Stability Chamber For Medical Device Shelf Life Testing

For many medical devices, the device itself is the durable part. A stainless instrument, a moulded plastic housing, a length of tubing, these change little over the years they sit on a shelf. What ages is the sterile barrier around them. A device sold sterile is sealed inside a barrier, a peel pouch or a tray with a lidding film, that keeps microbes out until the moment of use. That barrier is built from materials, adhesives and heat seals that weaken with time. A seal that opens or a film that cracks lets the sterility go, however sound the device inside. The shelf life of a sterile device is therefore usually the shelf life of its package. ISO 11607, the standard for that packaging, requires a maker to prove the sterile barrier holds its integrity all the way to the expiry date claimed. A stability study for such a device is aimed at the package no less than the product. The chamber’s job is to age the package through the years its seal has to survive. This is the deeper reason a device study and a drug study, run in the same chamber, are not the same study. A drug is its chemistry; its shelf life is the span that chemistry stays within limits. A sterile device is largely inert; its shelf life is the span its barrier stays shut. The chamber serves both. What it is asked to age, and what the bench then measures, are different things, the slow chemistry of a molecule in one case and the slow physics of a seal in the other.

■Buying years in weeks

Real time is slow. A device with a five-year shelf life would take five years to prove by real-time aging alone. A maker cannot wait five years to launch. ASTM F1980, the accelerated aging standard for sterile medical device packaging, offers a way to claim the date sooner. It rests on the Arrhenius relationship, the chemistry that says a reaction runs faster at a higher temperature. Aging is a slow reaction, the weakening of an adhesive, the embrittling of a film. Warming the package speeds it up in a way the standard can put a number to. That number is the Q10, the factor by which the aging rate changes for every ten degrees of temperature. Makers commonly use a Q10 of two, meaning the aging roughly doubles for each ten degrees, unless material data supports another value. From the Q10 and the two temperatures, the real storage temperature and the elevated aging temperature, comes an acceleration factor, the ratio of aged time to real time. It is the Q10 raised to the difference in temperature over ten. With a Q10 of two and an aging temperature of fifty-five degrees against a room temperature near twenty-three, the factor is about nine. A year of shelf life is reached in about forty days in the chamber. The standard works across a band of forty to sixty degrees, with fifty-five the common choice for sterile barrier materials, warm enough to age fast and cool enough to spare the materials a change real storage would never cause. Accelerated aging gives a maker an initial shelf-life claim, enough to launch the device, on the understanding that the number is provisional. The standard is careful to call its result conservative and to require that real-time aging confirm it. The chamber that does the accelerated aging has one demanding job, to hold that elevated temperature exactly, because the acceleration factor depends on it steeply. There is a logic to keeping the temperature only as high as fifty-five. Push it higher and the aging goes faster still, but the materials may start to behave in ways they never would on a shelf, an adhesive flowing, a film passing through a transition, so the test would age the package by a process real storage never sees. The standard’s band of forty to sixty degrees is the range where common barrier materials age faster without aging differently. The Q10 of two is a similar compromise, a conservative default that tends to understate the real acceleration, so a claim built on it errs toward the safe side. This conservatism is deliberate. An accelerated number that is slightly pessimistic protects the patient when the real-time data is not yet in, which is the reason a regulator accepts the accelerated claim as a starting point at all.

Accelerated aging buys the date. Real time keeps it.

■What the package ages out as

The aging shows itself first in the seal. A sterile barrier is held shut by a bond, a heat seal between two films or a film and a tray. That bond is the part chiefly exposed to time. As adhesives relax and polymers stiffen, the seal can lose the strength that keeps it shut, or develop a channel too fine to see that lets air and microbes pass. Either way the barrier fails before the device does. The materials themselves can change as well, a film growing brittle, a coating crazing, a plasticiser migrating out. A barrier that has gone brittle can crack at a fold or a corner where the package is flexed in handling. None of this is visible from the outside on day one. It is the work of the aging study to bring it forward, to put the months or years of slow change onto a package that can be opened and tested now, so a weakness that would show up in a warehouse in year four shows up on the bench in week six instead. The seal carries much of this risk because it is where two materials are joined. A join is always the weakest line. A heat seal is formed by melting two films together under heat and pressure. The bond it makes can be strong on day one and still relax over years as the polymers settle. A peelable seal, designed to open cleanly at the point of use, walks a narrow line, strong enough to stay shut on the shelf and weak enough to peel without tearing. Aging can push it off that line in either direction. The aging study is what shows where the seal sits after its years, whether it has held its strength, drifted weak, or grown so firm that opening it tears the film. All three are failures of a different kind. Only an aged package reveals which a design is prone to.

