ATDS 2026

For a consumer topical product, excessive full-thickness permeation may increase unnecessary systemic exposure and may depart from the intended cosmetic use. ATDS prioritizes: measurable deposition at the target site; a local biological response consistent with the proposed mechanism; a permitted consumer-relevant human endpoint; and minimization of unnecessary systemic exposure. Passage into systemic circulation is a success endpoint only when systemic action is intended and legally permitted for the product category.

Chapter 3. Skin and Follicular Barriers: The Physical Basis of Delivery Design

3.1 The “Brick-and-Mortar” Stratum Corneum

Corneocytes and the surrounding lipid matrix create the principal diffusion barrier. Molecules may enter skin through intercellular, transcellular, and appendageal pathways. The contribution of each route depends on molecular mass, lipophilicity, ionization, solubility, thermodynamic activity, and formulation behavior including evaporation, film formation, hydration, and interactions with skin lipids.

A higher formulation concentration does not necessarily produce a higher flux. Delivery may be limited if an active remains too stably associated with a carrier or matrix, crystallizes after exceeding solubility, degrades on the surface, or is tested with a receptor medium that fails to maintain sink conditions.

3.2 Hair Follicles as Both Pathway and Reservoir

Follicular openings occupy a small fraction of the skin surface but can provide shunt pathways and local reservoirs. The original work of Lademann and colleagues showed that particles can deposit deeply and persist within follicles under specific conditions. [14] This supports the rationale for follicular targeting; it does not establish that every nanoparticle reaches living structures deep in a follicle or that its cargo is released and taken up by target cells.

At minimum, ATDS distinguishes three observations: formulation or particles at the follicular opening or infundibulum; continued movement of an intact carrier into a deeper follicular region; and release of cargo into the target tissue. A lipophilic fluorescence signal alone cannot establish the latter two.

3.3 Facial, Scalp, and Body Skin Are Not Interchangeable

Skin thickness, follicular density, sebum, barrier integrity, and use behavior vary by anatomical site. Data from excised abdominal or back skin cannot be assumed to represent scalp. Depilation, shaving, and cleaning may damage the barrier. A study should report the test site, tissue source, thickness, storage and freeze-thaw history, integrity screening, and relevant donor demographics. [3]

3.4 Use Behavior Is Part of the Dose System

Actual delivery is affected by applied dose, massage, residence time, washing, layering with other products, temperature, humidity, and repeated use. OECD TG 428 requires application conditions that simulate human exposure and provides commonly used finite-dose ranges for solids and liquids as methodological references. [1] Each ATDS protocol should explain how the test dose relates to expected consumer use. Infinite-dose conditions must not be used solely to create a more favorable result.

Chapter 4. Technology Landscape and State of the Evidence

4.1 A Conventional Formulation May Still Be the Best Solution

Solutions, gels, emulsions, and creams can alter delivery through solvent choice, pH, ionic strength, oil-water partitioning, film formation, and occlusion. ATDS does not presume that a nanosystem is superior to a conventional formulation. Each carrier should be evaluated against meaningful controls such as blank carrier, free active, a conventional formulation containing the same active level, and an appropriate market comparator where justified.

4.2 Liposomes, Deformable Vesicles, and Ethosomes

Lipid vesicles may protect unstable ingredients and modify release and skin partitioning. Seminal studies on highly deformable vesicles and ethosomes reported enhanced skin delivery of selected actives under specific compositions and test conditions. [15-16] A carrier name is not a substitute for validation of the final formulation. Phospholipid source, cholesterol or surfactant ratio, ethanol content, particle size, lamellarity, deformability, encapsulation efficiency, leakage, and oxidation can all change performance.

4.3 Nanoemulsions, SLNs, and NLCs

Nanoemulsions, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) may improve dispersion, protection, and local retention of poorly soluble ingredients. Film formation and occlusion can also alter hydration of the stratum corneum. Risks include polymorphic transition, active expulsion, particle growth, Ostwald ripening, surfactant irritation, and drift in the release profile during shelf life. ATDS connects initial particle characterization to actual delivery performance through shelf life rather than measuring size only at raw-material release.

4.4 Chemical and Physical Enhancement

Alcohols, glycols, fatty acids, terpenes, and surfactants may increase delivery by altering solubility, partitioning, or stratum-corneum lipid organization. Enhancement must be evaluated together with irritation, barrier recovery, and long-term-use risk. Microneedles, iontophoresis, ultrasound, laser, and other physical approaches substantially alter the barrier and can change product classification, operator requirements, and safety obligations; they are outside the non-invasive ATDS conformity scope.

4.5 Extracellular Vesicles

EVs are particles released from cells, delimited by a lipid bilayer, and unable to replicate independently. MISEV2023 recommends operational EV terminology and complementary characterization of particles, membrane-associated components, cytosolic components, and non-EV contaminants. [12] For consumer ingredients, ATDS also addresses donor and cell source, culture conditions, separation and purification, residual medium, nucleic-acid and protein impurities, bioburden, potency, freeze-thaw effects, and stability after incorporation into the final formulation.

Biological-activity studies provide a rationale for skin and follicular research. Rajendran and colleagues, for example, observed effects of MSC-EVs on dermal papilla cells in vitro and on the hair cycle in mice, while noting that reproducible evidence would be required for translation to humans. [17] Such data are mechanistic and preclinical. They do not directly support claims of hair regrowth or delivery to the follicular root from a non-invasive consumer product.

4.6 Advanced Methods in 2026

Non-invasive confocal Raman microscopy, stimulated Raman scattering, MALDI imaging, optical coherence tomography, microdialysis, reconstructed human skin, and skin-on-chip systems are expanding spatial and temporal measurement of local delivery. FDA research published in 2024 illustrated the potential of stimulated Raman scattering microscopy for evaluating the local bioavailability or equivalence of topical products. [7] ATDS treats these techniques as advanced supportive evidence, provided method applicability, detection limits, spatial resolution, and quantitative calibration are established.

