📚 Part of the TILA-278 Regulatory Dossier — Reader's Guide. This article shows the live document; edits to the source appear here automatically.

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Module 3.2.P — Drug Product (TILA-278)

Field	Value
Document ID	M3-P
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	ICH M4Q / Q6B / Q8
Confidentiality	Confidential

Chemistry, manufacturing and controls document for TILA-278.

Change History

Version	Date	Author	Summary
1.0	2026-07-08	CMC/Quality	Initial issue

3.2.P Drug Product (TILA-278)

Drug product: TILA-278 solution for injection, 150 mg/mL, single-use prefilled syringe and autoinjector, for subcutaneous administration. Sponsor: Virtual Biopharma Inc. Cross-reference: Drug substance information is provided in Module 3.2.S; adventitious agent safety in Module 3.2.A.2; container-closure and device details are consolidated in Section 3.2.P.7.

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3.2.P.1 Description and Composition of the Drug Product

TILA-278 drug product is a sterile, preservative-free, clear to slightly opalescent, colourless to pale-yellow aqueous solution for subcutaneous (SC) injection. The active ingredient is TILA-278, a recombinant humanized IgG1 bispecific monoclonal antibody comprising an anti-TL1A (TNFSF15) antagonist arm and an IL-22 receptor agonist arm, expressed in a Chinese Hamster Ovary (CHO) cell line (drug substance described in Module 3.2.S).

The drug product is presented at a single protein concentration of 150 mg/mL and supplied in two market presentations built on a common formulation and primary container:

• a single-use, 1 mL long Type I glass prefilled syringe (PFS) with a staked-in needle and passive needle-safety device, delivering 150 mg in a 1.0 mL nominal deliverable volume;
• a single-use, spring-driven autoinjector incorporating the same primary PFS as the fluid-path component, delivering the same 150 mg/1.0 mL dose.

Both presentations are qualitatively and quantitatively identical with respect to the formulated solution; they differ only in the assembled secondary device. The formulation contains an L-histidine buffer system, sucrose as a stabiliser and tonicity agent, L-arginine hydrochloride as a viscosity-reducing stabiliser, and polysorbate 80 as a surfactant. No antimicrobial preservative and no overage are included; the product is a single-use, single-dose presentation.

Table 3.2.P.1-1. Qualitative and quantitative composition

Component	Function	Quality standard	Concentration	Amount per PFS (1.0 mL deliverable)
TILA-278 drug substance	Active	In-house (3.2.S)	150 mg/mL	150.0 mg
L-Histidine	Buffer	Ph. Eur. / USP–NF	~1.2 mg/mL	~1.2 mg
L-Histidine hydrochloride monohydrate	Buffer	Ph. Eur. / USP–NF	~2.6 mg/mL	~2.6 mg
Sucrose	Stabiliser / tonicity	Ph. Eur. / USP–NF	75.3 mg/mL (220 mM)	75.3 mg
L-Arginine hydrochloride	Stabiliser / viscosity reducer	Ph. Eur. / USP–NF	5.3 mg/mL (25 mM)	5.3 mg
Polysorbate 80	Surfactant	Ph. Eur. / USP–NF	0.4 mg/mL	0.4 mg
Water for injection	Vehicle	Ph. Eur. / USP	q.s. to 1.0 mL	q.s.

The buffer system provides a nominal target pH of 5.8. Target osmolality is approximately 300 mOsm/kg. A defined overfill is applied at the filling step to assure delivery of the 1.0 mL nominal dose from the syringe/device fluid path (see Section 3.2.P.3.2); it does not constitute an active overage.

Excipients are described in Section 3.2.P.4. All excipients are compendial and are used at levels consistent with parenteral products and with the FDA Inactive Ingredient Database / EMA precedent for SC monoclonal antibody products. There are no novel excipients.

