Draft standard CEI-MS-12: Residual solvent determination by… — submissions
The 15 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
15 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 requires the report to state who performed the determination
The respondent has read CEI-MS-12, Residual solvent determination by static headspace gas chromatography in draft and makes one submission.
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.
Absence of evidence is presented in a form a reader will take as negative evidence
The respondent read the draft of CEI-MS-12, Residual solvent determination by static headspace gas 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 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 states how long a prepared standard solution remains usable
This submission concerns CEI-MS-12, Residual solvent determination by static headspace gas chromatography and a convention used across the Institute’s output.
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.
This submission should be read alongside submission 002, which arises on the same draft.
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.
A single method cannot support the conclusion the standard permits
The respondent submits on CEI-MS-12, Residual solvent determination by static headspace gas chromatography, on a matter that is not specific to this draft but is visible in it.
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 respondent has read submission 002 with interest and adds one observation the secretariat may find useful.
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.
A determination does not record the version of the standard it was made under
The respondent’s comment on the draft of CEI-MS-12, Residual solvent determination by static headspace gas chromatography arises from applying it to hygroscopic material in ordinary laboratory conditions.
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.
The additional determinations required would materially increase release testing cost
Having read the draft under consultation, which concerns CEI-MS-12, Residual solvent determination by static headspace gas chromatography, the respondent submits as follows.
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 has read submission 005 and puts a further matter to the secretariat.
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.
A conformance claim is not defined and will be made loosely
The respondent submits on CEI-MS-12, Residual solvent determination by static headspace gas chromatography. The point would apply equally to any document in the series.
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 notes that submission 006 has already been made and confines this submission to a matter not covered by 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.
The standard does not state that a determination on one unit says nothing about the batch
The respondent submits on the draft of CEI-MS-12, Residual solvent determination by static headspace gas chromatography. 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 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.
References should carry a persistent identifier for every cited source
Having read the draft of CEI-MS-12, Residual solvent determination by static headspace gas chromatography, the respondent puts one point to the secretariat.
Several references in the draft carry a journal, a year and a volume but no persistent identifier. The respondent states that retrieval of such a reference is materially slower and that identifiers should be supplied throughout.
The respondent asks in the alternative that where an identifier exists but is not carried, the omission be explained rather than left as a gap the reader must interpret.
Submission 002 raises an adjacent matter. The respondent regards the two as separable and addresses only this one.
The secretariat accepts the second limb of this submission and declines the first. Identifiers are supplied wherever the Institute holds one. Where the Institute does not hold an identifier it will not supply one, because a reconstructed identifier that resolves to the wrong record is a worse defect than an absent one.
Every reference without a persistent identifier now carries an explicit statement that the identifier is not held by the Institute, so that its absence is a recorded fact rather than an apparent oversight.
The standard assumes a reference standard of known assigned content
The respondent notes that a stated vial mass may be substantially counter-ion and water, and submits with that in view.
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.
The search date is not on the face of the document
The respondent has read CEI-MS-12, Residual solvent determination by static headspace gas chromatography and submits on a matter of presentation.
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 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 preparation solvent is not specified and changes what is measured
This submission addresses the draft of CEI-MS-12, Residual solvent determination by static headspace gas chromatography from the standpoint of a laboratory that performs the determination routinely.
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 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.
Terms are used in senses that differ from established pharmacopoeial usage
The respondent submits on CEI-MS-12, Residual solvent determination by static headspace gas chromatography.
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 respondent has read submission 005 with interest and adds one observation the secretariat may find useful.
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.
Results are reported without an estimate of measurement uncertainty
This submission concerns the draft standard CEI-MS-12, Residual solvent determination by static headspace gas chromatography. The respondent’s interest is in mass balance and in what a certificate has to carry before one can be formed.
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.
This submission should be read alongside submission 011, which arises on the same draft.
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 in the standard addresses transfer of the method between laboratories
The draft of CEI-MS-12, Residual solvent determination by static headspace gas chromatography was read from the standpoint of a laboratory that assigns content against a reference material.
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.
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.