Chapter 5. ATDS Design Principles

5.1 Final-Formulation Principle

Particle size, activity, or cell-assay results obtained for an ingredient in buffer do not represent the product in its final package. Core delivery claims must be based on the final formulation, final concentration, final mixing procedure, and intended market package. Dual-chamber and reconstituted lyophilized products must also address completeness of reconstitution, mixing uniformity, user-operation tolerance, and the in-use period after reconstitution.

5.2 Target-Marker-Endpoint Alignment

Before testing, each program should establish a three-part map: target tissue compartment, quantifiable analyte or marker, and endpoint corresponding to the proposed consumer claim. Detection only in the stratum corneum cannot support “dermal delivery.” Detection of a carrier dye cannot establish delivery of active cargo. Increased penetration alone cannot establish improvement in wrinkles, firmness, or hair growth.

5.3 Orthogonal-Evidence Principle

Higher-level delivery conclusions require at least two complementary method classes: one that provides mass-balance-oriented quantitation, such as LC-MS/MS, radiolabel analysis, immunoassay, or a validated nucleic-acid method; and another that provides spatial localization, such as histology, Raman analysis, or microscopy. Imaging requires free-dye, blank-carrier, tissue-autofluorescence, and channel-crosstalk controls.

5.4 Method-Suitability Principle

Quantitative methods should establish selectivity, accuracy, precision, range, limits of detection and quantitation, stability, and necessary robustness. ICH Q2(R2) and Q14 provide mature concepts of fitness for intended purpose and analytical lifecycle management, which ATDS applies in a risk-proportionate manner to consumer-product R&D. [8-9] Sophisticated instrumentation is not a substitute for method validation.

5.5 Mass-Balance Principle

Diffusion-cell studies should account, as far as practicable, for the dosing device, skin-surface wash, tape strips, epidermis, dermis, receptor fluid, and apparatus residues. Incomplete recovery can make a compartment percentage misleading. For EVs or complex nanosystems, separate balances may be needed for particles, cargo, and free markers.

5.6 Controls and Falsifiability

Every claim that a delivery technology improves performance should include controls capable of disproving it: free active, empty carrier, non-optimized carrier, base formulation containing the same active concentration, and relevant inactivated or degraded controls. A method intended for release, change control, or comparability should distinguish intentionally altered lower-performing batches or meaningful process changes.

5.7 Safety and Efficacy Are Different Questions

Irritation, sensitization, and human patch testing address tolerability. IVRT addresses release. IVPT addresses aspects of skin permeation and local availability. A controlled human use study addresses consumer-relevant outcomes under normal use. ATDS does not allow one of these studies to substitute for the entire evidence chain.

Chapter 6. Technical Requirements for the Nine Evidence Gates

6.1 G0: Market, Ethical, and Ingredient Admissibility

Before costly delivery studies begin, a target-market admissibility memorandum should address product category, ingredient permissibility, restrictions on human- or animal-derived materials, nomenclature and labeling, advertising boundaries, possible new-efficacy or new-claim pathways, drug or quasi-drug or medical-device implications, and public-data obligations.

An INCI name is a labeling nomenclature tool; it does not establish safety, approval, purity, or efficacy. [23] Japan defines a permitted scope of ordinary cosmetic efficacy expressions, including keeping the scalp and hair healthy, imparting firmness to skin, and making fine lines caused by dryness less noticeable. [31] In China, the Standards for Cosmetic Efficacy Claim Evaluation place responsibility on the registrant or notification holder for the scientific validity, truthfulness, reliability, and traceability of substantiation. [30]

Human-derived cells or products require donor consent, privacy protection, ethics oversight, infectious-agent risk control, cell-bank identity, and end-to-end traceability. Whether a material may be used as a cosmetic ingredient must be established market by market through competent regulatory and legal review; a nomenclature or notification document from one country must not be extrapolated to another.

6.2 G1: QTPP and Claim Map

Each product should maintain a QTPP and Claim Map covering the intended population, application site, dose, frequency, leave-on or rinse-off conditions, target skin compartment, primary analyte, intended local action, acceptable systemic exposure, material safety risks, target markets, and candidate market language.

6.3 G2: Identity of Ingredients, EV Materials, and Carriers

General requirements include ingredient name and composition, source, process-flow diagram, critical raw and ancillary materials, impurity profile, certificate of analysis, lot number, and change history. Nanoparticle and colloidal systems should be characterized for size distribution rather than mean size alone, dispersity, zeta potential where applicable, morphology, concentration, encapsulation or loading, free fraction, pH, osmolality for mucosal applications, and relevant degradation products.

Minimum EV documentation includes:

• Donor or cell type, cell identity, cell-bank tier, passage range, and source of culture medium;

• Cell status at collection, culture conditions, separation, concentration and purification workflow, and yield;

• At least two complementary particle-analysis methods, including instrument settings and reportable range;

• A combination of membrane-associated and cytosolic EV proteins and assessment of non-EV contaminants, informed by MISEV2023;

• Residual medium proteins, nucleic acids, host-cell protein or debris, process residues, and bioburden;

• A potency assay relevant to intended use, with clear normalization per particle, protein mass, or delivered dose; and

• Retention of identity, integrity, and potency after freeze-thaw, lyophilization, reconstitution, and incorporation into the final formulation.

The “cup-shaped” morphology seen in conventional TEM can be a preparation artifact and is not sufficient for release of intact EVs. A negative calnexin result alone does not establish purity. ATDS requires a multi-attribute evidence set rather than one positive and one negative marker.

6.4 G3: Final Formulation and Critical Quality Attributes

Finished-product CQAs should be selected by risk assessment and may include appearance, pH, viscosity or rheology, density, assay and uniformity, size and dispersity, solid-state form, encapsulation efficiency, free-active fraction, oxidation indices, volatile components, release performance, and microbiological attributes. Microstructure and rheology can materially affect release and skin delivery from semisolid products; FDA Q3 concepts and the EMA cutaneous-products guideline provide high-rigor comparison models. [5]

For multilayer systems described as “EVs encapsulated again within liposomes,” the claimed architecture must first be demonstrated. A simple mixture of EVs and liposomes, secondary encapsulation of EVs, fusion between EV membranes and artificial lipids, and transfer of selected cargo into liposomes are distinct physical states with different CQAs and delivery implications.

