Draft standard CEI-MS-07: Sub-visible particulate matter in… — 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 additional determinations required would materially increase release testing cost
The respondent read the draft of CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions and has confined this submission to a single requirement.
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 require retention of the primary data
This submission addresses the draft of CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions from the standpoint of a reader who will act on a result produced under 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.
The scope does not say which materials the standard excludes
This is a submission on the draft of CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions, made by a respondent who applies comparable procedures daily.
The scope states what the standard applies to. The respondent states that in practice the difficult question is whether a borderline material is in scope, and that the draft leaves it to be inferred.
The respondent proposes an explicit exclusion list.
The secretariat accepts this submission. A scope stated only positively is a scope that will be stretched.
The scope now states both what the standard applies to and what it does not, with the excluded classes named and, where another standard covers them, cross-referenced.
Absence of evidence is presented in a form a reader will take as negative evidence
The respondent submits on CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions.
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 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.
The standard should state a pass limit
The respondent’s comment on the draft of CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions arises from performing examinations of this kind in a pharmacy setting.
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.
The standard assumes a reference standard of known assigned content
Having read the draft of CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions, the respondent puts one point to the secretariat.
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 single determination is permitted where duplicates would be inexpensive
The respondent notes that CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions will be applied to lyophilised material whose appearance changes on storage, and submits with that in view.
The respondent states that the draft permits a result to be reported from one injection, and that the marginal cost of a duplicate is small relative to the value of detecting a preparation error.
The respondent proposes that duplicate determinations be mandatory.
The secretariat accepts this submission in part. Duplicate preparation and injection are required, and a criterion for agreement between them is stated. The proposal to require full duplicate sample preparation on separate days is declined as disproportionate.
The standard now requires duplicate preparation and injection with a stated maximum difference between the two, and requires that a difference exceeding it be investigated before any figure is reported.
The search date is not on the face of the document
The respondent has read CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions in draft and makes one submission.
The draft carries a publication date and a review date but not the date on which the evidence was last searched. Those are three different dates and only the third tells a reader how current the assessment is. A document published in one quarter may rest on a search run two quarters earlier, and nothing on the page allows that gap to be measured.
The respondent proposes that the search date be printed adjacent to every certainty rating rather than in the methods section, on the ground that a reader who acts on a rating is unlikely to have read the methods section first.
The respondent notes submission 004 above and does not repeat the ground it covers.
The secretariat accepts this submission. The distinction between publication, review and search dates is real and the draft did not make it visible where it mattered.
The search date is now printed adjacent to every certainty rating and is carried in the document metadata, so that the interval between the search and the reading is visible without reference to the methods section.
The standard should require documented operator competence
The respondent submits on CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions. The point would apply equally to any document in the series.
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 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.
Nothing requires a laboratory to demonstrate ongoing performance
The respondent submits on the draft of CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions. A physical-quality attribute is informative and routinely left unreported, and a standard that makes one routine is worth having.
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’s submission overlaps with submission 004 and was prepared without sight of it.
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 conformance claim is not defined and will be made loosely
This is a submission on CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions.
The respondent states that the draft nowhere defines what it means for a determination to conform, and that in the absence of a definition the phrase will be applied to determinations that meet some of the requirements.
The respondent proposes an explicit definition and a requirement that partial conformance be described as such.
The respondent has read submission 009 above and makes this submission independently of it.
The secretariat accepts this submission. An undefined conformance claim is a marketing phrase.
Conformance is now defined as meeting every requirement classified as critical together with the stated system suitability criteria, partial conformance must be described by naming the requirements not met, and a claim of conformance made without the sampling statement is not conformant.
A single method cannot support the conclusion the standard permits
Having read the draft under consultation, which concerns CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions, 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.
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 matrix interferes with the determination and no control is required
The draft of CEI-MS-07, Sub-visible particulate matter in reconstituted peptide solutions was read from the standpoint of a laboratory reconstituting material for analysis.
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.
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.