Last updated 2026-09-01in-progress
SGL-001 Specification
Every SGL-001 parameter with its value, the evidence behind it, a confidence rating, and the question still open. Three prior conflicts with the product site are now resolved; storage and shelf life remain unpublished.
Conflicts
sgl001.signal.clinic (fetched 2026-09-01 — spray.signal.clinic now redirects here) still doesn't publish a storage condition or shelf life, for a product format that makes both unusually hard to get right.
No storage temperature and no shelf life are published anywhere on the current site. See the storage and shelf-life rows below: the consensus storage condition for EVs is −80°C, a single freeze-thaw cycle costs 23–36% of particles, and the one human trial's batches were valid for 30 days. Silence on this point is not a neutral omission; it is the parameter most likely to decide whether the product works at the point of administration.
Per the map's standing rule, this is not resolved in Signal's favour, and it is not softened. What Signal does about its own site is the operator's call.
Resolved since the last check (2026-08-27 → 2026-09-01)
The product site — now at sgl001.signal.clinic, spray.signal.clinic redirects here as of this check — was updated between the two dates below. Three of the four conflicts this artifact previously recorded no longer hold, verified directly against the live page on 2026-09-01. Recorded here rather than deleted, per this repo's standing rule against silently overwriting a prior finding.
1. Container arithmetic — resolved. The site previously read 100 Doses / bottle, which combined with 100 µL per dose and a 10 mL bottle left no room for priming or dead volume: 100 × 100 µL = 10.0 mL exactly, and a non-pressurised multiple-dose metered spray cannot deliver 100% of its fill (EMA/CHMP/QWP/49313/2005 §4.5.1.13, Table 4.2.2). The site now reads Multiple / Metered doses / bottle — no specific count is published. The self-contradiction this created no longer arises, because the site no longer asserts the figure that created it. This doesn't answer the underlying regulatory question — a real dose count will still have to reconcile with fill volume and priming loss once one is published — only that the site's current text doesn't self-contradict.
2. The published dose is now labelled a target, not a specification — resolved as a conflict, kept as an open scientific question. The site now states, verbatim, on its science page: "Target dose (in development): 5×10⁹ exosomes per 100 µL spray. This design target is not a validated specification or derived from human data." The homepage labels the same figure Target dose (in development). This was previously recorded as a conflict because the site asserted 5×10⁹ as if it were the product's settled dose; it no longer does, and its own disclaimer now says so.
The honest note stays, because the site's disclaimer doesn't change the arithmetic. 5×10⁹ is still 6.25× the highest dose given in the only human intranasal EV trial (NCT04388982 / Xie et al. 2023: 8×10⁸ particles, n=9, uncontrolled), and 62.5× its concentration (5×10¹⁰ particles/mL vs. that trial's 8×10⁸ particles/mL). That comparison is what the Specification table's confidence rating for this parameter rests on below — it is now a note on an acknowledged development target, not a conflict with Signal's own materials.
3. "0.22 µm filtration" is now labelled a process step, not a quality attribute — resolved. The site previously listed 0.22 µm Sterile filtration alongside the dose and format figures as if it were a release specification. It now reads 0.22 µm filtered / Process — explicitly labelled as a process step, not a quality attribute. The underlying gap is unchanged and stays open in the Specification table's Analytics row below: no sterility test result, endotoxin limit, mycoplasma result, or particle-count method is published. Only the mislabeling is resolved.
Specification
Confidence key: high = direct human evidence for this product; moderate = human evidence for the class, or a hard regulatory/physical constraint; low = derived, scaled, or inferred; none = no basis found.
