods (Medical  Devices) Regulations (TG(MD)R Sch3)
• Brazilian Good Manufacturing Practices (RDC ANVISA 16/2013)
• Japan Ordinance on Standards for Manufacturing Control and Quality Control of Medical Devices and In Vitro Diagnostic Reagents (MHLW Ministerial Ordinance No. 169)
• Quality System Regulation (21 CFR Part 820)

MD SAP members are listed below,

• Therapeutic Goods Administration of Australia
• Brazil’s Agência Nacional de Vigilância Sanitária
• Health Canada
• Japan’s Ministry of Health, Labour and Welfare, and the Japanese Pharmaceuticals and Medical Devices Agency
• U.S. Food and Drug Administration

MDSAP audit uses a process approach and built based on a foundation of risk management.MDSAP audit approach is available here.

– Management

– Measurement, Analysis and Improvement

– Design and Development

– Production and Service Controls.

– Purchasing

– Medical Device Adverse Events and Advisory Notices Reporting

– Device Marketing Authorization and Facility Registration.

Audit approach also have links to the applicable regulatory requirements for participating jurisdictions 

Kindly refer the US FDA CDRH Learn- Inspections - Global Harmonization to know more about MDSAP

US FDA Expanded Access for Medical Devices

Expanded access pathway allows the manufactures or physician to use an investigational medical product to use the patients with a serious or life-threatening disease or condition when there are no available alternative options.

There are three below options are available,

• Emergency Use
• Compassionate Use (or Individual Patient/Small Group Access)
• Treatment Investigational Device Exemption (IDE)

Emergency use

During emergency, investigational device can be used immediately, to treat an individual patient life-threatening situation (there are no alternative options and no time to use existing procedures to get FDA approval for the use).

Physician shall follow the patient protection procedures as possible. Some of the protection procedures are getting concern from patient (Informed consent process), Concurrence from Institutional Review Board (IRB) chairperson and Authorization from the device manufacturer.

Reporting of Emergency use

• Criteria: Devices with IDE    
• Who report: IDE sponsor
• Timelines: within 5 days
• Information to be submitted: IDE Report

• Criteria: Devices without IDE
• Who report: physician 
• Timelines: within 5 days
• Information to be submitted: a description of device used, details of the case, and the patient protection measures that were followed

Compassionate Use (or Individual Patient/Small Group Access)

If there is investigational device is the only option to treat a patient faced with a serious or life-threatening disease or condition.

First device manufacturer shall agree to provide the device under compassionate use.

Approval process for devices with IDE

IDE sponsor should submit an IDE supplement requesting approval for a compassionate use.

IDE supplement contents,

• Patient conditions and circumstances necessitating treatment
• why alternative therapies are unsatisfactory
• deviations from approved clinical protocol to treat the patient
• Patient protection measures

Approval process for devices without IDE

Physician or manufacturer shall submit the compassionate use request to FDA with above information and along with a description of the device provided by the manufacturer

Timelines for review

 IDE supplements have the same statutory 30-day review cycle. Average timelines are within 15 days of receipt.

FDA Actions: Approve, Approve with conditions, or Disapprove the request.

Follow-up Report: Within 45 days, the person who submitted the request shall provide the below details to FDA,

• Patient outcome
• If any problems occurred because of device use

Treatment Investigational Device Exemption (IDE)

If an approved IDE is extended under new IDE to include additional patients with life-threatening or serious diseases. This is called a treatment IDE.

Treatment IDE Application contents are listed below,

1. Name, address, and telephone number of the sponsor
2. Intended use of the device, the criteria for patient selection, and a written protocol describing the treatment use
3. Rationale for use of the device
4. Description of clinical procedures, laboratory tests, or other measures that will be used to evaluate the effects of the device and to minimize risk
5. Procedures for monitoring the treatment use
6. Name and address of the monitor
7. Instructions for use for the device and all other Labeling 
8. Information that is relevant to the safety and effectiveness of the device for the intended treatment use
9. A statement of the sponsor's commitment to meet all applicable responsibilities under the IDE regulations
10. Example of the agreement to be signed by all investigators participating in the treatment IDE and certification that no investigator will be added to the treatment IDE before the agreement is signed
11. Device price (if sold) and a statement indicating that the price is based on manufacturing and handling costs only

FDA actions:Approve, Disapprove or withdrawal of approval of treatment IDEs

Follow-up Report:

• To whom reported: IRB and FDA    
• Who report: Sponsor
• Timelines: Semi-annual basis
• Information to be submitted: Progress reports      

References:

Expanded Access

Expanded Access for Medical Devices