6.5 G4: Stability, Packaging, and Reconstitution-at-Use Systems

ISO/TR 18811 recognizes that cosmetic product types and conditions of use vary widely and that no single stability protocol applies universally. The manufacturer should justify the selected methods, conditions, and specifications. [27] ATDS stability programs should address long-term and accelerated conditions, temperature cycling, freeze-thaw, light exposure, transport vibration, in-use stability, and package compatibility in a risk-based manner rather than mechanically importing medicinal-product conditions.

Dual-chamber or lyophilized reconstitution systems should also verify fill volume in each chamber, reconstitution time, completeness of mixing, tolerance to user technique, recovery of activity, particle size or aggregation after reconstitution, post-reconstitution potency, and the microbiological in-use window. Compatibility of preservatives with EV and liposomal systems must be measured. “Preservative-free” is not by itself a safety advantage. ISO 17516 and ISO 11930 can support microbiological quality and antimicrobial-protection assessment. [25-26]

6.6 G5: In Vitro Release Testing

IVRT assesses the rate and extent at which an active is released from the final formulation; it does not use skin as the barrier. Method development should select a membrane that does not become an additional rate-limiting step and a receptor medium that maintains analyte stability, solubility, and sink conditions. Dose, diffusion area, temperature, agitation, sampling schedule, replacement volume, and sample stability should be defined.

A fit-for-purpose IVRT method should demonstrate precision, linearity or range, mass balance, robustness, and discriminatory ability, including detection of meaningful formulation or process changes. FDA's 2022 IVRT guidance separates method development, validation, and pivotal study stages and explains how a validated IVRT can support quality control and manufacturing-change assessment. [4]

For EV or particulate systems, the measured entity must be defined in advance: free cargo, total cargo, intact particles, a potency endpoint, or a combination of endpoints. Total protein alone rarely represents release of the intended active entity.

6.7 G6: IVPT, Layer-Specific Deposition, and Follicular Delivery

IVPT should preferentially use healthy, intact human skin appropriate to the intended use. Animal skin or reconstructed models can support screening, but extrapolation across models must be justified and, where necessary, validated. Protocols should document donors, anatomical site, thickness, storage, freeze-thaw history, integrity testing, diffusion-cell configuration, receptor medium, skin-surface temperature, dose, exposure time, washing, and tissue-separation procedures.

FDA's 2022 draft IVPT guidance identifies flux (J) and cumulative permeated amount (AMT) as important endpoints. It suggests that pilot work include multiple skin donors, for example four to six, and at least four replicate sections per treatment from each donor; final donor numbers should be based on pilot variability and statistical power. [3] ATDS treats this as a high-rigor reference, not as a fixed sample-size requirement for every cosmetic study.

For a locally acting consumer product, reports should include at least:

• Time-resolved receptor-fluid concentration, cumulative permeated amount, and flux;

• Distribution among surface residue, stratum corneum, epidermis, dermis, and receptor fluid;

• Total recovery and an explanation of unrecovered material;

• Within-donor and between-donor variability, exclusion rules, and complete underlying data; and

• A local-deposition metric matched to the intended compartment, rather than a single “total absorption percentage.”

Follicular projects should use differential tape stripping or cyanoacrylate follicular biopsy, histology, or another method capable of separating follicular and non-follicular routes. Conventional tape stripping does not produce layers of uniform stratum-corneum depth; OECD's 2022 guidance discusses this and related uncertainty. [2]

6.8 G7: Safety and Tolerability

Safety assessment begins with ingredient hazards and realistic exposure. It should address impurities, microorganisms, irritation, sensitization, phototoxicity, periocular use, inhalation for sprays, foreseeable misuse, systemic exposure, and vulnerable populations. OECD TG 439 uses reconstructed human epidermis to identify skin irritants. Updated TG 442C, 442D, 442E, and Guideline 497 support integrated approaches to skin sensitization using methods that address multiple key events. [18-21]

Human patch or repeat-use studies should begin only after adequate ingredient and formulation safety information exists, with ethics review and appropriate medical oversight. A negative Human Repeat Insult Patch Test (HRIPT) does not prove “absolute safety” and does not replace eye-irritation, phototoxicity, microbiological, or systemic-risk assessment.

Human-derived EV materials may require consideration of immunogenicity, residual bioactive substances, unknown cargo, and donor- or culture-process-related risks. Endotoxin limits should be justified by use, exposure, and analytical suitability. “<0.5 EU/mL” is not a universal international threshold for every cosmetic used on intact skin.

6.9 G8: Human Performance, Claims, and Lifecycle

Human performance studies should directly correspond to final market language. Protocols should be preregistered where appropriate or at least prospectively lock the primary endpoint, sample-size rationale, randomization and blinding, comparator, statistical analysis plan, missing-data handling, and adverse-event management. Instrumental endpoints, expert grading, standardized imaging, and participant-reported outcomes may be combined, but their hierarchy should be specified in advance.

China requires scientific testing and reasonable evaluation of cosmetic efficacy claims and places responsibility for the scientific validity, truthfulness, reliability, and traceability of the published substantiation abstract on the responsible entity. [30] EU common criteria address legal compliance, truthfulness, evidential support, honesty, fairness, and informed decision-making. [28-29] In the United States, cosmetic and drug status depends on intended use; claims to restore hair growth or affect the structure or function of the body may establish drug intended use. [32-33]

An ERL 5 product should also have CQA and performance trends for at least three representative batches, demonstrated method transfer or external-laboratory reproducibility, change control, and post-market complaint and adverse-event monitoring. Under MoCRA, a responsible person must maintain records supporting adequate cosmetic safety substantiation, and the evidence should derive from scientifically robust methods. [34]

Chapter 7. ATDS Test Methodology

7.1 Method-Selection Matrix

Methods should be selected from the research question, not from the equipment already available in a laboratory.

