📚 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 — Device & Combination Product (TILA-278)

Document ID: M3-DEV
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): 21 CFR 4; ISO 11608

Device & Combination-Product Information — TILA-278

The subcutaneous presentation of TILA-278 in a prefilled syringe/autoinjector is a combination product (21 CFR Part 4). This section summarises device design controls (design inputs/outputs, verification and validation), human-factors / usability engineering (use-related risk analysis and a validation study), biocompatibility (ISO 10993), and essential performance requirements. 21 CFR 4/820.30; ISO 11608; IEC 62366.

TILA-278 is a recombinant humanized IgG1 bispecific monoclonal antibody (anti-TL1A antagonist arm / IL-22 receptor agonist arm), expressed in a Chinese Hamster Ovary (CHO) cell line and formulated as a high-concentration (150 mg/mL) sterile aqueous solution for subcutaneous (SC) injection. The two market presentations — a single-use prefilled syringe (PFS) with a passive needle-safety guard and a single-use, spring-driven autoinjector incorporating the same primary container as its fluid-path component — are intended for repeat self- or caregiver-administration by adults with moderate-to-severe ulcerative colitis (UC), predominantly in the home/non-clinical setting. The engineering challenge that shapes the entire device programme is the reliable SC delivery of a viscous protein solution by a lay user with an active inflammatory bowel disease: the device must overcome the solution's dynamic viscosity across the full label-claim shelf life and temperature range, deliver the complete labelled dose, provide unambiguous end-of-dose feedback, and prevent sharps injury. The primary container-closure system, its material selection (low-tungsten Type I glass barrel, staked-in 27-gauge thin-wall stainless-steel needle, controlled cross-linked siliconisation, fluoropolymer-laminated bromobutyl plunger stopper), the extractables/leachables (E&L) programme, and the device functional-performance specifications are defined in Sections 3.2.P.2.4 and 3.2.P.7 and are cross-referenced rather than repeated here. This section provides the combination-product regulatory framework, the design-control and design-validation narrative, the human-factors/usability programme, the biocompatibility evaluation, and the sterility, reliability, risk-management, labelling, and lifecycle content that a reviewer expects for the device constituent part.

1. Regulatory Classification and Combination-Product Framework

TILA-278 in either presentation is a single-entity (co-packaged into one product) combination product comprising a biological-product constituent (the TILA-278 solution) physically combined with a device constituent (the PFS or autoinjector delivery system), as defined at 21 CFR 3.2(e). The primary mode of action is attributable to the biological constituent — the therapeutic effect derives from TL1A antagonism (anti-inflammatory/anti-fibrotic) combined with IL-22R agonism (epithelial and mucosal-barrier repair), not from the delivery device. Accordingly the combination product is regulated under a Biologics License Application (BLA) pursuant to 21 CFR Part 601, reviewed by CDER as the lead centre with device-constituent expertise obtained through intercenter consultation with CDRH.

Current good manufacturing practice for the combination product follows the streamlined approach of 21 CFR 4.4(b): the operation is based on the drug/biologic cGMP system (21 CFR 210/211) and is supplemented with the specified device Quality System provisions applicable to the device constituent — in particular design controls (21 CFR 820.30), corrective and preventive action (820.100), purchasing controls (820.50), acceptance activities (820.80 and 820.86), and traceability/records (820.30(j), Design History File). An overarching quality management system consistent with ISO 13485 and a product-realisation risk-management process consistent with ISO 14971 span both constituents.

For the European Union, the integral device constituent of a single-integral combination product is addressed under Article 117 of Regulation (EU) 2017/745 (MDR): the marketing-authorisation dossier includes a Notified Body Opinion (NBOp) on the conformity of the device part with the relevant General Safety and Performance Requirements (Annex I of the MDR). For the Republic of Korea, the drug-led combination product is submitted under the MFDS biologic-product framework with the delivery device evaluated as an integral constituent. The design-control, human-factors, biocompatibility, and functional-verification evidence summarised here supports each of these regional submissions from a common technical file.

2. Device Configurations and Essential Design Inputs

Configurations. Two configurations are built on a common primary container and formulated solution and differ only in the assembled secondary device:

• Prefilled syringe (PFS) — the primary syringe fitted with a plunger rod, finger flange, and a passive needle-safety guard that deploys automatically after full plunger travel; manual injection by the user.
• Autoinjector — the identical primary syringe integrated into a single-use, disposable, spring-driven autoinjector that automates needle insertion, dose delivery, and needle retraction/shielding, with an audible and visual end-of-dose indicator.