| Parameter | Value | Basis | Confidence | Open question |
|---|---|---|---|---|
| Particle count per dose | 5×10⁹ particles / dose, published on sgl001.signal.clinic as a stated development target, not adopted here as a spec — the site itself now says "This design target is not a validated specification or derived from human data" (see Resolved §2). | Site's own disclaimer, fetched 2026-09-01. The only human intranasal anchor is Xie et al. 2023 / NCT04388982: 2×10⁸, 4×10⁸, 8×10⁸ particles per administration, n=3 per arm, open-label, no control; authors concluded "a dose of at least 4×10⁸ particles could be selected for further clinical trials." 5×10⁹ is 6.25× the top arm. | low — the target has no stated derivation; the class anchor it exceeds is itself n=9 and unblinded | On what evidence was 5×10⁹ selected as the development target? If it was scaled from a rodent study, from which one, at what body-weight assumption? Allometric scaling from a 25–30 g mouse is not arithmetic, and no intranasal EV dose-ranging study in humans has been run above 8×10⁸. |
| Particle concentration | 5×10¹⁰ particles/mL (derived from 5×10⁹ / 100 µL) | Arithmetic on the two published figures. Comparator: 8×10⁸/mL in the Xie trial — 62.5× lower. | low | EV preparations aggregate at high concentration; trehalose is used specifically because it "narrows the particle size distribution" and prevents freeze-induced aggregation (Bosch et al. 2016). Has aggregation been measured at 5×10¹⁰/mL, and does the size distribution still meet a 30–150 nm claim at that concentration? |
| Doses per container | Open. Site now states Multiple metered doses / 10 mL bottle — no number published (previously "100 doses," which didn't reconcile with the stated fill; see Resolved §1). |
Fetched 2026-09-01. EMA/CHMP/QWP/49313/2005 §4.5.1.13 requires actuations per container ≥ label; Table 4.2.2 requires minimum-fill justification and priming/re-priming studies for this dosage form — none of that is affected by whether a number is published. | none — no dose count is currently published to evaluate | Whatever dose count is eventually published will need to reconcile with the 10 mL fill and 100 µL dose volume the same way the withdrawn "100 doses" figure didn't. |
| Dose volume per nostril | Open. Published as "100 µL" per dose, without stating whether that is per nostril or per administration. | 100 µL is squarely inside normal metered nasal pump range (Aptar UDS: metered dose "up to 100 µL"; Bidose: 100 µL per actuation, 200 µL per device). Clinical ceiling: ENA Clinical Practice Guideline on Intranasal Medication Administration — "The ideal volume for intranasal medication administration is 0.2–0.3 mL per nare," and "volumes greater than 1 mL per nare are not reliably absorbed and often result in medication runoff." Xie et al. used 1 mL per administration, sprayed "about once a minute for 10 min" alternating nostrils — a slow split instillation, not a single bolus. | moderate on the ceiling, none on which convention the published figure uses | Is 100 µL one actuation into one nostril, or the total across both? The two readings differ 2× in delivered dose. Separately: the volume ceiling is why the concentration has to be extreme — you cannot buy particle count with volume here, only with concentration, and concentration is where aggregation lives. |
| Fraction reaching the olfactory region | Open — and the constraint the "nose to brain" framing rests on. | Xi et al. 2016, four nasal spray pumps in an MRI-based sectional adult nasal cast: "the majority of nasal spray droplets deposited in the anterior nose while only a small fraction (less than 4.6%) reached the olfactory region," concluding "standard nasal devices are inadequate to deliver clinically significant olfactory dosages." Seifelnasr et al. 2023 reached 22.7 ± 3.7% olfactory deposition only under optimised conditions: head tilted 45–60°, nozzle 5–10°, two doses, no inhalation flow. | moderate (in vitro casts, not in vivo human imaging) | With a standard metered spray and no positioning protocol, the delivered olfactory dose may be under 5% of the labelled dose. Is there an administration protocol (head position, nozzle angle, breath-hold) attached to the product, and is it in the physician instructions? Positioning is part of the dose. |
