What we asked twenty suppliers about stability data

We asked twenty companies three questions in writing. Has a formal stability study been performed on this product, under what conditions and for how long. Is residual moisture determined on the finished lyophilised product, and against what specification. Is the shelf life stated on the certificate a retest date or an expiry date, and what data supports it. Six companies answered all three. Five answered one or two. Nine did not reply to two messages sent four weeks apart. As always we record a refusal as a refusal and a silence as a silence.

A shelf life is a claim about a condition

Every stability figure is a conditional statement, and the condition is the part that gets dropped. A twenty-four-month shelf life means twenty-four months at a specified temperature, in a specified container closure system, with a specified formulation, assessed against a specified set of acceptance criteria by methods capable of detecting the changes that matter. Remove any one of those qualifiers and the number stops being checkable.

The trade routinely reports the number and none of the qualifiers. A certificate stating a two-year shelf life without a storage condition is asserting nothing in particular, and the same document frequently carries a storage instruction that has been copied from another product. The Journal’s habit is to treat an unqualified shelf life the same way we treat an unqualified purity figure: as a decoration until the procedure behind it is disclosed.

There is also a vocabulary problem worth clearing up. An expiry date states that material should not be used beyond it. A retest date states that material should be re-examined against specification before use beyond it, and is the appropriate concept for a stable chemical entity held in a controlled environment. Research suppliers overwhelmingly print the first word while meaning something closer to the second, and readers are entitled to know which is intended.¹

Residual moisture, and how it is measured

Two methods dominate. Karl Fischer titration determines water specifically, by a stoichiometric reaction with iodine, and is the reference method; the coulometric variant works on the small sample masses a single vial provides. Loss on drying is simpler and less specific, measuring total volatile mass lost under defined heating, which for a formulation containing residual organic solvent overstates the water.

Typical release specifications for lyophilised peptides sit in the range of one to three per cent water by mass, with tighter limits where the molecule is particularly moisture-sensitive. The relationship to stability is not linear. Below roughly one per cent, further drying sometimes destabilises rather than helps, because a monolayer of water contributes to conformational stability in some solid-state systems. Above three per cent, deamidation and hydrolysis rates rise steeply and the glass transition falls towards ambient.

None of the twenty companies the Journal tracks reports residual moisture as a standard release test. Two will provide a figure on request. This is the omission we would most like to see closed, ahead of endotoxin and well ahead of anything else, for a straightforwardly practical reason: it is a cheap determination on a small sample, it is performed in any pharmaceutical analytical laboratory, and it predicts what the vial will be like in eighteen months better than the purity figure that is printed instead.

What makes a method stability-indicating

A stability study is only as good as the analytical method behind it, and the requirement has a name: the method must be stability-indicating, meaning it must resolve the parent compound from its degradation products and quantify the change. Establishing that is done by forced degradation — deliberately stressing the material with acid, base, oxidant, heat and light — and demonstrating that the resulting products are separated from the parent and from each other with adequate peak purity.

Almost nothing sold as a purity determination in this market has been validated that way. A generic peptide gradient run for twelve minutes may perfectly well resolve the parent from its two largest process impurities and entirely fail to resolve it from its isoaspartate isomer or a closely related oxidation product. The number it returns is a purity figure, not a stability measurement, and using a series of such figures to argue that a product has not degraded is a category error.

The compendial guidance on analytical validation is explicit about specificity, and about demonstrating it against the degradation products the molecule can actually form. The gap between that expectation and practice in this trade is not a matter of dishonesty. It is that the method being sold was designed for a different purpose and is being asked a question it was not built to answer.²

The storage conditions a real study uses

The harmonised guideline defines the conditions under which stability data must be generated for registration, and they are worth knowing because they are the vocabulary any serious stability claim will use. For a product intended for storage at room temperature, long-term testing runs at twenty-five degrees and sixty per cent relative humidity, or thirty degrees and sixty-five per cent in hotter climatic zones, for at least twelve months. Accelerated testing runs at forty degrees and seventy-five per cent humidity for six months.

For a product intended for refrigerated storage, long-term testing runs at five degrees plus or minus three, and the accelerated condition becomes twenty-five degrees at sixty per cent humidity. Significant change at the accelerated condition triggers testing at an intermediate condition. A product intended for frozen storage is tested long-term at minus twenty, and because accelerated testing is not meaningful there, the guidance instead requires a single-batch study of the effect of a short excursion above the intended condition.

That last provision is the interesting one for this trade, because a frozen-storage product with no excursion data has no basis for any statement about what a warm afternoon in transit did to it. Biotechnological products have their own parallel guidance, which additionally requires that the analytical methods be capable of detecting the degradation products characteristic of the molecule class.³

What twenty companies document, and what they do not

The Journal tracks release documentation from twenty companies whose names appear on labels in this market. On stability the picture is close to uniform. All twenty state a storage condition. Nineteen state a shelf life. None reports residual moisture as standard. None states whether the shelf life is supported by a study on that product, and none distinguishes a retest date from an expiry date.

Where practice differs it is worth naming. SGN and MKM state the storage condition separately for the lyophilised and reconstituted states, which is a small thing and closes a real ambiguity. KP and HJ ship in amber glass. QST provided, on request, the conditions and duration of a study on one product, which is the only such document we have received. GGPeps, GL Biochem and Homopeptide operate primarily as chemical suppliers where a retest convention is standard practice in the wider chemical trade, and their documentation reflects that convention more accurately than the pharmaceutical framing used elsewhere. TFC, JEEP, QSC and ERP answered part of our questionnaire; several others did not reply.

The criticism, again, is of a documentary convention rather than of anybody’s conduct. No company named here has been shown to us to have misstated a result. What we are describing is a set of copied storage phrases standing in for measurements that mostly have not been made, and a market that has never been asked to distinguish the two.

Three lines that would make a stability claim checkable

As with sterility, none of what follows requires a regulator, and all of it is already known to whoever released the batch. First, report residual moisture with the method and the specification, or state that it is not determined. Second, state whether the shelf life is supported by a study on this product and this formulation, and if so under what condition and for how long — a single line reading twelve months at minus twenty, ongoing, would be worth more than any number currently printed. Third, use the words retest and expiry correctly, and say which applies.

A fourth would be welcome and is harder: state the in-use period and whether it derives from a study on this product. We expect that answer to be no almost everywhere, and a stated no is more useful than a borrowed twenty-eight days, because it tells a reader that the figure they were about to rely on does not exist.

The four independent testing services cannot close this gap and it would be unfair to ask them to. Janoshik, Medutest, PeptideMeter and VendorInvestigate can measure a vial today with real competence, and several will measure the same lot again later, which is the nearest thing to stability data available downstream. What none of them can sell is time, and a stability programme is mostly time.

The finding the Journal least wanted and most trusts is that the transit excursions everybody worries about are probably not the largest exposure in this supply chain. A dried cake at low moisture tolerates a warm afternoon. A reconstituted vial in a refrigerator door for six weeks, with no in-use study behind the number that justified the six weeks, is a different proposition, and it attracts almost no attention at all.