Draft standard: bacterial endotoxin testing of peptide… — submissions
The 12 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
12 submissions were received. Each is published in full below with its declared interest, the secretariat response and the disposition. The Institute publishes submissions it did not accept in the same form as those it did.
A determination does not record the version of the standard it was made under
The respondent read CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for… in draft. The point applies to it and to the series generally.
The respondent states that the standard will be revised and that results reported under different versions will circulate together, indistinguishable from one another.
The respondent proposes that the standard identifier and version be carried on the face of every determination.
The secretariat accepts this submission. A conformance claim against an unspecified version is not a conformance claim.
Every determination reported under this standard now carries the standard identifier and version on its face, and a claim of conformance that does not identify the version is recorded by the Institute as not conformant.
Nothing in the standard addresses transfer of the method between laboratories
This is a submission on CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for….
The respondent states that determinations under this standard will be performed by different laboratories on the same material and that without transfer criteria their results are not comparable.
The respondent proposes a transfer protocol with acceptance criteria for inter-laboratory agreement.
The respondent has read submission 001 with interest and adds one observation the secretariat may find useful.
The secretariat accepts this submission in part. Acceptance criteria for agreement between laboratories are added. A full transfer protocol is not, because transfer is a quality-system activity rather than a determination and the series does not address quality systems.
The standard now states the maximum difference between laboratories analysing the same sample at which results are treated as agreeing, and requires that a comparison across laboratories state whether that criterion was met.
The standard assumes a reference standard of known assigned content
The respondent read the draft of CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for… and has confined this submission to a single requirement.
The respondent states that for many compounds in scope no reference standard with an assigned content exists, and that the standard as drafted has nothing to say to a laboratory in that position.
The respondent proposes that the standard state what can be determined without one and how such a determination should be labelled.
The secretariat accepts this submission. A standard applicable only where a reference standard exists is silent in the cases most in need of it.
The standard now states which determinations remain available without a reference standard of assigned content, requires that such determinations be labelled as relative rather than absolute, and requires the assumption used in place of an assigned content to be stated.
A superseded version should remain reachable from the version that replaced it
The respondent submits on CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for…, on a matter that is not specific to this draft but is visible in it.
The respondent states that the draft supersedes an earlier document and that a reader who cited the earlier version has no way to reach it from the new one, which makes it impossible to see what changed.
The respondent asks that every version carry a link both to what it supersedes and to what supersedes it.
The secretariat notes this submission. The corrections and versioning policy already requires bidirectional version links and every superseded document is retained at its own address.
No amendment arises. The requirement is stated in the corrections and versioning policy and the amendment log of this document links to the version it replaced. The respondent is correct that the link was absent from the draft page furnished for consultation, which was a defect of the consultation copy and not of the policy.
The standard does not say what to do with a result outside the expected range
The respondent has read CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for… in draft and makes a single submission.
The respondent states that the draft describes how to obtain a result and stops, and that the handling of an unexpected result is where the integrity of a determination is decided.
The respondent proposes that repetition be permitted only under stated conditions and that every determination performed be reported, including those superseded.
The respondent notes that submission 004 has already been made and confines this submission to a matter not covered by it.
The secretariat accepts this submission. A standard silent on repetition permits the selective reporting it exists to prevent.
The standard now requires that every determination performed on a sample be reported, that a repeat be permitted only where an assignable cause is documented, and that the assignable cause be stated on the face of the report.
The additional determinations required would materially increase release testing cost
Having read the draft of CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for…, the respondent puts one point to the secretariat.
The submission is made on behalf of a manufacturer. It states that the draft adds two determinations to those in existing compendial practice, and estimates the additional analytical burden per batch.
The submission does not dispute the analytical reasoning and asks that one of the two be made conditional rather than universal.
The respondent endorses the general approach taken in submission 005 and asks that it be extended to the matter identified here.
The secretariat accepts this submission in part. One determination is made conditional on a stated risk factor. The other is retained because the evidence supplied by the respondent does not bear on whether it is necessary, only on what it costs.
One of the two determinations is now required only where the stated risk factor is present, with the factor defined in the scope, and the other is retained as a universal requirement with the reasoning stated. The submission is identified as an industry submission.