7.2 Minimum Reporting for Diffusion-Cell Studies

A diffusion-cell report should identify the cell type, effective diffusion area, receptor volume, agitation, skin-surface temperature, membrane or tissue mounting, receptor-medium composition and degassing, sampling and volume-replacement correction, dose application, exposure period, wash recovery, and sample storage. Static Franz cells and flow-through cells can both be suitable; selection should correspond to analyte stability, sink conditions, and the use scenario. [1]

Skin integrity may be evaluated through transepidermal water loss, electrical resistance or impedance, dyes, or reference compounds. Thresholds should be established for the laboratory's tissue thickness, apparatus, and conditions rather than copied from an unrelated study. Excluding a cell after seeing an unfavorable result is unacceptable; exclusion rules should be prespecified.

7.3 Finite Dose, Washing, and Consumer-Use Conditions

A finite dose better reflects routine application and can capture solvent evaporation, supersaturation, or crystallization. Rinse-off products should reproduce label-relevant contact time and washing. Leave-on products should remain for the intended period. Scalp protocols should state whether massage is used, whether hair shafts remain, and whether styling products are layered. A dose materially above actual use should be labeled mechanistic or exploratory and should not directly support a consumer claim.

7.4 Layer Separation and Mass Balance

At study end, investigators should recover the dosing device, surface residue, tape strips, epidermis, dermis, receptor fluid, and apparatus residues in a defined sequence. Container adsorption and extraction recovery should be validated for adsorptive proteins, peptides, and vesicles. If intact EVs cannot be measured directly, a tiered set of surrogate endpoints may be used, but each surrogate must be identified as representing particle number, a specific membrane protein, nucleic-acid cargo, total protein, or another defined analyte.

7.5 Six Essential Controls for Imaging

• Autofluorescence control using untreated tissue;

• Free-dye control;

• Empty-carrier or blank-EV control;

• Single-channel controls and crosstalk compensation;

• Surface-wash or quenching control to exclude adherent signal; and

• Positive and negative controls aligned with the quantitative assay.

Images should report scale, depth coordinates, acquisition parameters, exposure or gain settings, rules for selecting representative fields, and blinded analysis. A publication must not consist only of the most visually favorable image. A single fluorescent label is insufficient to establish penetration of an intact vesicle.

7.6 Raman and Label-Free Spatial Analysis

Confocal Raman microscopy and stimulated Raman scattering can reduce behavior changes caused by fluorescent labels and provide depth-resolved information. Limitations include spectral overlap, detection limits, depth resolution, interindividual skin differences, and quantitative calibration. FDA research supports the potential of these methods in local-bioavailability studies, but output from a commercial Raman instrument should not automatically be treated as regulatory-grade proof of absorption. [7]

7.7 Biological Potency Assays

A potency assay should reflect the intended mechanism and be sensitive to critical processing and degradation. Possible endpoints include receptor engagement, cell signaling, oxidative-response measures, barrier-related readouts, or dermal-papilla-cell endpoints. Positive and negative controls, dose-response, normalization, and acceptance ranges should be specified. For complex EV materials, a single proliferation assay should not be the sole potency test; higher evidence levels may use complementary mechanistic and functional assays.

7.8 Statistics and Uncertainty

Variation among skin donors is often substantial. Statistical models should preserve donor hierarchy and must not treat multiple diffusion cells from one donor as independent participants. Reports should include within-donor and between-donor variation, confidence intervals, effect sizes, and complete data rather than p values alone. Exploratory studies may generate hypotheses; confirmatory studies should prespecify the primary endpoint and success criterion.

Chapter 8. Dedicated Module for EVs and Human-Derived Materials

8.1 Nomenclature and Scientific Boundary

ATDS uses extracellular vesicles (EVs) as the default scientific term. A specific population should be called exosomes only when sufficient evidence supports endosomal biogenesis. A formally assigned INCI name may be used where required for product labeling, but a nomenclature name must not be presented as proof of biological origin.

Within the tiptop system, ExosomeBeta- is the proprietary brand designation for an EV raw material that meets the applicable tiptop ATDS requirements. The designation does not change the scientific identity of the material. It must always be accompanied in technical records by the source, material code, batch, specification, methods, ATDS version, and evidence status. ExosomeBeta- must not be used as a substitute for the scientifically accurate term EV, nor as an automatic claim of purity, exosomal biogenesis, penetration, targeting, safety, or efficacy.

8.2 Source, Ethics, and Traceability

Human-derived programs should establish unidirectional traceability from donor to cell bank, production batch, raw-material batch, and finished-product batch. Documentation should address lawful source, informed consent, ethics opinion, infectious-disease screening strategy, cell identity, genetic stability or tumor-related risk as appropriate to the cell type and use, passage range, antibiotic use, animal-derived components, and deviations.

A “no new tissue collection” or sustainability narrative should be used only if the supply chain documents the origin and use of the cell bank and demonstrates that ongoing human-tissue collection is not required. Such a statement does not replace biosafety or market-admissibility assessment.

8.3 Manufacturing Process Control

Critical process parameters may include cell density, confluence, culture duration, harvest window, medium lot, temperature, pH, dissolved oxygen, centrifugation or filtration settings, membrane material, tangential-flow parameters, chromatography conditions, and aseptic or low-bioburden handling. Links between each parameter and a CQA should be supported by risk assessment, process characterization, or design of experiments.

8.4 Identity, Purity, and Impurities

MISEV2023 does not support defining all EVs by one marker or fixed size range. [12] ATDS uses a combination of:

• Single-particle or ensemble size and concentration methods, such as NTA, TRPS, or nano-flow cytometry, with reportable range and refractive-index limitations;

• Morphology by TEM, cryo-EM, or AFM, with sample-preparation conditions;

• A combination of EV-associated membrane and cytosolic proteins;

• Assessment of non-EV co-isolates, organelle-associated materials, and culture-medium contaminants;

• Total and specific protein, lipid, nucleic acid, and cargo measurements; and

• Association between particle attributes and potency rather than pursuit of the highest particle count.