■What the tests look for after aging

When a package comes out of the aging chamber, it is tested for what the aging might have taken. The seal is pulled apart and its strength measured, to see whether the bond that holds the barrier shut has weakened. The package is checked for leaks, by drawing a dye through any channel in the seal or by holding the package under water and watching for bubbles, because a barrier that leaks no longer protects. Where the standard calls for it, the sterility itself is challenged, the aged package exposed to microbes to confirm none get through. The device inside is tested for its own function, in case the years of warmth changed a material it depends on. These are package and material tests, far from the chemical assays a drug would face. A drug study asks how much active is left in the formulation. A device study asks whether the seal still holds and the device still works, a question of physical integrity that the chamber ages the package to answer and the bench then reads. The seal-strength test is a peel, the lid pulled from the tray or the two films apart at a steady rate, the force recorded across the seal. A value that has dropped after aging warns that the bond is weakening, before it fails outright. The leak tests catch what strength alone cannot. A dye-penetration test floods the seal with a coloured liquid that wicks through any open channel and shows as a line of colour, finding a path too fine to see. A bubble test submerges the inflated package and watches for the stream of bubbles a leak makes. Together the strength and the leak tests describe a seal from two sides, how hard it is to open and whether it is open already. The device’s own function is checked last, because a barrier that held perfectly is worth nothing if the device inside has aged past use.

■The aging study in practice

An aging study is run on a set of packages, never on one alone. Several identical units are aged together, so a failure in one can be told from a trend across many. Enough are made to test at each point the protocol calls for. A baseline set is tested at time zero, before any aging, to fix the starting condition every later result is measured against. The accelerated set is held at the aging temperature for the span that stands in for the full claim, then pulled and tested. The real-time set is sampled at intervals along the calendar, at one year, two years, and on to the dated life, each pull tested the same way as the baseline. The packages are aged in the configuration they will ship in, sealed and handled as a real unit, because a study on a loose or an idealised sample proves less than one on the product as sold. Where the device is the worst case in some respect, the largest, the heaviest, the one with the hardest seal to hold, that is the unit aged, so the claim rests on the hardest case the product line presents. The study is, in the end, a comparison, the aged package against the fresh one, read at points fixed before the aging began.

■Why the aging temperature has to be exact

The acceleration factor turns steeply on the aging temperature. Because the factor is the Q10 raised to a difference in temperature, a small error in temperature becomes a larger error in the aging it claims. Run the chamber a degree below the target and the package ages slower than the arithmetic assumes, so the days in the chamber stand for fewer real years than the study credits them with. The shelf life is then overstated, a date claimed longer than the package was aged to prove, which is the error that matters for a patient. Run the chamber a degree above the target and the bias runs the safer way, the package over-aged and a claim it passes left conservative. Either way the chamber is no longer representing the years it says it is. A drug study near room temperature is forgiving of a small drift. An accelerated aging study at fifty-five degrees, leaning on an exponential, is not. The chamber has to hold its aging temperature to a tight band, and to hold it evenly across the load, so every package in the chamber ages by the same factor. How that evenness is proven, across the volume, is the work of mapping. What matters here is that the shelf-life claim a maker prints rests on the chamber having aged the package by exactly the factor the arithmetic assumed.

■Where humidity comes in

Temperature drives the accelerated aging. For some materials humidity matters too. A barrier film that absorbs moisture, an adhesive whose bond depends on staying dry, a device part that can corrode, ages differently in damp air than in dry. Where the materials are sensitive to it, the aging is run at a controlled humidity together with a controlled temperature, so the package meets the moisture it would see on a real shelf alongside the heat that speeds its aging. The chamber then has to hold both, the elevated temperature and the chosen humidity, steady together for the span of the study. For a material indifferent to moisture, a dry oven is enough and humidity is left out of the protocol. The decision rests on what the barrier and the device are made of, the same material knowledge that sets the Q10 and decides whether accelerated aging is sound at all. A stability chamber that holds temperature and humidity together covers either case, the dry aging of a moisture-proof package and the damp aging of one that is not.

