MEDICAL AND COMBINATION DEVICE QUESTIONS

FAQs List

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Medical Device Testing Questions

What medical device testing methods do I need to comply with?

A test method should follow good logic, planning and start with a risk analysis. Once the failure modes and risks associated with a device have been identified, testing plans and protocols can be developed to  quantify the magnitude of these risks. Hence, the goal of a test method and process is to provide evidence that the risks associated with a device are negligible or at least acceptable when compared to the benefits derived from use of the device.

Which standards does my medical device have to comply with?

Many devices are associated with specific consensus standards, usually ISO and ASTM, which describe the design and/or performance. More recently published standards sometimes include details of information that is to be supplied to users, packaging requirements and human factors.

There are also many more general (horizontal) standards which are not device specific. Examples are: for packaging ISO 11607, for quality management ISO 13485, for toxicity ISO 10993, IEC 62366 for human factors, ISO 14971 for risk analysis.

The FDA publishes a list of Recognized Consensus Standards. This is always a good place to start looking for those which are relevant to your product. There may also be FDA Guidance for your device and again horizontal Guidance such as  FDA Guidance Applying Human Factors and Usability Engineering to Medical Devices

Biocompatibility testing questions.

Is biological testing still required for medical devices?

The 2018 version of ISO 10993 emphasises risk assessment and chemical understanding. This means that if the combination of chemicals and materials in a device are known and their toxicity is known, this information can be combined to with knowledge of the product's use to eliminate biological testing when appropriate. It is still a good idea to conduct cytotoxicity testing and in some cases an investigation of local effects.

Is chemical extract testing required for medical devices?

ISO 10993 has chemical characterisation as the first requirement in the testing matrix. It encourages the use of this chemical analysis when insufficient information is available to define all the required toxicity end points. It is only required if the material review and risk assessment conclude that this information is not  available.

How do I calculate sample requirements for medical device biocompatibility testing?

Part 12 of ISO 10993 details the ratio of extract solvent volume to device surface required to produce the test fluids. This ratio can be applied to devices and pharmaceutical containers. Your testing supplier will be able to advise you on what volume of fluid is required for each test. In the case materials characterisation, and leachables and extractables the required volume is often 50 to 100ml.

What is the testing biocompatibility matrix?

The biological evaluation matrix in ISO 10993 lists end points for toxicity assessment for medical devices. The end points required are defined according to the invasiveness of the device's use and its duration of contact. An end point is a toxicological risk that must be discussed and evaluated with the object of showing that the risk from a device is insignificant when compared to the benefit. Examples are cytotoxicty, geneotoxicity and mutagenicity.

What is chemical characterisation?

Chemical characterisation is a combination of information obtained by reviewing information sources including:

·         the input materials (specification, MSDS, safety testing)

·         processing (heating, contact with other materials, other stresses)

·         the storage conditions,

·         sources of contamination,

·         the effects of sterilisation ,

·         any information obtained from chemical testing.

 This is the information that a Toxicologist can use to weigh up the risks of using the device. This Toxicological Risk Analysis can conclude whether or not the device is safe to use or if biological testing is required to confirm some aspect of safety. Hence, biological testing is the ‘gold standard’ but also the ‘last resort’.

EMC questions

Why is EMC testing required for my medical device?

Medical equipment must be immune to the influence of reasonable levels of interference from radiated or conducted emissions. That is to say, its performance should not be altered by emissions from equipment in the vicinity. Equally the device in question must not emit levels of interference that would influence other equipment. The syringe pump on bed B should not effect the pacemaker in bed A.

What is EMC testing?

All electrical and electronic equipment will emit some electromagnetic interference and could be effected by external radiation. Electromagnetic compatibility (EMC) testings measure emissions and resistance to interference both from radiation and conducted through wiring.

Extractables and leachables questions

What is extractables and leachables testing?

It is obviously undesirable for a medication or a medical device to introduce unwanted substances to the human body. E&L testing investigates substances (organic and inorganic) that probably will be and possibly could be released to a patient form medical devices, pharmaceutical production and pharmaceutical packaging. The aim is to identify and quantify chemical species to allow an informed toxicological risk assessment.

Extractables and leachables definition

Leachables are materials which are likely to migrate into drug products during storage or production. They can subsequently be identified in laboratory investigations.

Extractables could similarly find their way into medications but with a lower probability. They are identified in the laboratory using ‘forced’ extraction.

In the case of medical devices leachables are substances that are likely to be released to a patient during use. Extractables are materials that could be released in long term use or if the device is damaged.