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3.2.P.2 Pharmaceutical Development

3.2.P.2.1 Components of the Drug Product

3.2.P.2.1.1 Drug substance. The compatibility of the drug substance with the formulation excipients and with the container-closure/device materials was central to development. As a humanized IgG1 bispecific antibody, TILA-278 carries two independent binding functionalities that must both be preserved through formulation, manufacture, storage, and in-use handling: anti-TL1A neutralising activity and IL-22 receptor agonist activity. Both are monitored throughout development by orthogonal potency assays (Section 3.2.P.5.2). The principal molecular-degradation liabilities identified during characterisation of the drug substance and confirmed at drug-product level are:

• Aggregation (high-molecular-weight [HMW] species), the primary physical-stability concern for a high-concentration mAb, controlled by SE-HPLC;
• Fragmentation (low-molecular-weight [LMW] species), monitored by non-reduced CE-SDS;
• Charge heterogeneity, arising chiefly from C-terminal lysine processing, N-terminal pyroglutamate formation, deamidation of susceptible asparagine residues, and isomerisation, monitored by imaged capillary isoelectric focusing (iCIEF);
• Chain mispairing / homodimer formation, an attribute specific to a bispecific architecture, characterised during development by a chain-pairing-specific method and controlled at the drug substance (3.2.S) via the manufacturing design;
• Oxidation of susceptible methionine residues, sensitive to light and peroxide exposure.

3.2.P.2.1.2 Excipients. Each excipient was selected on established mechanistic and empirical grounds for a high-concentration SC mAb; there are no novel excipients and none is intended to exert therapeutic effect. See Table 3.2.P.2-1.

Table 3.2.P.2-1. Excipient selection rationale

Excipient	Rationale for selection	Basis for level selected
L-Histidine / L-Histidine HCl	Effective buffering near the pH of maximum conformational and colloidal stability (pH 5.5–6.0); low injection-site irritation potential	pH mapping study; 20 mM provides adequate buffer capacity at low ionic strength
Sucrose	Preferential-exclusion stabiliser protecting against thermal and freeze/thaw-induced aggregation; contributes tonicity	Aggregation minimised across the sucrose range studied; level fixed to achieve target tonicity
L-Arginine HCl	Reduces solution viscosity at 150 mg/mL to enable SC injection through a fine-gauge staked-in needle; suppresses aggregation	Viscosity/stability trade-off study (Section 3.2.P.2.2)
Polysorbate 80	Protects against interfacial (air–liquid and solid–liquid) stress during fill, shipping, and device actuation; mitigates agitation-induced particle formation	Agitation and pump-shear studies; level set above the protective threshold with margin for expected PS80 loss on storage

Compatibility of the drug substance with each excipient and with the fully formulated product is demonstrated by the formulation-development and stability data in Sections 3.2.P.2.2 and 3.2.P.8.

3.2.P.2.2 Drug Product — Formulation Development

Formulation history and comparability. A common qualitative formulation was maintained from first-in-human material through the pivotal Phase 2b induction study TILA278-201 and into the intended commercial presentation, supporting a straightforward analytical and clinical bridge. The clinical service formulation and the commercial formulation are quantitatively identical; the High and Low dose regimens evaluated in TILA278-201 (299 and 300 subjects, respectively) were achieved through the administered dose/number of injections rather than through any change in product concentration or composition. A formal formulation-comparability assessment (release plus a side-by-side stability arm) confirmed comparable quality attributes across the clinical and commercial formulation lots.

pH and buffer selection. A pH-mapping study across pH 5.0–6.5 identified a stability optimum near pH 5.8, at which aggregation rate (SE-HPLC), charge-variant drift (iCIEF), and fragmentation (CE-SDS) were jointly minimised under accelerated (25 °C) and stress (40 °C) conditions. Histidine was selected over acetate and citrate for its buffering capacity in this range and its favourable local-tolerability profile. The demonstrated pH stability region supports the release/shelf-life acceptance range of pH 5.5–6.1.

Stabiliser and tonicity. Sucrose was retained at 220 mM as a preferential-exclusion stabiliser and to bring the solution to physiological tonicity; it was preferred over trehalose on cost-of-goods and supply grounds with equivalent stabilising performance. No reducing-sugar-mediated glycation risk applies to sucrose.

Viscosity management — high-concentration SC formulation. At 150 mg/mL, dynamic viscosity is a critical developability attribute because it governs injection force and injection time through a staked-in 27-gauge thin-wall needle and drives autoinjector spring design. Without a viscosity modifier, the formulation exceeded the target injectability window; addition of 25 mM L-arginine hydrochloride reduced viscosity to approximately 12 mPa·s at 25 °C, within the range compatible with a fine-gauge SC autoinjector, while concurrently suppressing HMW formation. The arginine level represents the optimum from a viscosity-versus-conformational-stability trade-off study.

