Draft standard CEI-MS-06: Sterility testing of peptide… — submissions
The 13 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
13 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.
The standard should state a pass limit
Having read the draft of CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials, the respondent puts one point to the secretariat.
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.
Point estimates are given without an interval
The respondent submits on the draft of CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials. Microbiological determinations are the ones whose absence matters most for material that will be injected.
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.
The standard would be applied more consistently with a worked example
The respondent has read CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials in draft and makes one submission.
The respondent states that the requirement most often misapplied in practice is the one the draft states most briefly, and that a worked calculation would settle it.
The respondent proposes a worked example showing the same data treated correctly and incorrectly, with both results stated.
Submission 002 raises an adjacent matter. The respondent regards the two as separable and addresses only this one.
The secretariat accepts this submission. An example showing only the correct treatment does not show the reader what they are doing wrong.
A worked example is added showing the same primary data treated two ways, with both resulting figures stated and the difference between them quantified, so that the consequence of the misapplication is visible rather than described.
Nothing in the standard addresses transfer of the method between laboratories
The respondent notes that CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials will be cited to support a claim about material presented for injection, and submits with that in view.
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.
Results are reported without an estimate of measurement uncertainty
This submission addresses the draft of CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials from the standpoint of a laboratory that would have to demonstrate conformance with it.
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.
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.
Nothing prevents a chromatogram being reprocessed until it passes
The respondent submits on CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials, 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 respondent notes submission 001 above and does not repeat the ground it covers.
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 document should state what a reader ought to do
The respondent submits on CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials. The point would apply equally to any document in the series.
The draft assesses evidence and stops. The respondent, a practising clinician, states that a reader arriving at the document with a decision to make is left to convert an assessment into an action without help, and proposes that each document close with a recommendation.
The respondent argues that other evidence bodies issue recommendations and that declining to do so transfers the difficult part of the work to the reader.
The secretariat does not accept this submission, and records that the point is a reasonable one rather than a misunderstanding.
The Institute assesses evidence and does not issue recommendations, because a recommendation embeds values and a resource context that the Institute does not hold and cannot state. That constitutional limit is published on the methodology page and is not varied by consultation. The submission remains published in full.
Terms are used in senses that differ from established pharmacopoeial usage
This submission concerns CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials and makes one point.
The respondent identifies three terms used in the draft in senses that differ from their established pharmacopoeial meanings.
The respondent proposes that established usage be followed or that the departure be stated explicitly at first use.
The secretariat accepts this submission. A term used in a private sense inside a document that will be read alongside compendial texts is a source of avoidable error.
The three terms now follow established pharmacopoeial usage, the glossary records the definition and its source, and where the Institute uses a term in a narrower sense the departure is stated at first use in the standard.
The standard does not state that a determination on one unit says nothing about the batch
The respondent read the draft of CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials and has confined this submission to a single requirement.
The respondent states that determinations under this standard are generally performed on a single unit and that certificates then travel with every unit of a batch, so that a single-unit result is routinely read as a batch result.
The respondent proposes that the standard require a sampling statement on the face of every determination.
This submission should be read alongside submission 004, which arises on the same draft.
The secretariat accepts this submission. The inference from unit to batch is the most consequential unstated assumption in supply documentation.
Every determination made under this standard now carries a sampling statement recording how many units were sampled, from what population and by what plan, and the standard states that a determination on a single unit supports no inference about any other unit.
Nothing requires a laboratory to demonstrate ongoing performance
The respondent’s comment on the draft of CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials arises from performing the determination on preparations of this kind.
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 respondent has read submission 002 with interest and adds one observation the secretariat may find useful.
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 submits on CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials.
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 specifies how to test a unit and not which units to test
The respondent has read CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials in draft and makes a single 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.
A field classified as critical is not one a reading turns on
The respondent read CEI-MS-06, Sterility testing of peptide preparations presented in sealed vials in draft. The point applies to it and to the series generally.
The respondent examines the fields classified as critical and states that two of them are administrative rather than interpretive, so that a certificate could be rendered uninterpretable by an omission that changes no reading.
The respondent proposes that a field be classified critical only where its absence changes what the figure means.
Submission 011 concerns the same document. The respondent’s point is a different one.
The secretariat accepts this submission in part. One field is reclassified as recommended on the test the respondent proposes. The second is retained as critical because its absence prevents the determination being attributed to a batch.
The classification test is now stated in the standard: a field is critical where its absence changes the meaning of a reported figure or prevents attribution to a batch. One field has been reclassified under that test and the reasoning recorded.
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.