Both deliver the 150 mg/mL solution at a 1.0 mL nominal deliverable volume through a 27-gauge thin-wall staked-in needle (dimensional and material specifications, tolerances, and supplier drawings in Section 3.2.P.7).

Intended use, users, and use environment. The intended use is SC self-injection (or caregiver injection) for the treatment of moderate-to-severe UC. The user population includes adults who may present with disease-related fatigue, urgency, arthralgia, or manual-dexterity and visual limitations; the use environment is unsupervised and non-clinical (home, travel). These intended-use characteristics are formal design inputs and drive the essential performance requirements, the usability-engineering programme (Section 4), and the labelling/instructions-for-use (Section 9).

Essential performance requirements. The device-constituent essential performance requirements are derived from the Quality Target Product Profile (Module 3.2.P / M3-QTPP), the intended use, the use environment, and the applicable standards of the ISO 11608 series for needle-based injection systems. Acceptance criteria for each attribute are established and reported in Section 3.2.P.7; the requirements and their standard basis are summarised below.

Table M3-DEV-1. Essential performance requirements and design-input basis

Essential performance requirement	Design-input basis	Standard / method basis	Acceptance criterion
Deliver the full labelled dose SC	Dose / exposure–response	ISO 11608-1	Delivered volume ≥ 1.0 mL; dose accuracy within 5 % of label (see 3.2.P.7)
Reproducible injection (delivery) time — autoinjector	Usability; hold-against-skin tolerability	ISO 11608-5	Defined in 3.2.P.7
Activation/actuation force within user capability	UC-population dexterity/strength	ISO 11608-5	Defined in 3.2.P.7
Break-loose and glide force — PFS	Manual-injection usability at 150 mg/mL viscosity	ISO 11608-3	Defined in 3.2.P.7
Needle penetration appropriate for SC route	Anatomy; SC delivery	ISO 11608-1	27-gauge thin-wall staked-in needle; SC depth
Unambiguous end-of-dose feedback	Complete-dose assurance	IEC 62366-1 / ISO 11608-5	Audible/visual/tactile cue verified
Passive needle-safety / lock-out after use	Sharps-injury prevention	ISO 11608-1	Functions as intended (pass)
Robustness to shipping, drop, and temperature cycling	Distribution and use environment	ISO 11608-1; transport-simulation standards	Functional after challenge
Container-closure integrity of the fluid path	Sterility maintenance	USP <1207>	Meets integrity criteria

3. Design Controls, Verification, and Validation (21 CFR 820.30)

The device constituent is developed and maintained under a design-control system compliant with 21 CFR 820.30 and consistent with ISO 13485, with the full record retained in the Design History File (DHF) and the released configuration captured in the Device Master Record (DMR).

Design and development planning; design inputs and outputs. A design and development plan defines the deliverables, reviews, and responsibilities. Design inputs comprise the essential performance requirements of Table M3-DEV-1, the intended use/user/environment specification, applicable standards (ISO 11608-1/-3/-5, IEC 62366-1, ISO 10993 series, ISO 14971), and the constraints imposed by the drug constituent (notably the ~150 mg/mL solution viscosity that governs spring energy and needle selection). Design outputs are the component and assembly specifications, drawings, tolerances, the DMR, and acceptance procedures (Section 3.2.P.7).

Design verification confirms that design outputs meet design inputs. The verification programme is executed with representative combination-product units filled with the TILA-278 drug product (and, where a worst-case rheology challenge is required, with solution at the maximum end-of-shelf-life viscosity) and includes: delivered-volume/dose accuracy, injection (delivery) time, activation force, break-loose and glide force, needle-safety/lock-out function, end-of-dose indication, free-fall/drop resistance, temperature cycling, and simulated-transport robustness. Testing is conducted across the specified conditioning envelope (including cold-chain-removed, room-temperature-equilibrated use) and at end-of-shelf-life to bound the effects of silicone-oil redistribution, plunger–barrel interaction, and viscosity on delivery performance. Sample sizes and acceptance are set on a statistical reliability/confidence basis (attribute and variables sampling with tolerance-interval justification) commensurate with the criticality of each function.