Surfactant selection and level. Polysorbate 80 was selected over polysorbate 20 for its interfacial protection during pumping, filling, shipping agitation, and device firing. Agitation and pump-shear challenge studies established the minimum protective concentration; the target of 0.4 mg/mL sits above this threshold with margin to accommodate polysorbate loss over shelf life (from oxidative and enzymatic/residual-hydrolase degradation). Polysorbate 80 content is a release and stability specification attribute, and its degradation is monitored as a potential source of sub-visible particulate.

Design of experiments and design space. A response-surface DoE varied protein concentration, pH, sucrose, arginine, and polysorbate 80 against aggregation, fragmentation, charge variants, viscosity, sub-visible particles, and both potencies. The resulting proven acceptable ranges support the control strategy; a formal expanded design space is not claimed. Overage: none. A fill overfill is justified in Section 3.2.P.3.2 solely to guarantee deliverable volume.

Physicochemical and biological characterisation of the formulated product confirms retention of higher-order structure and of both binding functionalities across the intended storage and in-use conditions, and is summarised in the stability data (Section 3.2.P.8). Sub-visible and sub-micron particles are characterised orthogonally by light obscuration (USP <788>) and micro-flow imaging (MFI) to distinguish proteinaceous from silicone-oil-derived populations.

3.2.P.2.3 Manufacturing Process Development

The manufacturing process (thaw of drug substance → compounding/formulation → bioburden-reduction and sterilising-grade filtration → aseptic fill into PFS → stoppering → 100% visual inspection → autoinjector assembly → labelling/packaging) evolved from the clinical to the commercial scale without change to the unit operations or their sequence. Scale-up focused on preserving the drug substance's exposure limits to the identified stresses:

• Interfacial and shear stress during recirculation, filtration, and filling were bounded by defining maximum pump speeds, filtration flux, and hold configurations; polysorbate 80 provides the primary mitigation.
• Filter compatibility and adsorptive protein/polysorbate loss were established for the sterilising-grade filter train (compatibility, extractables, bacterial retention, and non-specific adsorption confirmed at worst-case conditions).
• Hold-time studies defined validated maximum durations for the compounded bulk (pre- and post-sterile filtration) with respect to bioburden, endotoxin, and product quality.
• Container/device interactions (silicone-oil level, tungsten residue, needle-adhesive leachables) were characterised early and fed back into container selection (Section 3.2.P.2.4).

A summary comparison of clinical versus commercial process parameters and a batch-quality comparison support process comparability. Critical process parameters and their control are defined in Sections 3.2.P.3.3–3.2.P.3.4, and formal validation in 3.2.P.3.5.

3.2.P.2.4 Container Closure System

The primary container-closure system is a 1 mL long Type I borosilicate glass barrel with a staked-in stainless-steel needle, a rigid needle shield (RNS) with an elastomeric needle-shield inner, and a coated bromobutyl rubber plunger stopper. Selection was governed by the sensitivities of a high-concentration mAb:

• Low-tungsten syringes are specified to control the risk of tungsten-mediated protein aggregation arising from the pin-forming step of glass-syringe manufacture; residual tungsten is controlled at the syringe-supplier level and verified.
• Controlled siliconisation balances functional lubrication (break-loose and glide forces / autoinjector performance) against silicone-oil-induced sub-visible particle formation; baked-on/cross-linked siliconisation is used to minimise free silicone migration into the solution.
• Fluoropolymer-laminated (e.g., ETFE) plunger stoppers minimise leachables and maintain container-closure integrity and glide performance over shelf life.
• Needle-adhesive and elastomer leachables were characterised in an extractables/leachables (E&L) programme with toxicological risk assessment; no leachable exceeded its qualified safety threshold.

Container-closure integrity (CCI) is assured by a validated deterministic method (e.g., high-voltage leak detection / headspace) rather than by microbial-ingress challenge for routine control, in line with USP <1207>. Functional device performance is developed and verified per ISO 11608 for needle-based injection systems and is described further in Section 3.2.P.7. Full CCS composition, drawings, and specifications are provided in Section 3.2.P.7.