| Source cell line and passage | Open. | Not published. Class precedent: Xie et al. used allogeneic human adipose MSCs from "healthy young adult donors'" liposuction tissue, manufactured in cGMP-compliant labs. Passage limits are not specified in that trial, and the EV-manufacturing review cited in cdmo-readiness.md (Thakur & Rai 2024) does not give numerical passage thresholds either — it states only that engineered cell lines "provide a better opportunity for scale up and reproducibility." |
none | Cell type, tissue source, donor traceability, master/working cell bank status, and a passage ceiling with a stated senescence justification. This is question 1 on the CDMO readiness list and remains unanswered. |
| Isolation method | Open. | Not published. Xie et al. used "precipitation and ultracentrifugation... with polyethylene glycol applied for the enrichment," reporting a yield of 3×10¹⁰–5×10¹⁰ nanoparticles from 500 mL conditioned medium. | none | Which method, and what is the yield per litre of conditioned medium? At the trial's yield, a bottle at the previously-published (now withdrawn, see Resolved §1) 100-dose figure would need 5.0–8.3 L of conditioned medium at 100% downstream recovery — before any loss to filtration, concentration or fill; real recovery is well below 100%, so the true figure is higher even at that dose count. Whatever dose count is eventually published, this conditioned-medium-per-bottle number, not the per-dose figure, is what sets batch cost. |
| Filtration | 0.22 µm filtration, published on sgl001.signal.clinic and now explicitly labelled Process, not a quality attribute (see Resolved §3) |
Fetched 2026-09-01. Standard for EV preparations, since most EVs are 20–150 nm and pass a 0.2 µm membrane. But sterilising-grade membranes are rated at 0.2 µm against a particle population overlapping that rating, so loss is expected and must be quantified. | low | What is the measured particle recovery across the filtration step? No sterility test result, endotoxin limit, or other release assay is published — an unmeasured-loss filtration step makes every upstream particle-count figure unverifiable at the point of fill. |
| Excipients and buffer | Open. | Not published. Xie et al. used saline, composition unstated. Evidence for doing better: 25 mM trehalose in the isolation and storage buffer "narrows the particle size distribution and increases the number of individual particles per microgram of protein," and prevents the freeze-thaw–induced aggregation seen in PBS alone (Bosch et al. 2016, Sci Rep 6:36162). A 50-study systematic review found "no variations... in EV concentration following storage for up to one year at −80 °C supplemented with trehalose." | low (class evidence is good; nothing is fixed for this product) | Is there a cryoprotectant/stabiliser in the formulation at all? For a multi-dose container there is a second, separate question: an antimicrobial preservative. EMA Table 4.5.2.1 makes preservative content a release test for multiple-use metered nasal sprays where a preservative is present — and preservatives are membrane-active, which is a direct formulation risk for lipid vesicles. |
| Storage temperature | Open. Evidence supports −80°C; no published value. | Systematic review of 50 studies (Ahmadian et al. 2024, Stem Cell Res Ther 15:453): −80°C is the consensus long-term condition; −20°C showed up to "90% loss" over 26 weeks in one report; 4°C is viable "up to 1 week"; at 37°C EVs lose "all their bioactivity after just four days." Xie et al. shipped on dry ice and stored at −80°C, thawing at room temperature before use. | moderate for the class, none for this product | −80°C storage and a 100-dose in-clinic bottle are hard to hold simultaneously. What is the actual storage condition, and what is the in-use condition once a bottle is thawed and opened? |
| Shelf life | Open. No published value. | Only human anchor: Xie et al. report their batches "remained valid for 30 days." Freeze-thaw is the dominant destructive variable — a single cycle costs 23–36% of particles, three cycles 37–43% (Ahmadian et al. 2024). | low | Shelf life at the storage condition, and in-use shelf life after first actuation, are two different numbers and neither is published. For a multi-dose container the in-use number is the binding one: it determines how many of the bottle's doses are still on-specification when given — whatever the eventual dose count turns out to be (see Doses per container, above, currently unpublished). Stability, not potency, is what decides whether this format is viable. |