Design validation confirms that the device meets user needs and intended uses under actual or simulated use conditions. It integrates (i) the summative human-factors validation study (Section 4), (ii) simulated-use and actual-use reliability demonstrations across the range of representative users and conditions, and (iii) confirmation that the device reliably delivers the intended SC dose that underpins the clinical exposure achieved in study TILA278-201. Design transfer establishes that the verified/validated design is correctly translated into production and assembly specifications; design changes are controlled through the change-management system with re-verification/re-validation as risk dictates.

4. Human-Factors / Usability Engineering

Usability engineering is conducted per IEC 62366-1 and the FDA human-factors guidance for medical devices and combination products, integrated with the risk-management process of ISO 14971.

Use specification and use-related risk analysis. A use specification defines the intended users (UC patients and caregivers), uses, and environments. A use-related risk analysis (use-FMEA / task analysis) decomposes the full use scenario — storage retrieval, room-temperature equilibration, inspection, cap removal, site selection, placement, actuation, hold-to-completion, needle-safety confirmation, and disposal — into tasks and identifies critical tasks whose failure could cause harm (for example, incomplete dose from premature device removal before end-of-dose indication, use of a damaged or wrong-temperature unit, or failure to confirm needle-safety engagement). A perception–cognition–action model and a known-use-problem analysis of marketed PFS and autoinjector systems informed hazard identification and the mitigation of use errors previously observed with analogous self-injection devices.

Formative and summative studies. Iterative formative evaluations refined the device, the instructions for use (IFU), the labelling, and any training materials, with each iteration reducing use-error frequency and severity on the critical tasks. A summative (validation) human-factors study was then conducted with representative participants — including patients with UC and lay caregivers, spanning the relevant range of dexterity, vision, and prior injection experience — performing all critical tasks in a simulated home-use environment without hands-on assistance. Use errors, difficulties, and close calls were captured and subjected to root-cause analysis; residual use-related risk was evaluated for acceptability. Instructions for use, labelling, and training constitute the principal risk-control measures for use-related hazards, and their adequacy was demonstrated in the summative study. The usability-engineering file concludes that the critical tasks are performed successfully by the intended users and that residual use-related risks are acceptable in the context of the clinical benefit.

5. Biocompatibility (ISO 10993)

The biological safety of the patient-contacting and fluid-path materials is evaluated within a risk-management process in accordance with ISO 10993-1. Contact is categorised by nature and duration: the staked-in needle is an externally communicating component with limited (≤ 24 h, repeated) tissue/breached-skin contact during injection, while device-housing surfaces that contact intact skin are surface-contacting components of limited duration.

Fluid-path (indirect) contact is addressed principally through the chemical characterisation and toxicological-risk-assessment arm of the programme: extractables/leachables studies on the glass, needle, needle adhesive, elastomeric closure, and silicone (Sections 3.2.P.2.4 and 3.2.P.7) provide the chemical characterisation per ISO 10993-18, and the identified leachables are subjected to a toxicological risk assessment per ISO 10993-17, with no leachable exceeding its qualified safety threshold. Patient-contacting components (needle, needle-shield exterior, housing) are evaluated for the biological endpoints appropriate to the contact category — cytotoxicity (ISO 10993-5), sensitisation (ISO 10993-10), and irritation/intracutaneous reactivity (ISO 10993-23) — supplemented by material-mediated pyrogenicity and, where warranted by the risk assessment, acute systemic toxicity. The evaluation leverages materials with established biocompatibility and long clinical use in marketed injectable delivery systems; the overall biological-evaluation report concludes that the device constituent presents an acceptable biological-safety profile for its intended repeated SC use.

6. Device Sterility Assurance and Container-Closure Integrity

The fluid path is presented sterile. Sterility of the filled syringe is assured by the validated aseptic fill-finish process for the drug product (Section 3.2.P.3.5), and the primary-container components entering the sterile fluid path (barrel, staked-in needle, plunger stopper) are sterilised and, where applicable, depyrogenated by validated processes achieving a sterility assurance level of 10⁻⁶ (e.g., ISO 11135 for ethylene oxide or ISO 11137 for radiation, as applicable to the component). Non-fluid-path secondary components of the autoinjector are supplied non-sterile. Container-closure integrity (CCI) of the fluid path — the microbial and physical barrier that maintains sterility across shelf life and device handling — is demonstrated by a validated deterministic method in accordance with USP <1207> (Sections 3.2.P.2.5 and 3.2.P.7) and is monitored on stability in lieu of routine sterility testing. Device actuation, drop, and transport challenges are performed with attention to maintaining CCI, so that mechanical handling of the combination product does not compromise the sterile barrier.