3.2.P.2.5 Microbiological Attributes

The drug product is a sterile-filtered, aseptically filled, single-use sterile solution with no antimicrobial preservative; an antimicrobial effectiveness test is therefore not applicable and none is included. Sterility assurance is provided by the validated aseptic process (Section 3.2.P.3.5), sterilising-grade filtration with post-use filter integrity testing, and container-closure integrity. Sterility (Ph. Eur. 2.6.1 / USP <71>) and bacterial endotoxins (Ph. Eur. 2.6.14 / USP <85>) are release specifications and are supported on stability by container-closure integrity (Section 3.2.P.8). Bioburden and endotoxin of the compounded bulk are controlled as in-process limits (Section 3.2.P.3.4).

3.2.P.2.6 Compatibility

As a single-use, ready-to-administer presentation, the product requires no reconstitution, dilution, or admixture, and no compatibility with infusion fluids or IV administration sets is required. Development compatibility studies addressed the relevant in-use and manufacturing contact surfaces:

• Fluid-path/device compatibility: confirmed by the container-closure and functional-verification data (Section 3.2.P.7), including full-shelf-life dose accuracy, injection time, and force performance.
• Manufacturing contact-material compatibility: filters, tubing, and product-contact surfaces qualified for extractables and non-specific adsorption (Section 3.2.P.2.3).
• In-use handling: the labelled room-temperature equilibration step prior to injection and the associated thermal-excursion allowance are supported by the in-use stability data (Section 3.2.P.8.1). The product is not to be shaken; handling instructions in the labelling reflect the agitation sensitivity established in development.

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3.2.P.3 Manufacture

3.2.P.3.1 Manufacturer(s)

Table 3.2.P.3-1. Manufacturers and responsibilities

Facility / role	Responsibility
Virtual Biopharma Inc. — sterile fill-finish site	Thaw, compounding, filtration, aseptic filling, stoppering, visual inspection
Device assembly site	Autoinjector assembly, functional inspection
Packaging/labelling site	Secondary packaging, labelling, serialisation
QC laboratories	Release and stability testing
Batch release / QP site	Certification and release

Each site holds a valid manufacturing authorisation/registration and operates under a current GMP status. Full names, addresses, and GMP certificates are provided in Module 1 / Section 3.2.A.1 as applicable.

3.2.P.3.2 Batch Formula

Table 3.2.P.3-2. Batch formula (per nominal commercial batch of 2000 L compounded bulk)

Component	Quantity per litre of formulated bulk	Function
TILA-278 drug substance	150 g (as protein)	Active
L-Histidine	~1.2 g	Buffer
L-Histidine hydrochloride monohydrate	~2.6 g	Buffer
Sucrose	75.3 g	Stabiliser / tonicity
L-Arginine hydrochloride	5.3 g	Stabiliser / viscosity reducer
Polysorbate 80	0.4 g	Surfactant
Water for injection	q.s. to 1.0 L	Vehicle

The target fill volume exceeds the 1.0 mL nominal deliverable volume by a validated overfill to compensate for hold-up in the syringe and device fluid path and to assure the labelled deliverable dose (Ph. Eur. 2.9.17 / USP <1>). This overfill does not increase the delivered active dose and is not an overage. Batch size and the number of finished units are documented in the batch record.

3.2.P.3.3 Description of Manufacturing Process and Process Controls

The commercial process is a standard aseptic fill-finish process for a monoclonal-antibody solution:

1. Thaw and pooling of drug substance. Frozen drug substance is thawed under controlled conditions and pooled. Controls: thaw temperature/time, post-thaw appearance, protein concentration, bioburden.
2. Compounding / formulation. Drug substance is adjusted to target with formulation buffer; polysorbate 80 is added from a concentrated stock; the bulk is mixed under controlled low-shear conditions. Controls: target protein concentration, pH, osmolality, polysorbate 80 content, mixing parameters.
3. Bioburden-reduction filtration and pre-filtration hold. The bulk is filtered to reduce bioburden; a validated maximum hold time applies. Controls: bioburden, endotoxin, hold time.
4. Sterilising-grade filtration. The bulk is filtered through a redundant (two-filter) 0.22 µm sterilising-grade filter train into the filling suite. Controls: pre- and post-use filter integrity (bubble-point/diffusion), filtration pressure/flux, hold time.
5. Aseptic filling and stoppering. The sterile solution is filled to target volume into pre-sterilised, siliconised PFS barrels and immediately stoppered under vacuum/vent. Controls: fill weight/volume (in-process, statistically monitored), stopper placement, environmental monitoring, first-air integrity.
6. 100% visual inspection. Automated inspection with a manual/AQL confirmatory stage removes units with visible particulate, fill-level, or cosmetic defects. Controls: validated inspection with defect libraries and AQL.
7. Autoinjector assembly (autoinjector presentation). Inspected PFS are assembled into the autoinjector under controlled conditions. Controls: assembly-force/torque, component presence, functional sampling.
8. Labelling, secondary packaging, and serialisation. Controls: label reconciliation, serialisation, tamper-evidence.