Claims such as “99.9% purity,” “99% activity,” or “99% main peak” have scientific meaning only when the metric, denominator, method, analytical range, and underlying data are disclosed. Particle concentrations and sizes measured by different instruments cannot be compared directly without method bridging.

8.5 Lyophilization, Reconstitution, and Secondary Liposomal Protection

Lyophilization can improve storage and transport convenience, but ice formation, interfacial stress, osmotic stress, and drying stress may cause aggregation, membrane damage, or potency loss. Formulation development should evaluate protectants, freezing rate, primary and secondary drying, and residual moisture, then verify post-reconstitution size, aggregation, markers, cargo, and potency.

Secondary liposomal protection should not be described only as “freshness locking” or “precision penetration.” Evidence should establish the architecture, encapsulated fraction, free-EV and free-liposome fractions, release and skin-delivery behavior after compounding, and the effects of preservatives, surfactants, and high alcohol concentrations on both lipid bilayers.

8.6 Evidence Tiers for EV Delivery

8.7 Red Lines for EV Products

• Do not use data from injection, microneedles, or disrupted skin to substantiate routine use on intact skin.

• Do not describe an acellular consumer product as live cells, cell transplantation, or regenerative cell therapy.

• Do not infer homing to or repair of an organ solely from the tissue or organ of cell origin.

• Do not present an INCI or JCIA name as evidence of approval, safety, or efficacy.

• Do not extrapolate one raw-material batch to every formulation, concentration, and shelf-life interval.

• Do not claim absolute safety, zero risk, or guaranteed efficacy.

Chapter 9. Facial-Care Application Module

9.1 Target-Compartment Design

Facial products should first distinguish among surface or stratum-corneum, viable-epidermal, dermal, and systemic targets. Hydration, emollience, protection, and reduction in the appearance of dryness-related fine lines may arise at superficial layers. Stronger mechanistic statements such as “promotes dermal collagen” or “cell-level repair” require exposure in the corresponding compartment, mechanism-consistent evidence, and human outcomes, and may exceed ordinary cosmetic-claim boundaries in some markets.

9.2 Recommended Evidence Package

• Final-formulation CQAs and long-term, accelerated, and in-use stability;

• IVRT release with relevant formulation controls;

• Layer-specific delivery in excised human skin from a facially relevant site or a justified substitute;

• Eye-irritation risk assessment for periocular use;

• Human tolerability and a performance study matched to the proposed claim;

• Standardized photography, instrument calibration, environmental equilibration, and blinded image grading; and

• Review of market language against the law of each target jurisdiction.

9.3 Use with Energy-Based Procedures or Post-Procedure Skin

Energy-based procedures and post-procedure skin may involve a changed barrier and therefore constitute a risk context different from intact skin. ATDS 2026 does not permit intact-skin data to substantiate post-procedure use or post-procedure absorption data to substantiate routine topical use. A specific interval such as “30 minutes after treatment” requires medical and regulatory review, consistency with device instructions, professional supervision, and dedicated safety and clinical evidence.

Chapter 10. Scalp and Follicular Application Module

10.1 Defining the Intended Use

An ordinary scalp cosmetic may be designed around permitted expressions relating to cleansing, moisturization, scalp or hair condition, flaking or itching, hair gloss, and resistance to breakage. Goals such as preventing hair loss, regrowing hair, altering the follicular cycle, or treating androgenetic alopecia may fall into materially different product categories across markets. In the United States they can indicate drug intended use; in Japan they may require evaluation under quasi-drug or hair-growth product categories; in China they require review under special-cosmetic, new-efficacy, or other applicable rules. [31-33]

10.2 Special Requirements for Scalp Models

Scalp sebum, hair coverage, follicular density, and cleansing behavior influence delivery. If non-scalp excised skin is used, the substitution should be justified. Follicular studies should preferentially use suitable tissue containing terminal follicles and should report follicular density. Depilation, shaving, alcohol cleaning, and tape pretreatment can artificially increase penetration and must be distinguished from actual use.

10.3 Follicular-Delivery Endpoints

Reports should address total deposition in the follicular region, estimated depth distribution, distribution in non-follicular skin, receptor-fluid permeation, and surface residue. If the intended outcome is a local follicular reservoir, systemic permeation should not be the principal success metric. Cargo integrity in the follicular environment should be demonstrated, and the effects of sebum and follicular microorganisms on stability should be considered.

10.4 Human Endpoints

Legally permissible endpoints may include scalp hydration, sebum, TEWL, erythema, flaking, itching, hair breakage, combability, and standardized hair count or diameter. Studies involving hair growth should account for the hair cycle, season, hair-loss type, medication, hormones, and an observation period of at least several months. A short-term consumer questionnaire cannot establish hair growth.

Chapter 11. Safety, Quality, and Manufacturing Systems

11.1 Bridging Cosmetic GMP and Biological Raw Materials

ISO 22716 addresses quality aspects of cosmetic production, control, storage, and shipment. It does not cover R&D itself and does not automatically resolve every risk presented by human-derived biological materials. [24] ATDS recommends supplementary modules for cell banks, donor traceability, biosafety, closed processing, environmental monitoring, process residues, cold-chain or lyophilization control, and potency release.

“Pharmaceutical-grade GMP” is not a universally defined promotional term that can be used independently of a certificate, site, product scope, and regulatory system. External communication should identify the actual authorization or certification held by the facility and its scope.

11.2 Microbiological Control

Cosmetics used on intact skin are generally controlled to market-appropriate microbiological limits; they are not automatically required to be sterile. Periocular and mucosal products, children's products, preservative-free water-based systems, and multi-use reconstituted products require heightened risk controls. ISO 17516 can support microbiological-quality evaluation and ISO 11930 can support antimicrobial-protection assessment. [25-26] A claim of sterility requires a manufacturing, validation, container-closure, and sterility-testing system suitable for sterile products.