Are there special extractables and leachables requirements for biologics and biosimilars?

The delivery of a formulation should not be accompanied by any harmful or undesirable substances. Therefore E and L studies are conducted to quantify substances migrating from production and packaging systems into the injected dose. In the case of biologics, there are some further complications. Production processes can be complex and involve extended dwell times, along with the presence of biological activity, this increases the likelihood of transfer of materials from container systems. Once packaged, proteins and other biologically active substances risk being denatured by contact with surfaces. Also, agglomeration and other physical changes can occur.

For biologics and biosimilars the process and requirements for identifying transferable substances is the same as any other injectable. The analysis, however, needs to additionally consider:

Effects on cell growth and protein expression in production

Loss of tertiary structure in storage

Physical changes to the presentation of the formulation

Changes to excipients and other non-active elements of the formulation.

Injection system validation questions

What are the important factors in a PFS validation?

The most important things about a pre-filled syringe or injector pen are that it delivers the correct dose in the correct place without introducing unwanted materials. Therefore, the most important things to validate revolve around dose accuracy and quality.

·         Is the volume correct?

·         Is the volume within tolerance, but not consistently high or low (chronic incorrect dose)?

·         Is the API still at the correct concentration (even after the full stability storage period)?

·         Can the syringe be actuated easily and the plunger depressed to deliver the complete dose?

·         Are any of these things altered by long or short term storage (over a range of storage conditions)?

Auto-injectors have additionally a requirement to deliver their dose to correct depth and over a limited time.

Repeat use injectors must demonstrate consistent dosing across cartridge positions and volume range.

Along with volume based dose accuracy what is being dosed needs to be established. This requires stability studies to demonstrate that the active ingredient is unchanged during storage. In addition analysis of any contamination, of the formulation, from production or container storage is required. This takes the form of extractables and leachables studies.

What is the difference between ISO 11608 and ISO 11040?       

There are two overlapping standards governing the requirements for auto-injectors, multi-dose pens and pre-filled syringes.

For diabetic or other repeat use injector pens ISO 11608 is the most relevant standard. It has sections concerned with the needles, the cartridges, the dose accuracy statistically and across positions in the cartridge. There are also sections for electronic and automated injectors as well as a section for physically impaired users.

ISO 11040 deals with dental syringes, glass syringes and cartridges, plastic syringes and cartridges and the stoppers.

It is likely that your product will need to be validated against the relevant sections of both standards. They overlap in subject matter but vary significantly on the aspects examined. Consult with your project manager at MET to develop the most effective approach for your device.

Packaging validation questions

What is accelerated aging for medical devices?

Accelerated ageing is used to avoid lengthy waiting periods before a product can be approved for marketing. A calculator is available here. The MDR makes provision for testing devices and packaging aged this way whilst waiting for results from naturally aged samples. It is necessary to demonstrate that medical devices are safe and effective throughout allowed storage and periods of use. This can be done using rapidly aged samples and later confirmed using ‘real time aged’ material.

What is the best temperature for accelerated aging of medical devices?

ASTM F1980 is generally used as a guide to ageing times and temperatures. It allows a range of temperatures to be used to speed up ageing according to project urgency and the nature of the product. The goal is to accelerate chemical and physical changes, but without inducing any changes that would not occur at normal storage temperatures. A very commonly used temperature is 55°C. When compared to a normal temperature of 25°C this delivers an 8 fold increase in the rate of decay. It usually not high enough to melt product or packaging, initiate any chemical reactions (that would not take place more slowly at 25°C), or cause other physical changes. The temperature and acceleration factor can be raised up to any point before these effects start to occur.

For example, 65°C is also usually a ‘safe’ temperature which halves the time requirement in the ageing chamber to 23 days per year of Real Time Equivalent (from 46 days at 55°C with the 25°C base temperature).

Which is the best transit simulation protocol to use for medical device packaging?

The 2019 edition of ISO 11607 lists ISTA 3A and ASTM D4169 as alternatives for transit validation. Both test regimes are intended for packages that can be handled in small parcel distribution. This is a worse case than pallet distribution and is normally the chosen direction.

What is transit simulation?

When sterile devices are distributed in the delivery chain there is significant risk of damage from vibration and impacts. Simulation is conducted to measure the effects of external impacts and internal product movement on the sterile barrier.  After cartons have been subjected to atmospheric conditioning and the transport inputs, the blister or pouch packs inside are tested for seal strength and integrity.

 

 

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