Like other items such as food, medicines etc. shelf-life study is also needed to be performed for medical devices and also required by many regulations such as MDD/MDR, FDA 510k etc. that require medical device to be labelled with an expiry date. However, there are not many guidelines or standards available that guide manufacturers on how to carry out this study and establish shelf life for their medical devices. It is totally upon the manufacturer to come up with a reliable way to perform the study and establish suitable evidence that support the shelf-life claim.

Briefly speaking, shelf life is defined as: “The duration or time period in which the medical device remains suitable for its intended use and also retains the required safety and performance characteristics acclaimed with the said device”

Shelf-life or stability study is compulsory not only for medical devices but also for the packaging. In general, there are two ways to carry out this study:

1. Real time aging
2. Accelerate aging

It is important to note that both the studies are required to be performed simultaneously as these two support each other and provide stronger evidence for the shelf-life claim to be made.

Some key factors that may impact medical device shelf-life and are needed to be considered while performing the study are:

1. Product Material
2. Product Manufacturing Processes
3. Product Intended Use
4. Packaging
5. Storage and transportation
6. Sterilization

Each of these factors can affect the overall performance and safety of the device on their own and should be kept in mind along with other factors while carrying out the study.

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Steam sterilization (also called autoclaving) is conducted in an autoclave which is a container that can withstand high pressure and temperature. Steam sterilization (also called autoclaving) is conducted in an autoclave which is a container that can withstand high pressure and temperature. The basic principle of steam sterilization, as accomplished in an autoclave, is to expose each item to direct steam contact at the required temperature and pressure for the specified time.

Parameters of Steam Sterilization

There are four parameters of steam sterilization:

Steam, pressure, temperature, and time. The ideal steam for sterilization is dry saturated steam and entrained water (dryness fraction ≥97%).Pressure serves as a means to obtain the high temperatures necessary to quickly kill microorganisms. Specific temperatures must be obtained to ensure the microbicidal activity.

The two common steam-sterilizing temperatures are 121°C (250°F) and 132°C (270°F). These temperatures (and other high temperatures) must be maintained for a minimal time to kill microorganisms. Recognized minimum exposure periods for sterilization of wrapped healthcare supplies are 30 minutes at 121°C (250°F) in a gravity displacement sterilizer or 4 minutes at 132°C (270°F) in a pre-vacuum sterilizer (Table 7). At constant temperatures, sterilization times vary depending on the type of item (e.g., metal versus rubber, plastic, items with lumens), whether the item is wrapped or unwrapped, and the sterilizer type.

Bowie-Dick-type test:

Bowie-Dick (Air-Removal) tests evaluate the performance of pre-vacuum sterilizers by confirming adequate air removal from the sterilizer chamber. These air removal tests have been improved over the years, but you may be wondering, are Bowie-Dick tests still relevant in sterilizers that have programmed leak tests?

To fully answer why this test is still important today, we must first understand why it is important to remove air from the sterilizer. Air within a steam sterilizer is often referred to as a non-condensable gas (NCG). As the name indicates, non-condensable gases do not condense when touching a colder item. These gases act like a shield between the steam and the item, potentially shielding bacteria and preventing proper sterilization.

For gravity displacement sterilizers the penetration time into porous items is prolonged because of incomplete air elimination. This point is illustrated with the decontamination of 10 lbs of microbiological waste, which requires at least 45 minutes at 121°C because the entrapped air remaining in a load of waste greatly retards steam permeation and heating efficiency.

Biological Indicators:

The oldest and most recognized agent for inactivation of microorganisms is heat. D-values (time to reduce the surviving population by 90% or 1 log10) allow a direct comparison of the heat resistance of microorganisms. Because a D-value can be determined at various temperatures, a subscript is used to designate the exposure temperature (i.e., D121C). D121C-values for Geobacillus stearothermophilus used to monitor the steam sterilization process range from 1 to 2 minutes. Heat-resistant non-spore-forming bacteria, yeasts, and fungi have such low D121C values that they cannot be experimentally measured.

Steam Sterilization Validation:

This Steam Sterilization validation will review the general requirements for performing a steam sterilizer validation via the “overkill” half-cycle method as described in ISO 17665 by using chemical and biological indicators including loading patterns.