■When accelerated aging is allowed

Accelerated aging is not allowed for every device. It works when the sterile barrier is made of heat-stable, well-characterised materials, the kind whose aging at fifty-five degrees is a faster version of their aging on a shelf, never a different process. A material that melts, softens or changes phase somewhere between room temperature and the aging temperature breaks the Arrhenius assumption, because the chamber would then age it in a way real storage never would. Accelerated aging also suits a shelf-life claim of about five years or less. For a longer claim, or for a material whose behaviour is not well understood, real-time aging carries more of the weight. The accelerated study is then treated with more caution. The choice of Q10 is part of this judgement. The default of two is an assumption. Where a maker has material science to justify a different value, the standard allows it, with the burden on the data. Accelerated aging is a tool with conditions attached, dependable only while its assumptions hold. This is why a maker does not lean on accelerated aging alone. The accelerated study is a means to launch, a defensible first claim while the slow proof gathers. If the assumptions behind it are sound, the real-time data will, year by year, agree with it. The early date then stands. If they are not, the real-time data will diverge. The maker learns it in time to correct the claim. The discipline is to treat the accelerated number with the caution its assumptions deserve, neither ignoring it nor trusting it past what the materials justify. A five-year claim launched on six weeks of warmth is a reasonable bet only when the chemistry of aging is understood well enough to make the bet safe.

■How a device differs from a drug

A medical device shelf-life study and a drug stability study run in the same kind of chamber and answer different questions. A drug study asks how the chemistry of the product changes, how much active remains and how much impurity has grown, against conditions a guideline fixes. A device study asks whether the package and the materials have survived, largely a question of physical integrity. The conditions differ too. A drug runs at a fixed storage condition, often twenty-five degrees and sixty percent humidity, the subject of its own setup. A device under accelerated aging runs hot, at fifty-five, to compress the years. Some products are both at once. A combination product, a drug delivered by a device such as a prefilled syringe or an inhaler, carries two clocks, the chemical shelf life of the drug and the physical shelf life of the device and its package. The shorter of the two sets the date. The chamber may serve either study, but the question it is asked, and the condition it holds, depend on which the product is. The combination product is where the two studies meet in one chamber and one box. A prefilled syringe ages as a drug, its formulation drifting, as a device, its plunger and seal hardening, and as a sterile package, its barrier weakening, all on the same shelf. A maker has to run the conditions each part needs, the fixed storage condition for the drug and the warmth for the device aging, then reconcile what each says about the life of the assembled unit. The expiry on the box is the earliest date any of the three reaches, because the product is unfit once any one of them is. The chamber serves each study in turn, or several products at once. The claim that comes out is governed by whichever clock runs down first.

■The standards behind it

Three standards stand behind a device shelf-life study. ASTM F1980 sets out the accelerated aging itself, the Arrhenius basis, the Q10, the temperatures and the arithmetic. ISO 11607 governs the sterile barrier packaging, in two parts, one for the materials and the design of the barrier, one for the processes that form and seal it. It is ISO 11607 that demands the real-time confirmation. ISO 13485, the quality system standard for medical devices, sets the framework the study runs inside, the controlled, documented way a regulated maker has to work. How a chamber is qualified and its data kept under that quality system is the subject of the compliance work, the same discipline a drug study runs under. The standards divide the labour, one setting the aging, one guarding the barrier, one governing the system. Between them they turn a warm chamber and a stack of pouches into a defensible expiry date. None of the three works alone. ASTM F1980 without ISO 11607 would age a package no one had defined as a sterile barrier. ISO 11607 without a quality system would set a requirement no one was bound to meet. The standards lock together, the method inside the packaging requirement inside the quality system, so a shelf-life claim becomes a result reached the way a regulator expects, beyond one laboratory’s opinion. A reviewer reading the file checks that each standard was followed and that the three agree, the aging done to F1980, the barrier proven to 11607, the entire study run under a system that 13485 governs.

■What the chamber gives a shelf-life claim

What a shelf-life study asks of a chamber is to age a package faithfully, fast or slow. For an accelerated study it has to hold an elevated temperature, fifty-five degrees or wherever the protocol sets it, exactly and evenly, for the weeks that stand in for years, so the acceleration factor the maker relies on is the factor the package met. For a real-time study it has to hold the storage condition, without event, for as long as the device is meant to last. A chamber that does either well lets a maker put an expiry date on a sterile device and defend it, that the seal will still hold and the device still work on the last day of the dated life. A device maker lives with both clocks at once, the fast one that lets the product reach patients now and the slow one that will, in time, either confirm the date or call it back. The chamber serves both, the same machine holding fifty-five degrees for the accelerated study and the storage condition for the real-time one, often running them for the same product side by side. Its work is unglamorous and exacting, to hold a temperature and a humidity steady and true for as long as the study needs, so the aging it imposes is the aging the arithmetic counted on. The chamber ages the package. The standards and the tests decide what the aging proved. The date on the box is the answer they reach together.

Envsin stability and accelerated aging chambers for medical device shelf-life testing under ASTM F1980 and ISO 11607.