Draft standard CEI-MS-04: Determination of water content in… — submissions
The 16 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
16 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.
Nothing in the standard addresses transfer of the method between laboratories
This submission concerns CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl… and a convention used across the Institute’s output.
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 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.
Nothing prevents a chromatogram being reprocessed until it passes
The respondent submits on CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl…, on a matter that is not specific to this draft but is visible in it.
Integration parameters can be adjusted after acquisition, and nothing in the draft requires the sequence of processing to be recorded. A result presented as a single determination may be the last of several.
The respondent proposes that the standard require an audit trail of processing, retained with the primary data.
The secretariat accepts the principle and adopts a narrower requirement.
The standard now requires the processing method and its version to be recorded with every result and the primary data to be retained. A full audit trail is recommended and not required, since it depends on software many laboratories in scope do not run.
The standard should require documented operator competence
The respondent’s comment on the draft of CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl… arises from applying it to hygroscopic material in ordinary laboratory conditions.
The respondent states that the determination described requires judgement, particularly at the integration step, and that a competence requirement would improve consistency more than any change to the criteria.
The respondent proposes that conformance be conditional on documented operator training.
The respondent supports submission 001 so far as it goes and adds the matter set out here.
The secretariat does not accept this submission. Operator competence is a quality-system matter governed by accreditation requirements the Institute does not administer and cannot verify.
The standard states performance and remains silent on competence. Where judgement affects the result, as at the integration step, the standard requires the judgement to be recorded rather than the operator to be qualified, which is the part the Institute can check from a report. The submission remains published in full.
Declared interests should appear on the document rather than on a separate page
The respondent submits on CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl….
The draft links to a central conflicts register. The respondent argues that a reader assessing whether to rely on a particular document should not have to leave it to find out who assessed it and what they declared.
The respondent proposes that the interests of every named contributor to a document be printed on that document.
The respondent read submission 003 after drafting this one and has not altered it, the two points being distinct.
The secretariat notes this submission and records that the draft already provides for it, which the respondent could reasonably have missed because the provision sits in an appendix.
Every document carries the declared interests of its named contributors in its front matter, and the central register exists so that a reader can see a person across all documents rather than one at a time. No amendment arises; the provision has been moved from the appendix into the body of the methodology document so that it is findable.
Nothing requires a laboratory to demonstrate ongoing performance
The draft of CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl… was read from the standpoint of a laboratory that assigns content against a reference material.
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.
Submission 001 concerns the same document. The respondent’s point is a different one.
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.
A superseded version should remain reachable from the version that replaced it
The respondent read the draft of CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl… and has confined this submission to a single requirement.
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.
Acceptance criteria are expressed in terms specific to one instrument family
The respondent has read CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl… and submits on a matter of presentation.
The respondent states that two criteria are expressed in units reported by one manufacturer's software and not by others, which makes conformance a function of the instrument rather than of the determination.
The respondent proposes that criteria be expressed in instrument-independent quantities.
The secretariat accepts this submission in part. Both criteria are restated in instrument-independent terms. The conversion from the manufacturer-specific quantity is given rather than removed, because laboratories will continue to read it from their software.
The acceptance criteria are now expressed in instrument-independent quantities, with the conversion from the common manufacturer-specific reporting units given in a note so that a laboratory can check conformance without recalculating by hand.
The standard assumes a reference standard of known assigned content
This submission addresses the draft of CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl… from the standpoint of a laboratory that performs the determination routinely.
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.
This point is adjacent to the one made in submission 002 and the respondent puts it in a form the secretariat can act on.
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.
The draft prescribes a procedure where it should state performance
This submission concerns the draft standard CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl…. The respondent’s interest is in mass balance and in what a certificate has to carry before one can be formed.
Several clauses specify a gradient, a column chemistry and a temperature. The respondent states that fixing these prevents a laboratory from using a validated equivalent, and that the Institute settled on stating performance when it scoped the series.
The respondent proposes that the prescriptive clauses be converted into performance requirements with the prescribed conditions retained as a worked example.
The secretariat accepts this submission. The draft departed from the position settled when the series was scoped, and the departure was not deliberate.
The prescriptive clauses are converted to performance requirements, the specific conditions are retained as a worked example clearly labelled as one, and a laboratory using a different validated procedure that meets the stated performance reports a conformant determination.
A system suitability criterion is unachievable on instrumentation in general use
The respondent notes that a stated vial mass may be substantially counter-ion and water, and submits with that in view.
The respondent, employed by a contract analytical laboratory, states that one of the suitability criteria in the draft can be met only on current-generation instrumentation, and that laboratories operating validated older systems would be unable to report a conformant determination.