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The IMDRF, like its predecessor, the Global Harmonization Task Force, recognized the value of developing a global standard for medical device quality that would grant companies access to marketplaces around the world based on the results of a single audit. After establishing a working group for the MDSAP in 2012, the IMDRF was able to initiate a three-year pilot project of the MDSAP that would run between 2014 and 2016 in participating countries.

The main goal of the MDSAP program is to establish an international coalition that can work together to provide medical device manufacturing oversight and improve safety outcomes on a global scale. A credible single audit program whose results are accepted globally would significantly reduce regulatory burden for medical device manufacturers, along with minimizing the frequent business interruptions associated with the current multiple audit system. The MDSAP would reduce costs for regulators – instead of each regulator conducting their own costly audit; a single audit would suffice for the acceptance of the product everywhere.

The IMDRF has built a strong international coalition that includes some of the world’s most important marketplaces and manufacturing/development hubs for medical devices. Here’s how the participating agencies around the world are moving towards adoption of the MDSAP.

United States FDA – American medical device companies should know that the FDA will accept the results of MDSAP audits rather than conducting a routine inspection, but will still conduct its own initial visits to manufacturers and “for cause” inspections.

Europe – While the current MDSAP program is based on the content of ISO 13485:2003, the EU now uses the updated ISO 13485:2016 as its standard for medical device QMS compliance and has not yet signed on to adopt the MDSAP.

Health Canada – After a successful three-year pilot of the MDSAP during 2014-2016, Health Canada decided that after January 1st, 2019, it would make a full transition to accepting only MDSAP compliance audits from medical device manufacturers.

ANVISA Brazil – Brazilian authorities plan to accept MDSAP for initial audits, but will continue to conduct their own inspections and audits for higher-risk devices.

MHLW Japan – Japanese authorities have fully adopted the MDSAP and will accept MDSAP audit results in place of an on-site J-QMS audit.

TGA Australia – Another 100% adopter of the MDSAP, the Australian Therapeutic Goods Administration now recognizes that medical device manufacturers who pass an MDSAP audit have satisfied their QMS requirements. The TGA recognizes MDSAP certificates as equivalent to CE certificates. For further information or any other queries, please contact us.

All medical devices have to undergo a biological evaluation of biocompatibility to fulfill the requirements in the EU Medical Device Regulation (MDR). The aim of the biological safety evaluation is to ensure that possible negative effects on human health caused by the materials in the product shall be identified and managed. 

It is intended to describe the biological evaluation of medical devices within a risk management process, as part of the overall evaluation and development of each medical device. This approach combines the review and evaluation of existing data from all sources with, where necessary, the selection and application of additional tests, thus enabling a full evaluation to be made of the biological responses to each medical device, relevant to its safety in use. The term “medical device” is wide-ranging and, at one extreme, consists of a single material, which can exist in more than one physical form, and at the other extreme, of a medical device consisting of numerous components made of more than one material.

The range of biological hazards is wide and complex. The biological response to a constituent material alone cannot be considered in isolation from the overall medical device design. Thus, in designing a medical device, the choice of the best material with respect to its biocompatibility might result in a less functional medical device, biocompatibility being only one of a number of characteristics to be considered in making that choice. Where a material is intended to interact with tissue in order to perform its function, the biological evaluation needs to address this.

Biological responses that are regarded as adverse, caused by a material in one application, might not be regarded as such in a different situation. Biological testing is based upon, among other things, in vitro and ex vivo test methods and upon animal models, so that the anticipated behavior when a medical device is used in humans can be judged only with caution, as it cannot be unequivocally concluded that the same biological response will also occur in this species. In addition, differences in the manner of response to the same material among individuals indicate that some patients can have adverse reactions, even to well-established materials.

ISO 10993 series is intended for use by professionals, appropriately qualified by training and experience, who are able to interpret its requirements and judge the outcome of the evaluation for each medical device, taking into consideration all the factors relevant to the medical device, its intended use and the current knowledge of the medical device provided by review of the scientific literature and previous clinical experience.

Informative Annex A contains a table that is generally helpful in identifying endpoints recommended in the biocompatibility evaluation of medical devices, according to their category of body contact and duration of clinical exposure. Informative Annex B contains guidance for the application of the risk management process to medical devices which encompasses biological evaluation.