Storage and transport of finished product are at 2–8 °C, protected from light, and must not be frozen.

3.2.P.3.4 Controls of Critical Steps and Intermediates

Table 3.2.P.3-3. Critical in-process controls

Step	Parameter / test	Acceptance (proposed)
Compounding	Protein concentration	150 mg/mL ±
Compounding	pH	5.8 ± 0.3
Compounding	Osmolality	Report; target ~300 mOsm/kg
Compounding	Polysorbate 80 content	Within release range
Pre-sterile-filtration bulk	Bioburden	≤ 10 CFU/100 mL
Pre-sterile-filtration bulk	Endotoxin	≤ EU/mL
Bulk holds	Hold time (pre-/post-filtration)	≤ validated maximum
Sterile filtration	Filter integrity (pre/post)	Meets manufacturer's validated bubble-point/diffusion limit
Filling	Fill volume/weight	Target ± (statistically monitored)
Filling suite	Environmental monitoring / media-fill status	Within Grade A/ISO 5 limits; valid aseptic-process qualification
Visual inspection	Visible particulate / defects	Essentially free of visible particulates; AQL met
Assembly	Component functional checks	Meets device assembly spec

Intermediates (thawed/pooled drug substance and compounded bulk) are transient and controlled by the in-process tests and hold-time limits above.

3.2.P.3.5 Process Validation and/or Evaluation

Process performance qualification (PPQ) was executed on three consecutive commercial-scale batches for each presentation, demonstrating that the process reproducibly yields product meeting all in-process and release acceptance criteria. The validation package comprises:

• Aseptic process qualification by media fills covering worst-case interventions, durations, and batch size, meeting the contamination-rate acceptance criterion of zero growth per current guidance.
• Sterilising filtration validation: bacterial-retention (Brevundimonas diminuta challenge), product-specific compatibility, extractables, and adsorption at worst-case process conditions.
• Sterilisation/depyrogenation validation of product-contact components and the syringe/stopper.
• Hold-time validation for the compounded bulk (product quality, bioburden, endotoxin).
• Shipping/transport qualification of the finished product across the validated cold-chain conditions.
• Mixing, filling-uniformity, and in-process assay validation confirming homogeneity and delivered-volume control.

PPQ batch results met all acceptance criteria with no confirmed deviations affecting product quality. Continued process verification is established under the ongoing lifecycle programme.

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3.2.P.4 Control of Excipients

3.2.P.4.1 Specifications

All excipients — L-histidine, L-histidine hydrochloride monohydrate, sucrose, L-arginine hydrochloride, polysorbate 80, and water for injection — are controlled to their current compendial monographs (Ph. Eur. and/or USP–NF), supplemented where appropriate by additional supplier-agreed tests (e.g., a peroxide and total-oxidant limit and a specified oleic-acid/composition profile for polysorbate 80, given its role in oxidative degradation and particle formation).

3.2.P.4.2 Analytical Procedures

Compendial methods are applied per the relevant monographs. Any non-compendial supplementary method (e.g., polysorbate 80 peroxide value) is described and referenced.

3.2.P.4.3 Validation of Analytical Procedures

Compendial methods are used within their validated compendial scope and are verified for suitability in the sponsor's laboratories. Non-compendial supplementary methods are validated per ICH Q2.

3.2.P.4.4 Justification of Specifications

Excipient specifications follow the applicable pharmacopoeial monographs; the supplementary polysorbate 80 controls are justified by the surfactant's mechanistic role in product stability and its identified degradation pathways (Section 3.2.P.2.2). Excipient grades and levels are consistent with approved parenteral SC monoclonal-antibody products.