Data from three instruments of different generations, showing the criterion met on one and missed on two, accompanied the submission.
This submission is made in the same spirit as submission 001 and on a different aspect of the draft.
The secretariat accepts this submission in part. The criterion is relaxed to the level the supplied data support for the general case, and retained at the stricter level for the specific discrimination that motivated it.
The suitability criterion is now stated at two levels, a general level achievable on instrumentation in common use and a stricter level required only where the standard is applied to the discrimination named in the scope, with the reason for the difference stated.
Nothing states how long a prepared standard solution remains usable
This is a submission on CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl….
The procedure requires a reference solution and does not say for how long it may be used. Peptide solutions at working concentration lose material to surfaces and to hydrolysis, and a solution used for a week will bias every result obtained against it in the same direction.
The respondent proposes that the standard require solution stability to be demonstrated over the period of use, or that a maximum period be stated.
The secretariat accepts this submission. A systematic bias applied uniformly to a sequence is the hardest kind to notice.
The procedure now requires solution stability to be demonstrated over the period of intended use, and the demonstration to be recorded with the result.
Quantitative claims are reproduced without the method that produced them
Having read the draft of CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl…, the respondent puts one point to the secretariat.
Several figures in the draft are quoted from sources that determined them by different methods. A figure obtained by one determination and a figure obtained by another are not comparable, and the draft places them in the same sentence without distinguishing them.
The respondent, an analytical chemist, proposes that every quantitative claim carry the method that produced it at the point of use rather than in the reference.
The secretariat accepts this submission. Placing two figures side by side is an implicit claim that they are the same kind of quantity, and in the cases identified they were not.
Every quantitative claim now carries the determination that produced it at the point of use, and figures obtained by non-comparable methods are no longer presented in the same row or sentence.
Results are reported without an estimate of measurement uncertainty
The respondent read CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl… in draft. The point applies to it and to the series generally.
The respondent, an analytical chemist, states that a figure reported to one decimal place implies an uncertainty the standard nowhere estimates, and that two determinations differing within the uncertainty will be read as a difference.
The respondent proposes that an uncertainty budget be required for every determination.
Submission 004 raises an adjacent matter. The respondent regards the two as separable and addresses only this one.
The secretariat accepts this submission in part. A repeatability figure and a stated reporting precision are required. A full uncertainty budget is not, because the standard is written to be usable by laboratories that do not maintain one and the requirement would exclude them without improving the reading.
Every determination now reports the repeatability observed in the run, the reporting precision, and a statement that two results differing by less than the stated repeatability are not distinguishable by this method.
The standard should state a pass limit
The respondent submits on the draft of CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl…. Content is the determination that turns a purity percentage into a mass of peptide, and it is the determination most often absent from a certificate.
The respondent states that a standard which reports a figure without a limit leaves the reader without a criterion, and that suppliers will set their own.
The respondent proposes a universal acceptance limit for the determination.
The secretariat does not accept this submission. An appropriate limit depends on the compound, the presentation and the intended route, none of which the standard fixes.
The standard states performance and reports the figure as determined. Setting a universal limit would attach a pass or fail to materials whose acceptable ranges genuinely differ, which would be a stronger claim than the Institute can support. The submission remains published in full and the point is recorded in the limitations.
A single method cannot support the conclusion the standard permits
Having read the draft under consultation, which concerns CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl…, the respondent submits as follows.
The respondent states that species invisible to this determination will not appear in the result, and that a conclusion about the material as a whole requires an orthogonal method.
The respondent proposes that an orthogonal determination be mandatory.
This point is adjacent to the one made in submission 002 and the respondent puts it in a form the secretariat can act on.
The secretariat accepts this submission in part. An orthogonal determination is required where a conclusion about the material as a whole is to be drawn. It is not required where the standard is used to report the quantity it measures.
The standard now distinguishes a determination of the measured quantity, which stands alone, from a conclusion about the material, which requires a named orthogonal determination, and states that the second claim made on the strength of the first alone is not conformant.
The preparation solvent is not specified and changes what is measured
The respondent has read CEI-MS-04, Determination of water content in lyophilised peptides by coulometric Karl… in draft and makes one submission.
Material that has aggregated will dissolve to different extents in different solvents, so a preparation in one solvent can report a purity that a preparation in another does not reproduce, on the same vial.
The respondent proposes that the preparation solvent be specified rather than left to the laboratory.
The respondent notes submission 008 above and does not repeat the ground it covers.
The secretariat accepts the reporting requirement and declines to specify a single solvent across all materials in scope.
The preparation solvent is now a required reporting field and the procedure names an acceptable range. Specifying one solvent for every material in scope would exclude compounds the standard is intended to cover.
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.