A medical device or material that comes in contact with the patient’s body is expected to perform its intended function without resulting in any adverse effect to a patient. Potential adverse effects can range from short-term (acute) to long-term (chronic) adverse effects to the body such as mutagenic effects. For this reason, medical devices are typically subject to biological evaluation and biocompatibility testing to evaluate the interaction between a device and tissue, cells or body fluids of the patient. The primary purpose of a device biocompatibility assessment is to protect patient from potential biological risks.

Steps:

The following series of steps can be taken while evaluating the medical devices and preparing the biological evaluation report:

• The general principles governing the biological evaluation of medical devices within a risk management process;
• The general categorization of medical devices based on the nature and duration of their contact with the body;
• The evaluation of existing relevant data from all sources;
• The identification of gaps in the available data set on the basis of a risk analysis;
• The identification of additional data sets necessary to analyses the biological safety of the medical device;
• The assessment of the biological safety of the medical device.

This document applies to evaluation of materials and medical devices that are expected to have direct or indirect contact with:

• The patient’s body during intended use;
• The user’s body, if the medical device is intended for protection (e.g., surgical gloves, masks and others).

This document is applicable to biological evaluation of all types of medical devices including active, non-active, implantable and non-implantable medical devices.

This document also gives guidelines for the assessment of biological hazards arising from:

• Risks, such as changes to the medical device over time, as a part of the overall biological safety assessment;
• Breakage of a medical device or medical device component which exposes body tissue to new or novel materials.

Other parts of ISO 10993 cover specific aspects of biological assessments and related tests. Device-specific or product standards address mechanical testing.

This document excludes hazards related to bacteria, molds, yeasts, viruses, transmissible spongiform encephalopathy (TSE) agents and other pathogens.

End Points:

Evaluation and Testing within a Risk Management Process provides a framework for determining the appropriate biocompatibility steps for planning a biological evaluation. Specific testing is dependent on the type of medical device or material and its intended use, and on the nature and duration of contact between the medical device and the body. According to the standard, an assessment for biological effects from the exposure of a medical device or material to human body can include testing such as cytotoxicity, sensitization, irritation or intracutaneous reactivity, systemic toxicity, sub chronic toxicity, genotoxicity, implantation and hemocompatibility, etc.

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7.

This is international harmonized standard for Medical Devices that discusses about the possible risk factors, its latest version (ISO 14971:2019).

Keys for identifying, evaluating, and mitigating hazards incorporated with medical devices to demonstrate conformity to product safety and performance requirements. This article provides an overview of the standard, but should not be used as a substitute for the actual text of the standard.

As in the case of a quality management system, a risk management system addresses the full lifecycle of a medical device; including the design, manufacture, and use of the device. Also, while ISO 14971:2019 does not, itself, require the implementation of a quality management system, risk management is most often an important part of a strong quality management system.

Compliance ISO 14971:2019 requires that a risk management system be established and maintained throughout the product lifecycle, and that all processes and results are stored in a risk management file. The risk management system will include processes for risk analysis, evaluation, and control. It is important to note that the standard does not define acceptable levels of risk for medical devices – this is left to the manufacturer to determine as part of their risk management processes.

It is important for the organizational personnel to have proper understanding about product usage, process techniques including with expectation of desire results and particular harmonized standards for the evaluation of product life cycle to address specific risks and fully demonstration of the risk mitigation by covering the residues and warning need to inform to the users.

Risk evaluation

The latest version of the standard and guidance, however, emphasize that the matrix should be the output of the risk management policy, which would define the criteria for risk evaluation.

Risk Controls:

When a hazard is found to have an unacceptable risk level, risk control activities are put in place to mitigate the risk. ISO 14971:2019 requires that “state-of-the-art” best practices that are used for similar devices be employed. State-of-the-art does not necessarily mean the most advanced processes and technical features, but rather those that are generally accepted in the industry. Risk control options should include, in order of importance:

• Inherent safety by design and manufacture
• Protective measures built into the device or into the manufacturing process
• Provided safety information, and where appropriate, training to users

Risk/benefit analysis should be performed and where benefit is determined to outweigh risk, the manufacturer will need to decide what safety information is necessary to disclose.