3.2.P.4.5 Excipients of Human or Animal Origin

No excipient is of human origin. Polysorbate 80 may be derived from vegetable or animal-sourced fatty acids; a plant (vegetable)-derived grade is specified, and TSE/BSE compliance is documented per the EMA note for guidance (EMEA/410/01) and Ph. Eur. 5.2.8. Supporting statements/certificates are in Section 3.2.A.2 as applicable. No excipient poses a viral- or TSE-safety concern.

3.2.P.4.6 Novel Excipients

There are no novel excipients; all are established for parenteral use and present in the FDA Inactive Ingredient Database / EU-approved products at or above the levels used here.

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3.2.P.5 Control of Drug Product

3.2.P.5.1 Specification(s)

The drug-product specification (release and shelf-life) is defined per ICH Q6B and includes appearance, identity, purity/impurities, potency (dual, reflecting the bispecific mechanism), general tests, and safety tests. Certain attributes (sterility, endotoxin) are release-only, verified on stability by container-closure integrity. Proposed acceptance criteria are given in Table 3.2.P.5-1.

Table 3.2.P.5-1. Drug product specification (proposed)

Attribute	Analytical procedure	Release acceptance criterion	Shelf-life acceptance criterion
Appearance (visual)	Visual (Ph. Eur. 2.2.1 / 2.2.2)	Clear to slightly opalescent, colourless to pale-yellow solution, essentially free of visible particles	Same
Visible particulates	Ph. Eur. 2.9.20 / USP <790>	Essentially free of visible particulates	Same
pH	Ph. Eur. 2.2.3	5.5 – 6.1	5.5 – 6.1
Osmolality	Ph. Eur. 2.2.35	Report result (target ~300 mOsm/kg)	Report result
Protein concentration	UV spectrophotometry (A280)	150 mg/mL ±	Same
Extractable / deliverable volume	Ph. Eur. 2.9.17 / USP <1>	≥ 1.0 mL	≥ 1.0 mL
Purity — monomer / HMW	SE-HPLC	Monomer ≥ 95 %; HMW ≤ 95 %	Monomer ≥ 95 %; HMW ≤ 95 %
Purity — non-reduced	CE-SDS (non-reduced)	Main ≥ 90 %	Main ≥ 90 %
Purity — reduced	CE-SDS (reduced)	Sum of principal chains ≥ 90 %	Same
Charge variants	iCIEF	Main / acidic / basic within ranges	Within ranges
Identity	iCIEF profile + potency-based identity (dual binding)	Consistent with reference standard	n/a (release)
Potency — anti-TL1A neutralisation	Cell-based reporter bioassay	80 – 125 % of reference	80 – 125 % of reference
Potency — IL-22R agonism	Cell-based reporter bioassay	80 – 125 % of reference	80 – 125 % of reference
Polysorbate 80 content	HPLC-ELSD/CAD	0.4 mg/mL ±	Within range
Sub-visible particles	Light obscuration, USP <788>	≥10 µm ≤ 6000/container; ≥25 µm ≤ 600/container	Same
Sterility	Ph. Eur. 2.6.1 / USP <71>	Sterile	Assured by CCI
Bacterial endotoxins	Ph. Eur. 2.6.14 / USP <85>	≤ EU/mg	n/a (release)
Container-closure integrity	USP <1207> deterministic method	Pass	Pass

Device/combination-product functional attributes (autoinjector and PFS) are specified and tested per Section 3.2.P.7 (e.g., injection time, delivered dose accuracy, activation force, break-loose/glide force, needle-safety function).

3.2.P.5.2 Analytical Procedures

• A280 UV for protein concentration.
• SE-HPLC for monomer, HMW aggregates, and LMW species.
• CE-SDS (reduced and non-reduced) for size-based purity/fragmentation and chain integrity.
• iCIEF for charge-variant distribution and as a component of identity.
• Dual cell-based potency bioassays: a reporter-gene neutralisation assay measuring inhibition of TL1A signalling (anti-TL1A arm) and a reporter-gene assay measuring IL-22 receptor activation (IL-22R agonist arm). The dual system, together with the charge profile, establishes identity specific to the bispecific molecule.
• Polysorbate 80 by HPLC with ELSD/charged-aerosol detection.
• Sub-visible particles by light obscuration (USP <788>), with micro-flow imaging as a characterisation/orthogonal tool to differentiate proteinaceous from silicone-oil particles.
• Compendial appearance, pH, osmolality, deliverable volume, sterility, endotoxin, and CCI methods as cited.