| Container and device | Open beyond format. Published: "10 mL · METERED SPRAY", intranasal. | Published format only; no device manufacturer, actuation volume tolerance, pump type, spray pattern, or plume geometry. Comparable qualified platforms exist (Aptar UDS unidose, up to 100 µL; Aptar Bidose, 2 × 100 µL with 25 µL/shot overfill) but these are single- and two-dose devices — the opposite architecture to a 100-dose bottle. | low | A multi-dose metered nasal spray is a single-patient device; a multi-dose bottle used across a clinic's patients is a cross-contamination question before it is a stability question. Is one bottle one patient? At the Xie schedule (2×/week, 12 weeks = 24 administrations), whatever dose count the bottle eventually publishes will determine how many courses one bottle spans — at the previously-published, now-withdrawn 100-dose figure it would have been roughly four. |
| Analytics on every lot | Open. Nothing published. | The applicable release set is the union of two regimes. (a) Nasal dosage form — EMA Table 4.5.2.1 for non-pressurised multiple-use metered dose sprays: description, assay, mean delivered dose, delivered dose uniformity, microbial/microbiological limits, sterility (if sterile), preservative content (if present), number of actuations per container, and particle/droplet size distribution — with the guideline requiring that "the vast majority of the particles / droplets are larger than 10 microns" to show deposition is localised in the nasal cavity. (b) EV product — the only human-trial precedent, Xie et al.: TEM morphology, NTA with ">80% of the particles... between 30 and 160 nm", CD63⁺/CD81⁺/CD9⁺/TSG101⁺ and calnexin⁻ by western blot, sterility negative, endotoxin < 100 EU/mL, mycoplasma negative. Reporting conventions follow MISEV2023 (Welsh et al. 2024, J Extracell Vesicles 13:e12404). | moderate — the required set is well defined by primary regulator guidance; none for what SGL-001 actually runs | Two distinct droplet populations are in tension: the nasal guideline wants droplets >10 µm to keep deposition nasal rather than pulmonary, while the EV specification is about 30–160 nm vesicles inside those droplets. Both must be measured; they are not the same test. And there is still no potency assay in either regime — the "Signal Index" is a marketed cognitive score, not a lot-release measurement. |
Derived figures
Stated separately because they are arithmetic on published numbers, not measurements, and each carries an explicit assumption.
Three rows below depend on the "100 doses per bottle" figure the site published as of 2026-08-27. That figure is no longer published — see Resolved §1 — so these three rows no longer compute from a current site figure. Kept for the historical record rather than deleted, marked accordingly. The remaining two rows depend only on the per-dose figure (5×10⁹, still published as a development target) and are unaffected.
| Figure | Value | Working | Assumption |
|---|---|---|---|
| Particles per bottle (superseded — depended on the withdrawn "100 doses" figure) | 5×10¹¹ | 100 doses × 5×10⁹ | Both were published 2026-08-27; the dose count no longer is |
| Bottle vs. the full published human course (superseded, same reason) | 26× | 5×10¹¹ ÷ (24 administrations × 8×10⁸) | As above |
| One dose vs. that full course | 26% | 5×10⁹ ÷ 1.92×10¹⁰ | Compared against the highest arm of NCT04388982 across all 24 administrations — depends only on the per-dose figure, still current |
| Conditioned medium per bottle (superseded — depended on the withdrawn "100 doses" figure) | 5.0–8.3 L | 5×10¹¹ ÷ (3–5×10¹⁰ per 500 mL) | Xie et al.'s reported yield; 100% downstream recovery, which is not achievable — treat as a floor |
| Delivered olfactory dose per 5×10⁹ dose, standard spray | < 2.3×10⁸ particles | 5×10⁹ × <4.6% | Xi et al. 2016 cast data with standard spray pumps and no positioning protocol; in vitro, not in vivo — depends only on the per-dose figure, still current |
The two current rows are worth sitting with: a single dose already contains a quarter of the cumulative particles the only human trial's highest arm received across its full 12-week course, and under standard administration the fraction of a labelled dose that actually reaches the olfactory region may be smaller than the entire labelled dose of that trial's lowest arm. Neither depends on a bottle-level figure the site no longer publishes.
Sources consulted
Primary sources, fetched or extracted directly this run.