Production and post-production information

A substantial change in ISO 14971:2019 standard is the expansion of requirements for production and post-production activities. The manufacturer will need to perform a full review of the risk management process prior to commercial distribution. The review should ensure that the risk management plan has been appropriately implemented, the overall risk is acceptable, and that procedures are in place to gather and maintain risk data during production and post-production of the medical device. ISO 14971:2019 aligns closely with the ISO 13485:2016 section 8 requirements for feedback, analysis of data and CAPA.

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On April 5, 2017, the EU adopted the Medical Device Regulation, replacing the two existing directives, the Medical Devices Directive and the Active Implantable Medical Devices Directive.

The purpose of the new MDR is to increase safety and efficiency in the EU medical device market. The predecessors of the MDR; the Active Implantable Medical Devices Directive (AIMDD) and the Medical Devices Directive (MDD), which were introduced in the early nineties, served their purpose for a long time and helped create the market for medical devices in Europe.

This note provides an insight into key requirement of MDR.

Product scope expansion – The MDR applies to an expanded range of medical devices including products that were not previously covered by the MDD and AIMDD. Specific examples of newly covered medical devices include those that do have not a medical intended purpose, such as colored contact lenses and cosmetic implant devices and materials. Also included in the scope of the MDR are devices designed for the purpose of “prediction and prognosis” of a disease or other health condition.

Identification of “person responsible for regulatory compliance” – Device manufacturers are now required to identify at least one person within their organization who is ultimately responsible for all aspects of compliance with the requirements of the MDR. The organization must document the specific qualifications of this individual relative to the required tasks. Special relief for some of these provisions may be applicable to small enterprises and start-up entities.

Reclassification of devices according to risk, contact duration and invasiveness – Annex VIII of the MDR details the requirements governing the classification of medical devices. In several instances, the MDR classification requirements are more rigorous than those in the MDD or AIMDD, resulting in the assignment of a higher risk class for some devices and the need to meet more stringent requirements than in the past.

More rigorous clinical evidence for class III and implantable medical devices – Device manufacturers are now required to conduct clinical investigations to support claims of both safety and performance in a medical device in cases where sufficient clinical evidence is not available. Manufacturers are also required to collect and retain post-market clinical data as part of the ongoing assessment of potential safety risks.

Systematic clinical evaluation of Class IIa and Class IIb medical devices – Manufacturers should carefully consider the MDR’s strict requirements on the use of evidence of equivalence in determining whether or not a clinical investigation is required.

Implementation of unique device identification –The MDR mandates the use of unique device identification (UDI) mechanisms with medical devices. This requirement is intended to support the ability of manufacturers and Authorities to trace specific devices through the supply chain, and to facilitate the prompt and efficient recall of medical devices that have been found to present a safety risk. In addition, the European Databank on Medical Devices (EUDAMED) has been expanded to provide more efficient access to information on approved medical devices.

Common Specifications for Single-Use Devices – The EU Commission has published a set of “Common Specifications” applicable to the reprocessing of medical devices intended solely for single use. Published in August 2020 in the Official Journal of the European Union, Commission Implementing Regulation (EU) 2020/1207 presents a detailed set of procedures and steps to be followed by device manufacturers in the reprocessing single-use devices for reuse, quality management system requirements, and traceability provisions.

Rigorous post-market oversight – The MDR mandates increased post-market surveillance (PMS) authority by the Notified Body. Unannounced audits, along with product sample checks and product testing will strengthen the EU’s enforcement regime and help to reduce risks from unsafe devices. Annual safety and performance reporting by device manufacturers is also required in many cases.

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ETO is a colorless gas that is flammable and explosive. The four essential parameters (operational ranges) are: gas concentration (450 to 1200 mg/l); temperature (37 to 63°C); relative humidity (40 to 80%) (Water molecules carry ETO to reactive sites); and exposure time (1 to 6 hours). These influence the effectiveness of ETO sterilization. Within certain limitations, an increase in gas concentration and temperature may shorten the time necessary for achieving sterilization.

The excellent microbicidal activity of ETO has been demonstrated in several studies and summarized in published reports.877 ETO inactivates all microorganisms although bacterial spores (especially Bacillus Atrophaeus) are more resistant than other microorganisms. For this reason, B. Atrophaeus is the recommended biological indicator.