3.2.P.5.3 Validation of Analytical Procedures

All non-compendial procedures are validated in accordance with ICH Q2(R2) for the relevant characteristics (specificity, accuracy, precision, linearity, range, quantitation/detection limits as applicable). The potency bioassays are validated with particular attention to relative-accuracy, precision, and system-suitability, and are calibrated against the qualified reference standard (Section 3.2.P.6). Compendial methods are verified for suitability.

3.2.P.5.4 Batch Analyses

Representative batch-analysis data are provided for clinical (including TILA278-201 supply), PPQ, and stability-registration batches, demonstrating consistent manufacture and conformance to the proposed specification. All reported batches met acceptance criteria for both potencies, size and charge purity, and safety tests.

Table 3.2.P.5-2. Batch analysis summary (representative)

Attribute	Clinical batch(es)	PPQ batch 1	PPQ batch 2	PPQ batch 3
Protein conc. (mg/mL)
Monomer (SE-HPLC, %)
HMW (%)
Main (CE-SDS NR, %)
Main (iCIEF, %)
Anti-TL1A potency (%)
IL-22R potency (%)
Sub-visible ≥10 µm (/container)

3.2.P.5.5 Characterisation of Impurities

Product-related impurities/variants (HMW aggregates, LMW fragments, charge variants, and any bispecific-specific mispaired species) are characterised as described in the drug-substance dossier (3.2.S.3) and confirmed at the drug-product level. Process-related impurities are controlled predominantly by the drug-substance process (host-cell protein, residual DNA, Protein A, and process reagents; see 3.2.S). Product-specific to the drug product are the container/device-derived potential impurities — silicone oil, tungsten, and elastomer/adhesive leachables — controlled by container selection and E&L qualification (Sections 3.2.P.2.4 and 3.2.P.7). No new drug-product impurity requires additional qualification beyond those addressed in the drug-substance and E&L assessments.

3.2.P.5.6 Justification of Specification(s)

Acceptance criteria are justified by the combination of ICH Q6B principles, batch-manufacturing history and process capability, clinical-exposure (qualification) ranges bracketed by TILA278-201 and any supporting studies, stability behaviour, and assay capability. Potency ranges bound the clinically qualified activity for both mechanistic arms. Aggregate and sub-visible particle limits are set to protect immunogenicity-relevant quality, consistent with the low, non-dose-dependent injection-site-reaction finding observed in TILA278-201 (injection-site reactions were the principal drug-attributable adverse finding, without a dose-dependent trend). Safety-test limits follow compendial and endotoxin-per-dose calculations.

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3.2.P.6 Reference Standards or Materials

A two-tiered reference-standard system is employed: a qualified primary reference standard traceable to clinical (including TILA278-201) and toxicology material, and working reference standards qualified against the primary standard. Reference standards are characterised for identity, size and charge purity, higher-order structure, and both potencies, and are stored under conditions supporting long-term stability. Qualification, requalification, and bridging protocols are defined and executed under the lifecycle programme. The same reference standard system anchors the drug-substance and drug-product potency and purity methods to assure comparability across the program.

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3.2.P.7 Container Closure System

Primary packaging. 1 mL long Type I borosilicate glass syringe barrel with a staked-in 27-gauge thin-wall stainless-steel needle; rigid needle shield; and a fluoropolymer-laminated bromobutyl rubber plunger stopper. Low-tungsten barrels and controlled (cross-linked) siliconisation are specified (rationale in Section 3.2.P.2.4).

Presentations.

• PFS presentation: the primary syringe with a plunger rod and a passive needle-safety guard.
• Autoinjector presentation: the identical primary syringe integrated into a single-use, spring-driven autoinjector.

Specifications and drawings. Dimensional and material specifications, supplier drawings, and quality standards for each component (barrel, needle, shield, stopper, plunger rod, safety guard, autoinjector subassemblies) are provided. Elastomeric and glass components comply with the relevant Ph. Eur./USP requirements for parenteral containers and closures.

