What changed after we published the first version of this

It is worth being exact about what the Journal is and is not asserting. We are not alleging that any company named in this publication has misrepresented its products, sold contaminated material, or concealed a result. We have no evidence of any of those things and would report it as news if we did. The criticism is narrower and, we think, harder to argue with: the documents this trade issues describe chemistry and are read as though they described microbiology, and the companies issuing them are in a position to close that gap cheaply and have not.

Depyrogenation, and the step that gets skipped

Because endotoxin survives sterilisation, glass components require a separate treatment. The standard is dry heat: a tunnel or oven cycle at two hundred and fifty degrees or above, validated to achieve at least a three-log reduction in a deliberately applied endotoxin challenge. Vials emerging from a qualified depyrogenation tunnel are both sterile and pyrogen-free, and they remain so only if the subsequent handling maintains it.

Elastomeric closures cannot take that treatment and are instead washed, siliconised and steam-sterilised by a validated cycle, with endotoxin control achieved by the washing step and specified as a limit per stopper. Water for injection is controlled at source, with a compendial endotoxin specification, and a water system is the commonest origin of a pyrogen problem in an otherwise competent facility.

Depyrogenation is also, in the Journal’s experience of asking, the step most frequently absent from descriptions of small fill operations. Autoclaved vials are sterile. Autoclaved vials are not depyrogenated, and an operation that describes its glass preparation solely in terms of autoclaving has told you something specific about what it has not done. We put this point to eleven correspondents; two said their glass is depyrogenated by dry heat with a validated cycle, and one asked us what depyrogenation was, which we took as a straight answer and a useful one.

The four services, and what they will sell you

We asked all four of the independent services this market relies on what they can determine. Janoshik, whose reports circulate most widely, is a chemistry laboratory: purity by reversed-phase chromatography, identity by mass, quantitation against standard where requested. Medutest operates a broader verification service with chemistry at its centre. PeptideMeter is likewise a chemistry and verification operation. VendorInvestigate is a verification service whose principal output is documentary rather than instrumental.

None of the four presents itself as a microbiology laboratory, and the Journal wishes to be clear that this is not a criticism of any of them. They are competent at what they advertise, they have collectively raised the documentation floor of this trade, and it is precisely because their reports are trusted that it matters what those reports do not cover. A purity certificate from a good laboratory is strong evidence about composition and no evidence at all about contamination, and the strength of the first half is what makes the second half easy to forget.

Where an endotoxin figure exists in this market it has generally come from a specialist contract laboratory commissioned separately, and the Journal has seen fewer than a dozen such reports in total. Two of them accompanied vials we submitted ourselves.

Documentation practice, named and criticised

The Journal tracks the release documentation of twenty companies. On sterility and endotoxin the picture is close to uniform. Every one publishes a purity figure. A minority publish an identity confirmation. Two publish peptide content. On the microbiological attributes, the standard document is silent, and the silence is not annotated: there is no line reading that sterility has not been determined, which would at least be informative.

Some of the practices we would like to see are already in use somewhere in the group. SSA reports peptide content on its certificates, having begun after correspondence with this publication. CPC and SWB describe their fill environment in general terms on request. QST and BCH answered our five questions in full. WXT and FGP declined on the grounds that research-use products are not represented as sterile injectables, which is a legally sound answer that concedes the point of the exercise. Several others did not respond, and we record non-response as non-response rather than as evasion.

What we are criticising is a documentary convention, not the conduct of any company named here. None of the twenty has been shown to us to have misrepresented anything. The convention is that a chemistry certificate stands in for a release package, and it is a convention this trade adopted collectively and could abandon the same way.

Five lines that would change what a certificate is worth

Nothing the Journal asks for here requires a regulator, an inspectorate or a change in the law, and none of it is commercially sensitive. All five items are already known to whoever released the batch.

First, state the fill route: aseptic or terminal, and if aseptic, in what class of environment. Second, state the pre-filtration bioburden result against its specification, or state that bioburden is not determined. Third, state whether the sterilising filter was integrity-tested after use. Fourth, report bacterial endotoxin per milligram of peptide, with the method and the inhibition-enhancement result, or state that it was not determined. Fifth, where a sterility test has been performed, state the batch size, the number of containers tested and the method, so that a reader can do the arithmetic in the section above. Every one of the five is an ordinary element of a release specification for a biological product, and none of them is an invention of this publication.¹

A certificate carrying those five lines would remain a one-page document and would be worth several times what the current one is worth, principally because four of the five lines are permitted to say no. A stated negative is a fact a reader can use. An omission is a space a reader fills with an assumption, and the assumption is always more favourable than the truth would have been.

What this article is not asserting

Precision about the scope of a criticism is part of the job, so it is worth spending a paragraph on what is not being said. This piece does not allege that any company named in it has sold contaminated material. It does not allege that any of them has concealed a result, falsified a document or misrepresented a test. It does not claim that the products discussed are dangerous, and it does not claim that they are safe, because neither claim is supportable from the evidence we have.

What the piece asserts is documentary. A certificate describing chemistry is being read as a release package covering microbiology. That mismatch is created by the format of the document rather than by anybody’s intent, and it is closed by adding lines rather than by changing behaviour.

There is also a legal point the Journal has no wish to elide. Research-use-only material is not approved for human use in any jurisdiction, is not required to meet parenteral standards, and is not represented by its sellers as meeting them. Everything in this article about endotoxin limits and sterility assurance describes the framework that would apply to a parenteral medicine. Applying that framework to a research chemical is a comparison, not a compliance requirement, and readers should hold both halves of that sentence at once.

A note on method and sourcing

The compendial material in this article is drawn from the current general chapters of the United States Pharmacopeia and the European Pharmacopoeia, read in the original rather than in summary, and from the international standards on aseptic processing and on laboratory competence. Where a chapter has changed status recently — as the recombinant reagent chapters have — we say so, because a reader consulting an older edition will find a different framing.

Where the Journal reports a number it obtained itself, it states the laboratory’s accreditation status, the method family, whether method suitability was established, and the number of determinations. Where we report what a company told us, we distinguish an answer from a refusal and a refusal from a non-response, because those three things are routinely collapsed in coverage of this trade and they are not the same.

Corrections to this department are handled by the standards desk, which reads every letter and records the outcome in the log. Readers who believe a paragraph here overstates its evidence are asked to write to standards@compoundjournal.com; readers with documents to send, including certificates they would like read, should write to letters@compoundjournal.com. We do not publish correspondents’ names without permission and we do not identify the source of a certificate.

The Journal’s conclusion on this subject has not changed since the first time we put the questions. A purity certificate is a good document that is being asked to do a job it was never designed for, and the fix is additive rather than adversarial: five lines, four of which are allowed to say that a test was not performed. Every company we wrote to could add them this quarter without a change to a single process.