Steps to an EO Validation

1. Process Challenge Device Selection

The process challenge device (PCD) is selected, providing a microbiological challenge system used to evaluate the delivered lethality of the selected process parameters. This is done by pacing a biological indicator (BI) within the product at a location where sterilizing conditions are the most difficult to achieve.

• Internal PCDs are usually medical products or devices selected by the manufacturer as one of the more difficult to sterilize products based upon product design and material composition and are used for validations.
• External PCDs are placed external to the product during routine processing to facilitate retrieval from the load after processing.

2. Reference Load Selection

A reference load selection is performed to identify the worst case load anticipated for routine sterilization. Items considered are product load density and volume, and product/packaging/load venting.

3. Protocol Generation

A protocol is generated documenting all validation activities, including:

• Scope &Objective
• Responsibilities
• Equipment Supplier Information
• Procedures (Acceptance criteria)

4. Ancillary Laboratory Testing

Ancillary laboratory testing is performed, including:

• Bioburden testing
• BI population verification testing

5. Physical and Microbiological PQ

The Physical and Microbiological PQ are typically performed in parallel with the Half Cycle Approach, structured as follows:

A Winter Conditions/Preconditioning Study may be done to simulate conditions in a trailer during colder weather months.

1 Fractional Cycle is performed with a minimal EO exposure time to validate the recovery of the biological indicator (BI) and establish the relationship between the BI and the natural product bioburden. The qualification consists of:

• Cycle performance analysis
• Product sterility testing
• Bacteriostasis/Fungistasis testing
• BI sterility testing (process challenge devices)

3 Half Cycles (4th half cycle needed if establishing a minimum load size) are performed to demonstrate the repeatability of a 6 spore log reduction of the BI utilizing minimum parameters, including one half of the intended routine exposure time. The qualification consists of:

• Cycle performance analysis
• BI sterility testing (PCDs)
• Load temperature/humidity monitoring
• EO concentration monitoring (parametric release only)

3 Full Cycles are performed for determination (and confirmation) of residues and for product/packaging functionality evaluations. The qualification consists of:

• Cycle performance analysis
• BI sterility testing (PCDs)
• EO/ECH residual testing (for 1X and 2X processing)
• Load temperature/humidity monitoring
• EO concentration monitoring (parametric release only)

6. Final Report

A final report is generated to:

• Document a review of the validation data
• Confirm the acceptability against the approved protocol for the sterilization process
• Approve the process specification

7. Revalidation

Revalidation of the established ethylene oxide process is performed on an annual basis. The revalidation consists of a review of the original validation data to confirm no changes have taken place. A reduced PQ (consisting of one-Half Cycle and one Full Cycle) may be performed if product or packaging changes have been made or if significant equipment or process changes have occurred. The reduced PQ is required every year for a parametric release process, but is commonly performed every other year for a BI release process.

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Usability engineering- also known as human factors engineering- is focused on designing medical device interface allowing people to interact with the product in the most efficient and error-free way. When we call a product is “intuitive” or user friendly” we are actually referring to its usability.
The main goal of usability is to design the interface of medical device keeping the intended users in mind and reducing as far as possible the use error associated with the device. It is important as many times we overlook the user interactions with the device and reduce the risks associated with perhaps the device material, biological concerns, safety etc. while some of the adverse events happen because of use error as well meaning the device outcome was different than what was anticipated but not due to device malfunction.

Usability Standards
IEC 62366 is the international standard that covers application of usability process on medical devices. It has two parts:
⦁ IEC 62366-1: Application of usability engineering to medical device
⦁ IEC 62366-2: Guidance on the application of usability engineering to medical devices
In case of electrical or electronic medical device, IEC 60601-1-6 is also referred too.
The clauses and required detail mentioned in the above standards can be customized based on the design and type of your medical device.

Usability Process

IEC 62366 describes a process to mitigate the risks associated with the correct use and use errors due to usability problems. The process is as followed:

⦁ Prepare use specifications
⦁ Identify frequently used functions
⦁ Identify known or foreseeable hazards and hazardous situation
⦁ Identify primary operating functions
⦁ Develop usability specifications
⦁ Prepare usability validation plan
⦁ Design and implement user interface
⦁ Verify user interface
⦁ Validate usability of medical device
⦁ Develop usability engineering file