Draft standard CEI-MS-11: Determination of aggregate content… — 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.
The standard does not require retention of the primary data
The respondent submits on CEI-MS-11, Determination of aggregate content by size-exclusion chromatography, on a matter that is not specific to this draft but is visible in it.
The respondent states that a reported figure cannot be checked without the chromatogram or spectrum from which it was derived, and that the draft requires only the figure.
The respondent proposes a retention requirement with a stated period.
The secretariat notes this submission. Retention is addressed in the certificate-of-analysis minimum data standard, which requires that primary data be retained and be identifiable from the certificate, and which applies to every determination reported on a certificate.
No amendment arises. The requirement exists in the standard that governs reporting rather than in each determination standard, and the cross-reference has been added here so that a reader working from this document alone can find it.
A determination does not record the version of the standard it was made under
This submission addresses the draft of CEI-MS-11, Determination of aggregate content by size-exclusion chromatography from the standpoint of a reader who will act on a result produced under it.
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 respondent has read submission 001 with interest and adds one observation the secretariat may find useful.
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.
The matrix interferes with the determination and no control is required
Having read the draft of CEI-MS-11, Determination of aggregate content by size-exclusion chromatography, the respondent puts one point to the secretariat.
The respondent states that the matrices in scope can suppress or enhance the response, and that without an inhibition and enhancement control a result cannot be attributed to the analyte.
Data showing recovery outside acceptable limits in an uncontrolled matrix accompanied the submission.
The secretariat accepts this submission. A determination on an interfering matrix without a validated control establishes nothing, and the draft permitted one.
An inhibition and enhancement control is now required for every determination under this standard, with stated recovery limits, and a determination reported without it is recorded as not conformant rather than as a low result.
The standard assumes a reference standard of known assigned content
The draft of CEI-MS-11, Determination of aggregate content by size-exclusion chromatography was read from the standpoint of a laboratory reconstituting material for analysis.
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.
Point estimates are given without an interval
The respondent submits on the draft of CEI-MS-11, Determination of aggregate content by size-exclusion chromatography. A physical-quality attribute is informative and routinely left unreported, and a standard that makes one routine is worth having.
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 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 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 additional determinations required would materially increase release testing cost
The respondent notes that CEI-MS-11, Determination of aggregate content by size-exclusion chromatography will be applied to lyophilised material whose appearance changes on storage, and submits with that in view.
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 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.
The standard does not state that a determination on one unit says nothing about the batch
The respondent has read CEI-MS-11, Determination of aggregate content by size-exclusion chromatography in draft and makes one submission.
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.
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 in the standard addresses transfer of the method between laboratories
This is a submission on the draft of CEI-MS-11, Determination of aggregate content by size-exclusion chromatography, made by a respondent who applies comparable procedures daily.
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.
Rounding conventions are not stated and change the reported result
The respondent has read CEI-MS-11, Determination of aggregate content by size-exclusion chromatography and submits on a matter of presentation.
The respondent states that the draft reports figures to varying precision and does not specify when rounding occurs in the calculation chain, which can move a result across an acceptance limit.
The respondent proposes that rounding occur only at the reporting step and that the convention be stated.
The secretariat accepts this submission. Intermediate rounding is a silent source of disagreement between laboratories analysing the same material.
The standard now requires that no rounding be applied before the reporting step, states the reporting precision for each quantity, and states the rounding convention used at that step.
Nothing requires a laboratory to demonstrate ongoing performance
This submission concerns CEI-MS-11, Determination of aggregate content by size-exclusion chromatography and a convention used across the Institute’s output.
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.
Absence of evidence is presented in a form a reader will take as negative evidence
The respondent read the draft of CEI-MS-11, Determination of aggregate content by size-exclusion chromatography and has confined this submission to a single requirement.
Where the Institute has identified no study, the draft states that no evidence was found. In several places that sentence sits immediately after a paragraph describing an adverse outcome, and the juxtaposition invites the reading that the compound was studied and found wanting.
The respondent proposes a standing formulation, used identically wherever the situation arises, distinguishing an outcome that was studied and not demonstrated from an outcome that has not been studied at all.
The respondent endorses the general approach taken in submission 001 and asks that it be extended to the matter identified here.
The secretariat accepts this submission. The two states are different, they support different decisions, and the draft rendered them in language a reader could not reliably separate.
A standing formulation has been adopted and is applied wherever an evidence gap is recorded, distinguishing an outcome assessed and not demonstrated from an outcome not assessed. The formulation is identical at every occurrence so that it can be recognised at a glance.
Nothing addresses the container the material was held in
The respondent’s comment on the draft of CEI-MS-11, Determination of aggregate content by size-exclusion chromatography arises from performing examinations of this kind in a pharmacy setting.
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.
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.