11.3 Elemental Impurities and Process Residues

Risk inventories should address heavy metals, solvents, surfactants, antibiotics, nucleases or proteases, filter aids, and medium components according to source and process. Acceptance criteria should reflect target-market rules, toxicological exposure, and method capability. “Below the most sensitive detection limit” is not a reproducible specification; reports should provide the method LOD or LOQ and units.

11.4 Change Control

Changes to a cell bank, medium, critical equipment, purification membrane, lyophilization cycle, phospholipid source, preservative system, package, manufacturing site, or analytical method may alter delivery performance. Risk-based change classification should determine which identity, stability, IVRT, IVPT, safety, or human studies must be repeated. ERL is not a permanent badge; it remains tied to a defined version and current evidence package.

Chapter 12. Transmucosal-Delivery Research Extension

12.1 Why It Must Be Separated from Transdermal Delivery

Oral and sublingual mucosa differ from skin in keratinization, saliva exposure, blood flow, and barrier architecture. Transmucosal delivery may reduce gastrointestinal degradation or part of first-pass metabolism, but the extent depends on the molecule, dosage form, residence time, swallowed fraction, and local metabolism. It must not be described as “oral transdermal delivery,” and skin IVPT does not substantiate it.

12.2 Product Category Comes First

A sublingual product may be regulated as a food, dietary supplement, health food, or medicinal product depending on its ingredients, dosage form, intended use, and jurisdiction. ATDS 2026 provides only research principles and assigns no conformity level in this module. Any oral or sublingual use of human-derived EV materials should first undergo market-admissibility and systemic-safety assessment.

12.3 Suggested Research Framework

Relevant methods may include stability and release in simulated saliva, permeation through porcine or human buccal mucosa, cell or reconstructed oral-epithelium models, mucoadhesion and residence, swallowed fraction, local irritation, systemic exposure, and human pharmacokinetics or biomarkers where permitted by the product category. Receptor-medium, tissue-integrity, and mass-balance principles resemble those used for skin, but models and endpoints must not be interchanged.

Chapter 13. The tiptop ATDS Translation Pathway

13.1 Corporate Position and Scientific-Industrial Connections

According to information provided by the issuer, tiptop's brand narrative is built on global scientific validation × Japan-based precision execution × Eastern life wisdom. Its industrial translation programs address human-derived EV materials from defined stem- or progenitor-cell sources and intended for target-site consumer applications, liposomal protection, lyophilized and dual-chamber reconstitution-at-use formats, and consumer applications for facial skin and scalp. ATDS converts these ingredients, formulations, and brand narratives into auditable Product Evidence Passports.

The relevant legal and operating entities are Tiptop Human Longevity Biotechnology Research Institute Limited, tiptop, and the wholly owned Japanese subsidiary 株式会社丸誉長寿バイオテック研究院. The Japanese legal name is retained as supplied; this document does not invent an English legal translation.

The ZUO Lab., Professor Wei Zuo, Dr. Ting Zhang, and Regend form part of the source-level scientific and upstream industrial context described in tiptop's evidence architecture. Based on issuer documentation, Regend is one of tiptop's suppliers of EV-related raw materials, while scientific translation advisors and the tiptop team maintain technical exchange concerning industrial production, purification and screening, lyophilization stability, particle-size control, quality evaluation, batch consistency, and the boundary of non-pharmaceutical consumer applications. tiptop then conducts consumer-grade industrialization activities, which may include screening, purification, lyophilization, stability evaluation, batch management, Japan-based production coordination, and ATDS evidence development.

This relationship must be described with disciplined attribution. Related publications and source-science records provide scientific background and are not direct evidence for the efficacy of a finished cosmetic product. For external communications by powered by tiptop sub-brands or products, any source-technology attribution to Regend, Wei Zuo, or Ting Zhang should follow the supplied communications rule and use The ZUO Lab. as the standardized source-level reference. Terms such as endorse, personally developed, clinically proven cosmetic efficacy, medical efficacy, treatment, injectable-grade, stem cell cosmetic, disease repair, cell regeneration, wound healing, or guaranteed efficacy should not be inferred.

ATDS does not preassign the “highest level” to a tiptop ingredient. All tiptop raw-material programs operate within the ATDS framework, and eligible EV raw materials may receive the ExosomeBeta- proprietary designation. Nevertheless, each material-formulation-package combination must independently pass the applicable evidence gates. This preserves scientific validity when the active, sub-brand, formulation, package, or target market changes.

13.2 Three Priority Demonstration Programs

13.3 Claims Not Recommended Before Product-Level Evidence

Before product-level evidence is complete, tiptop should not publish statements such as “multiple-fold increase in dermal absorption,” “70-90 nm golden absorption,” “precision homing to a human organ,” “reaches the follicular root,” “bypasses gastric acid and goes directly to cells,” “absolutely safe,” or “the world's first standard.” Suitable alternatives include:

• “Final-formulation release, layer-specific skin delivery, and human performance are evaluated under the ATDS framework.”

• “Ingredient addition level is not treated as proof of effective delivery; the evidence chain extends from material identity to a consumer-relevant outcome.”

• “The formulation is designed for a defined facial or scalp target site, and actual delivery is confirmed with product-specific data.”

• “ExosomeBeta- is tiptop's proprietary designation for an eligible EV raw material evaluated under applicable ATDS requirements; it is not an independent regulatory or scientific classification.”

• “ATDS is an enterprise technical initiative proposed by tiptop in 2026 and remains open to external scientific review.”

13.4 Twenty-Four-Month Roadmap

Months 0-3: foundational governance. Confirm ATDS name, version, and brand strategy; establish scientific-advisory and conflict-of-interest procedures; complete G0 and G1 for three demonstration programs; and commission method-gap assessments by two independent laboratories.

Months 3-9: method establishment. Demonstrate suitability of critical analytical methods, assemble the EV and carrier identity panel, establish IVRT and layer-recovery procedures, and use intentionally altered batches to demonstrate discriminatory ability.

Months 9-15: product-level verification. Conduct excised human skin or scalp studies, intermediate stability checkpoints, safety assessment, and pilot human studies; complete the first Product Evidence Passport.