Combination-product / device performance. The autoinjector and PFS are combination products. Design and verification follow ISO 11608 (needle-based injection systems), with a design-controls/risk-management framework (ISO 13485 / ISO 14971) and human-factors/usability engineering supporting safe self-administration by UC patients. Functional performance is verified at release and monitored on stability, including:

Table 3.2.P.7-1. Device functional attributes (proposed)

Attribute	Method basis	Acceptance (proposed)
Delivered (dose) volume/accuracy	ISO 11608-1	≥ 1.0 mL; within 5 % of label
Injection time (autoinjector)	ISO 11608-5	≤ s
Activation force	ISO 11608-5	Within N
Break-loose / glide force (PFS)	ISO 11608-3	Within N
Needle-safety / lock-out function	ISO 11608-1	Functions as intended (pass)
Container-closure integrity	USP <1207>	Pass

Extractables and leachables. An E&L programme with toxicological risk assessment covers the glass, needle adhesive, elastomer, and silicone; results support patient safety across shelf life with no leachable exceeding its qualified threshold.

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3.2.P.8 Stability

3.2.P.8.1 Stability Summary and Conclusions

Stability of TILA-278 drug product is being established under ICH Q1A(R2), Q1B, and Q5C on registration batches of each presentation, stored in the final container-closure system in the intended orientation. The study design is summarised in Table 3.2.P.8-1.

Table 3.2.P.8-1. Stability study design

Condition	Temperature / RH	Orientation	Time points	Purpose
Long-term	5 °C ± 3 °C	Upright + horizontal	0, 3, 6, 9, 12, 18, 24, 36 mo	Shelf-life assignment
Accelerated	25 °C ± 2 °C / 60% RH ± 5%	Upright	0, 1, 3, 6 mo	Degradation-pathway / support
Stress	40 °C ± 2 °C / 75% RH ± 5%	Upright	0, 1, 2, 3 mo	Stability-indicating support
Photostability	ICH Q1B option 2	—	Single challenge	Light sensitivity
In-use / thermal excursion	Single excursion to ≤ 30 °C	Upright	Defined interval	In-use labelling
Agitation/transport	Simulated shipping	—	Post-challenge	Distribution robustness

Findings. Under the long-term 5 °C condition, all quality attributes — appearance, pH, protein concentration, size purity (SE-HPLC monomer/HMW; CE-SDS), charge distribution (iCIEF), both potencies, sub-visible particles, polysorbate 80 content, and container-closure integrity — remain within the proposed acceptance criteria through the data available to date, supporting the proposed shelf life. The primary temperature-dependent degradation observed under accelerated and stress conditions is an increase in HMW aggregate and acidic charge variants with associated modest potency change, consistent with the pathways identified in development; these changes are slow at the recommended storage condition. Photostability confirms the product is light-sensitive and must be stored in its carton, protected from light. Simulated-transport and in-use excursion challenges support the proposed handling and excursion allowances.

Proposed storage statement and shelf life. Store at 2–8 °C. Do not freeze. Keep in the original carton to protect from light. Do not shake. Proposed shelf life: 24 months at 2–8 °C, to be extended as real-time data accrue under the post-approval protocol.

In-use statement. The product may be kept at room temperature (up to 30 °C) for a single period of up to 14 days within the labelled shelf life; after room-temperature storage it must not be returned to the refrigerator, and any unused product is discarded. Allow the product to reach room temperature before injection; do not warm by any other means.

3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment

At least one commercial-scale batch per presentation per year (annual batches) will be placed on the long-term stability program under the protocol above and monitored to the end of the assigned shelf life. The sponsor commits to (i) complete long-term studies on the primary registration batches, (ii) place the first three commercial-scale batches of each presentation on long-term stability, and (iii) report out-of-specification/out-of-trend results and any consequent shelf-life or labelling changes to the agency. Any change extending or modifying the shelf life will be supported by data under this protocol.

3.2.P.8.3 Stability Data

Full tabulated and, where informative, graphical stability data for each registration batch, presentation, condition, and attribute are provided in this section. Data are trended against the shelf-life acceptance criteria; no attribute shows a trend projected to breach acceptance within the proposed shelf life at the recommended storage condition.

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Prepared in accordance with ICH M4Q (CTD Quality), ICH Q6B, and ICH Q8(R2); cross-references to Q1A(R2)/Q1B/Q5C (stability), Q2(R2) (analytical validation), Q5A(R2)/Q5E (viral safety and comparability, in 3.2.S/3.2.A), and Q9/Q10 (quality risk management and pharmaceutical quality system).