- NCT04388982, ClinicalTrials.gov registry record — Ruijin Hospital, phase I/II, intranasal allogeneic adipose MSC exosomes in mild-to-moderate Alzheimer's disease. Registry lists doses as 5/10/20 µg in 1 mL; the publication reports the same arms in particles (2/4/8 ×10⁸). The unit mismatch between a registry entry and its own publication is itself worth noting.
- Xie X, et al. "Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer's disease: a phase I/II clinical trial." Gen Psychiatr. 2023;36(5):e101143. PMC10582850. n=9, open-label, no control arm; authors' own stated limitations include small sample size, absence of blinding, and that the maximum tolerated dose was not determined.
- EMA/CHMP/QWP/49313/2005 Corr, "Guideline on the pharmaceutical quality of inhalation and nasal products" — CHMP, adopted 23 March 2006, in effect 1 October 2006, harmonised with Health Canada. PDF pulled and parsed directly; Tables 4.2.2 and 4.5.2.1 and §§4.5.1.13, 4.5.2.1 quoted above.
- Xi J, Yuan JE, Zhang Y, Nevorski D, Wang Z, Zhou Y. "Visualization and Quantification of Nasal and Olfactory Deposition in a Sectional Adult Nasal Airway Cast." Pharm Res. 2016;33(6):1527–41. doi:10.1007/s11095-016-1896-2 (abstract retrieved via NCBI E-utilities).
- Seifelnasr A, Si XA, Xi J. "Visualization and Estimation of Nasal Spray Delivery to Olfactory Mucosa in an Image-Based Transparent Nasal Model." Pharmaceutics. 2023;15(6):1657. doi:10.3390/pharmaceutics15061657.
- Ahmadian S, et al. "Different storage and freezing protocols for extracellular vesicles: a systematic review." Stem Cell Res Ther. 2024;15:453. doi:10.1186/s13287-024-04005-7 (50 studies).
- Bosch S, et al. "Trehalose prevents aggregation of exosomes and cryodamage." Sci Rep. 2016;6:36162. doi:10.1038/srep36162.
- Gänger S, Schindowski K. "Tailoring Formulations for Intranasal Nose-to-Brain Delivery." Pharmaceutics. 2018;10(3):116. doi:10.3390/pharmaceutics10030116 — "On average nasal mucus is cleared every 10 to 20 min."
- Emergency Nurses Association, Clinical Practice Guideline: Intranasal Medication Administration (PDF parsed directly) — volume-per-nare limits quoted above.
- Welsh JA, et al. "Minimal information for studies of extracellular vesicles (MISEV2023)." J Extracell Vesicles. 2024;13:e12404. doi:10.1002/jev2.12404 — cited for reporting convention. The publisher's full text returned HTTP 403 and the PMC copy did not surface the marker-category tables; the specific category numbering was not verified this run and is not relied on above.
- Aptar Unidose (UDS) and Bidose (BDS) nasal spray system product pages — device volumes, as a reference point only; no device is specified for SGL-001.
spray.signal.clinic, fetched independently 2026-08-27 over HTTP/1.1. Published product figures quoted verbatim in the original Conflicts findings, now recorded under Resolved.sgl001.signal.clinic(homepage and/science), fetched 2026-09-01 — spray.signal.clinic now redirects here. Current published figures quoted verbatim above; this is the fetch behind the Resolved section and the current values in the Specification table.
Provenance
Input status. This agent's brief directs it to read
artifacts/evidence-base.md and artifacts/dose-landscape.md. Neither
exists — the literature agent has not run. Every dose figure below was
therefore sourced directly from the trial registry and the primary
publication by this agent, and should be re-checked against the dose
landscape once it exists. That is a gap in the inputs, not a substitute
for them.
Run history
- 2026-09-01Confirmed all three resolved on the live site; moved them to a new Resolved section and fixed three downstream table cells and the Derived-figures table that depended on the now-withdrawn '100 doses' figure. Storage and shelf life remain the one open conflict.
- 2026-08-27Artifact created; found that several published product numbers do not reconcile with each other or with precedent.