Months 15-24: external reproduction and publication. Replicate critical findings in a second laboratory; prepare a peer-reviewed paper, conference abstract, or complete method annex; and publish ATDS 1.1 with an independently reviewed demonstration case.

Chapter 14. Evidence Readiness Levels 0-5

An ATDS Evidence Readiness Level (ERL) indicates maturity of the evidence package, not the magnitude of product efficacy. The level must identify the product, formulation version, package, and target market.

14.1 Advancement Rules

ERL applies a weakest-link rule. A program cannot bypass an incomplete earlier gate because a later result appears favorable. If a human study shows improvement but the identity and stability of the final product remain uncertain, the evidence chain is incomplete. A level must be reassessed after expiry, a major formulation or packaging change, or a material change in regulatory boundaries.

14.2 Recommended External Marking

Before an independent certification system is established, use text only: “Developed under the ATDS 2026 framework; Evidence status: ERL X; scope: [module]; not a regulatory approval.” Do not use a seal that could be interpreted as approval by a government or international organization.

For an eligible EV raw material, ExosomeBeta- may appear as a separate proprietary material designation, for example: “ExosomeBeta- | evaluated under the applicable ATDS 2026 raw-material module | material code and batch specified in the technical dossier.” This wording does not confer a product ERL and must not be used without the corresponding technical dossier.

Chapter 15. Global Claim and Regulatory Mapping

15.1 China

China's Standards for Cosmetic Efficacy Claim Evaluation require scientific testing and reasonable evaluation of efficacy under normal conditions of use, supported by literature, research data, or testing, together with publication of a substantiation abstract. [30] ATDS human-study and method reports should be structured so that relevant information can be transferred into that abstract. Whether terms involving transdermal delivery, cells, repair, anti-hair-loss, or hair growth are permissible, or constitute new efficacy, requires product-specific review.

15.2 Japan

Japan defines a specific scope of efficacy expressions for ordinary cosmetics. The official notice lists 56 expressions, including keeping the scalp and hair healthy, imparting firmness to the skin, and making fine lines caused by dryness less noticeable. [31] Hair-loss prevention, hair growth, cell repair, and disease-related language may require a quasi-drug or medicinal-product pathway. ATDS data cannot expand the legally permitted advertising scope.

15.3 European Union

Commission Regulation (EU) No 655/2013 requires cosmetic claims to comply with six common criteria: legal compliance, truthfulness, evidential support, honesty, fairness, and informed decision-making. [28-29] The ATDS Product Evidence Passport should align with the Product Information File and Cosmetic Product Safety Report. Expressions such as “free from,” “hypoallergenic,” and “clinically proven” also require careful assessment under EU guidance.

15.4 United States

In the United States, intended use determines whether a product is a cosmetic or a drug. A claim to treat or prevent disease or affect the structure or function of the body can establish drug status even if the product is marketed as a cosmetic. FDA examples include restoring hair growth and “revitalizing cells.”[32-33] MoCRA strengthened requirements relating to facility registration, product listing, adverse-event reporting, and safety-substantiation records. [34]

15.5 ASEAN

The ASEAN Cosmetic Directive and ASEAN Cosmetic Claims Guideline require claims to remain within the cosmetic scope and to be supported by evidence. Labeling and advertising must not imply characteristics that the product does not possess. [35-36] Interpretation and enforcement can vary among Member States and should be checked country by country.

15.6 Four Levels of Compliant Evidence Language

Lower-level language must not be upgraded. Ex vivo epidermal deposition cannot become “human dermal absorption”; cell activity cannot become “clinically proven anti-aging”; and analytical detection cannot become “guaranteed consumer effectiveness.”

Chapter 16. Governance, Independent Review, and Transparency

16.1 Governance Structure

ATDS should establish a Scientific and Standards Committee with four working groups: methods; EVs and biological raw materials; safety and regulation; and clinical or consumer research. Membership, qualifications, conflicts of interest, terms, voting, and dissenting opinions should be disclosed. tiptop may retain brand and organizational ownership as the initiator, but independent experts should be able to reject a conclusion or require a lower evidence level.

16.2 Version Management

Each edition should publish its effective date, change summary, referenced-standard versions, and transition period. Updates to OECD, ISO, FDA, EMA, NMPA, MHLW, or a material scientific consensus should trigger an impact assessment within 90 days. Method annexes may be updated more frequently, while core principles should be reviewed at least annually.

16.3 Independent Laboratories

Third-party status does not by itself establish reliability. A laboratory should demonstrate relevant method competence, equipment qualification, analytical validation, raw-data integrity, sample blinding, deviation management, and conflict-of-interest control. Critical ERL 3-5 work should preferably be performed by two independent laboratories or by one laboratory with an independent data audit.

16.4 Data Disclosure

Public summaries should identify the product or formulation version, batch, sample, model, dose, comparator, primary endpoint, statistics, exclusions, limitations, and sponsor. Exact formulation details may remain confidential, but conditions that materially change interpretation must not be hidden. Negative and uncertain results should enter the version history to reduce selective publication.

16.5 Product Evidence Passport

Each product should maintain an electronic Product Evidence Passport recording G0-G8 status, ERL, report index, key CQA trends, supported and prohibited claims, market differences, changes, and adverse events. A consumer view may show an understandable summary; a partner or audit view may provide deeper evidence; and a regulatory view should retain a complete index to underlying records.

Chapter 17. 2026-2030 Frontier Roadmap

17.1 From Particle Size to Spatial Pharmaceutics

The next frontier is not simply a smaller particle. It is simultaneous resolution of carrier, cargo, tissue compartment, and time. Dual-label tracking, label-free Raman analysis, imaging mass spectrometry, and spatial omics can help distinguish carrier arrival, cargo release, and tissue response.

17.2 From Static Skin to Dynamic Human-Relevant Models

Reconstructed human skin, immune or follicular co-culture, skin-on-chip, and dynamic-fluid models can address limitations of excised skin, including the absence of circulation and long-term response. They require bridging to excised human skin and human endpoints; a “3D” or “chip” label does not automatically raise the evidence level.