Point estimates are given without an interval
Having read the draft under consultation, which concerns CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for…, the respondent submits as follows.
Several estimates in the draft appear as single figures. The respondent states that a point estimate without an interval invites a precision the underlying data do not support, and that the effect is worst where the estimate is drawn from a small contributing set.
The respondent proposes that no point estimate appear anywhere in the document set without its interval, including in summary tables and in the abstract.
The secretariat accepts this submission in part. Intervals are added wherever the source reports one. The proposal is declined for figures the source published without an interval, because the Institute will not compute an interval a source did not report.
Every estimate now carries its interval where the source reported one, and where it did not, the estimate is annotated as reported without an interval rather than left to appear as a precise figure.
Nothing addresses the container the material was held in
The respondent submits on the draft of CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for…. Microbiological determinations are the ones whose absence matters most for material that will be injected.
Adsorption to the container and oxidation in the headspace both change what is measured, and both depend on the container rather than on the material. The standard treats the vial as neutral.
The respondent proposes that container type and headspace atmosphere be reported where they are known.
The secretariat accepts the reporting requirement where the information is held and declines to require it where it is not.
Container type and headspace atmosphere are now reported where known, and recorded as not held where they are not, rather than omitted.
The standard specifies how to test a unit and not which units to test
The respondent has read CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for… in draft and makes one submission.
A determination made on a unit chosen by the party being assessed supports a claim about that unit. The draft is precise about the procedure and silent about selection, which is where the inference from unit to batch either holds or fails.
The respondent proposes that the standard state a minimum sampling plan, or, where that is not practicable, require the selection method to be reported with the result.
The secretariat accepts the reporting requirement. A minimum sampling plan is a matter for the party releasing the material.
The selection method is now a required field on every report made under this standard, and the limitations section states that a determination on a selected unit supports no inference about the batch.
Nothing requires the report to state who performed the determination
The respondent notes that CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for… will be cited to support a claim about material presented for injection, and submits with that in view.
The respondent states that certificates in circulation frequently reproduce results generated by a third party without identifying it, and that a reader cannot tell whether the releasing party performed the work.
The respondent proposes that the performing laboratory be a required field.
The secretariat accepts this submission. Attribution of a determination is a precondition of assessing it.
The report now requires the identity of the laboratory that performed the determination, its accreditation status where claimed, and a statement of whether the releasing party is the performing party, with the fields classified as critical.
The reporting threshold is not tied to a demonstrated limit of quantitation
This submission addresses the draft of CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for… from the standpoint of a laboratory that would have to demonstrate conformance with it.
The draft sets a reporting threshold as a fixed percentage. The respondent states that whether a laboratory can quantify at that threshold depends on the signal-to-noise achieved, and that the threshold should be conditional on demonstrating it.
The respondent proposes that a determination be reportable only where the signal-to-noise at the threshold is demonstrated in the run.
The secretariat accepts this submission. A threshold no one has demonstrated is a convention rather than a limit.
The reporting threshold is now conditional on demonstrating the required signal-to-noise at that threshold within the run, and a determination that cannot demonstrate it reports the achievable threshold instead of the nominal one.
Nothing requires a laboratory to demonstrate ongoing performance
The draft of CEI-MS-05, Bacterial endotoxin determination in peptide preparations intended for… was read by a respondent for whom the sample matrix is a routine complication rather than an exceptional one.
The respondent states that suitability criteria assessed within a run demonstrate that the run worked and not that the laboratory performs consistently over time.
The respondent proposes participation in a proficiency scheme as a condition of conformance.
The secretariat accepts this submission in part. A trend requirement on system suitability data is added. Proficiency scheme participation is not made a condition of conformance, for the same reason competence requirements are not.
The standard now requires that system suitability results be trended across runs and that a determination report whether the trend was within the laboratory's stated limits, which places the demonstration inside the document the Institute can read.
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- International Organization for Standardization. ISO/IEC 17025:2017 General Requirements for the Competence of Testing and Calibration Laboratories. ISO/IEC Standard 2017;3rd edition. identifier not held by the Institute
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.