7. Device Reliability and Shelf-Life Functional Performance

Because the device is used repeatedly by lay users over the product's shelf life, functional performance is qualified not only at release but across the assigned shelf life and the labelled in-use and thermal-excursion conditions. The autoinjector spring energy, and the PFS break-loose/glide profile, are designed against the maximum solution viscosity encountered at 150 mg/mL under worst-case (cold-equilibrated, end-of-shelf-life) conditions, so that delivered dose, delivery time, and activation/glide forces remain within the acceptance ranges of Section 3.2.P.7 throughout use. Functional attributes (delivered volume/dose accuracy, injection time, activation force, break-loose/glide force, needle-safety function, end-of-dose indication, and CCI) are verified at release and trended on stability (Section 3.2.P.8), with end-of-shelf-life timepoints bounding silicone-oil redistribution, plunger-set, and closure-relaxation effects. A reliability demonstration with defined confidence/reliability targets supports the essential performance claims, and continued functional monitoring is maintained under the lifecycle programme.

8. Risk Management Integration (ISO 14971)

Device and combination-product risk is managed within an overarching ISO 14971 risk-management file (supported by ISO/TR 24971 guidance) that spans the full product lifecycle and is integrated with the drug-product quality risk management (ICH Q9). The file consolidates the design (hardware) hazard analysis and design-FMEA, the use-related risk analysis/use-FMEA (Section 4), the process-FMEA for fill/finish and device assembly, and the biological and E&L risk assessments (Sections 5–6). Combination-product-specific hazards analysed include underdose or incomplete dose (premature removal, blockage of a viscous protein solution, mis-actuation), overdose, wet or failed injection, needle-stick/sharps injury, premature or no needle deployment, use of a compromised (frozen, damaged, expired, or contaminated) unit, and loss of sterility. Each hazard is linked to design and/or information-for-safety risk controls whose effectiveness is verified in design verification and validation; residual risks are evaluated individually and in aggregate against the clinical benefit demonstrated in TILA278-201, and the overall residual risk is judged acceptable. Production and post-production information, including complaints and field performance, feeds back into the risk-management file under the post-approval lifecycle process (Section 10).

9. Labelling, Instructions for Use, and Training

Patient-facing labelling — the carton, container label, and Instructions for Use (IFU) — is developed as a risk-control measure and validated through the usability-engineering programme (Section 4). The IFU covers inspection of the solution and device, room-temperature equilibration before injection, injection-site selection and rotation, step-by-step actuation, confirmation of dose completion via the end-of-dose indicator, needle-safety confirmation, and sharps disposal. Storage and handling instructions are aligned with the drug-product stability conclusions (Section 3.2.P.8): store at 2–8 °C, do not freeze, protect from light in the original carton, do not shake, allow to reach room temperature before injection, and observe the defined in-use/room-temperature excursion allowance. Any patient training materials and the graphical content of the IFU are finalised on the basis of formative and summative human-factors findings.

10. Post-Approval Lifecycle and Surveillance

Post-approval, the device constituent is maintained under the combination-product quality system with combination-product postmarketing safety reporting obligations (21 CFR Part 4, Subpart B) and applicable medical-device reporting requirements (21 CFR 803) and, in the EU, MDR vigilance via the Notified Body Opinion framework. Complaint handling and malfunction analysis feed the CAPA system and the ISO 14971 post-production risk-management loop; design changes to the device constituent are managed through change control with re-verification/re-validation and, where required, regulatory notification. Continued functional-reliability monitoring, ongoing stability of the device functional attributes (Section 3.2.P.8), and periodic reassessment of the use-related risk profile ensure that the delivery system continues to reliably administer the intended SC dose of TILA-278 across the marketed lifecycle.

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Prepared in accordance with 21 CFR Part 4 (combination-product cGMP; streamlined approach per 21 CFR 4.4) and 21 CFR Part 601 (BLA), with the device constituent developed under 21 CFR 820.30 design controls and ISO 13485; functional design and verification per the ISO 11608 series; usability engineering per IEC 62366-1; biological evaluation per the ISO 10993 series; and risk management per ISO 14971. Container-closure, E&L, and device functional specifications are provided in Sections 3.2.P.2.4 and 3.2.P.7; sterility assurance and stability in Sections 3.2.P.2.5, 3.2.P.3.5, and 3.2.P.8.