17.3 From Single-Batch Testing to Quality by Design

Risk assessment, design of experiments, process analytical technology, and multivariate models can link raw-material source, process parameters, CQAs, IVRT or IVPT, and human outcomes. ICH Q14's analytical-procedure lifecycle and risk-based thinking provide a useful reference for ATDS method governance. [9]

17.4 From Black-Box AI to Auditable Models

Machine learning may support formulation screening, stability prediction, spectral deconvolution, and batch trending. Training data, applicability domain, bias, external validation, and human review must be documented. AI prediction cannot replace measured evidence at a critical ERL gate.

17.5 From Enterprise Initiative to Multi-Stakeholder Consensus

The long-term ATDS pathway should begin with a public white paper, develop methods through interlaboratory comparison, test the framework across multiple brands and materials, and then submit consensus text to industry associations, scientific organizations, or standards bodies. Leadership is established when others can reproduce, challenge, and improve the work - not when an organization first declares itself the global standard.

Conclusion

The next unit of competition in consumer anti-aging is neither a more dramatic ingredient name nor a smaller isolated particle-size value. It is a complete, reproducible, and auditable body of delivery evidence.

ATDS 2026 proposes a more rigorous and sustainable enterprise practice: confirm market and ethical boundaries; define the target compartment and claim; establish ingredient and carrier identity; show that the finished formulation remains stable and releases through shelf life; quantify actual delivery using suitable human skin or scalp models; perform risk-based safety and human performance evaluation; and connect batches, laboratories, market language, and post-market data throughout the lifecycle.

For tiptop, the framework converts technical work on human-derived EV materials, liposomal systems, lyophilized reconstitution-at-use formats, and facial or scalp products into a common language that global partners can understand and verify. ExosomeBeta- gives tiptop an ownable brand designation for EV materials meeting applicable ATDS requirements, while the ATDS evidence gates prevent that designation from being mistaken for scientific proof or regulatory approval. No product may bypass product-level evidence merely because it contains an advanced ingredient.

ATDS should function not as a public-relations slogan but as infrastructure for long-term R&D, quality, and brand trust.

Appendix A. ATDS Product Evidence Package Checklist

A.1 G0-G1

• Target-market and product-category memorandum;

• Ingredient admissibility, source, nomenclature, and advertising-boundary opinion;

• Ethics, donor-consent, and biosafety records where applicable;

• QTPP, target compartment, primary analyte, and Claim Map; and

• Risk register and development decision log.

A.2 G2-G4

• Ingredient or carrier composition, process flow, batch record, and certificate of analysis;

• EV or nanosystem identity, purity, impurity, potency, and method reports;

• Where applicable, ExosomeBeta- eligibility record identifying material, batch, specification, ATDS version, and designation decision;

• Final-formulation CQAs, encapsulated and free fractions, rheology, and microstructure;

• Long-term, accelerated, light, freeze-thaw, transport, and in-use stability;

• Package compatibility, adsorption, leachables, fill, and dosing; and

• Reconstitution, mixing, and in-use window for dual-chamber or lyophilized systems.

A.3 G5-G6

• IVRT method development, validation, discriminatory ability, and formal study;

• IVPT protocol, donor information, integrity, dose, recovery, and raw data;

• Layer-specific quantitation, follicular-pathway analysis, imaging, and orthogonal evidence;

• Statistical analysis, deviations, exclusions, and uncertainty; and

• Three-batch or pre- and post-change performance comparison.

A.4 G7-G8

• Safety assessment and microbiological, irritation, sensitization, eye-irritation, and phototoxicity risk evaluation;

• Human-study protocol, ethics, registration or prospective lock, statistics, and report;

• Evidence summary and regional review for every claim;

• Method transfer or reproduction by a second laboratory;

• Post-market adverse events, complaints, trends, and CAPA; and

• ERL review record, version, validity period, and change history.

Appendix B. Minimum Structure of an IVRT or IVPT Report

1. Study title, number, version, sponsor, laboratory, and conflicts of interest;

2. Objective, prespecified hypothesis, and primary and secondary endpoints;

3. Product, formulation, package, batch, storage, and blinded code;

4. Analyte, reference standard, method validation, and sample stability;

5. Apparatus, membrane or skin, receptor medium, dose, temperature, and sampling;

6. Donor inclusion, integrity, random allocation, and replication;

7. Surface washing, tissue separation, extraction, and mass balance;

8. Raw data, equations, statistical model, and prespecified acceptance criteria;

9. Deviations, exclusions, missing data, outliers, and sensitivity analyses;

10. Results, limitations, claims supported, and claims not supported; and

11. Signatures, audit trail, data retention, and the valid scope of the report.

Appendix C. Communications Language Self-Check

C.1 Acceptable Scientific Templates

• “Under finite-dose conditions in excised human skin for X hours, deposition of the analyte in [specific compartment] increased relative to [comparator] by [effect size and interval].”

• “The findings are limited to the tested formulation, batch, tissue source, dose, and duration and do not represent all populations or use conditions.”

• “ATDS ERL 3 indicates product-level ex vivo delivery verification; it is not human efficacy evidence or regulatory approval.”

• “The human study supports [a specific permitted consumer endpoint] and is not intended for diagnosis, treatment, or prevention of disease.”

• “ExosomeBeta- is tiptop's proprietary designation for an eligible EV raw material evaluated under applicable ATDS requirements; it is not an independent scientific or regulatory classification.”

C.2 Prohibited Logical Leaps

Appendix D. Key Corrections to the Original Strategy Draft

Appendix E. Abbreviations and Controlled Terms

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Recommended Citation

tiptop. ATDS 2026: Advanced Transdermal Delivery Technologies and Evaluation for Consumer Anti-Aging (Enterprise Initiative Edition). Version 1.0. August 2026.

Contact and Technical Comment

tiptop welcomes review from specialists in skin science, pharmaceutics, extracellular vesicles, analytical methods, toxicology, cosmetic regulation, manufacturing quality, and consumer research. Future editions should document public comments, results of interlaboratory comparisons, and updates to method annexes.