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Pharmacy Manual (TILA278-201)

Document ID: TMF-010
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E6(R3)

Pharmacy Manual — TILA278-201

This Pharmacy Manual provides instructions for the site pharmacy in Study TILA278-201: receipt, storage (per the Module 3 conditions), accountability, preparation and subcutaneous administration of TILA-278, blinding handling, and return/destruction. ICH E6(R3); GMP Annex 13/IMP.

TILA-278 is a recombinant, humanized IgG1 bispecific monoclonal antibody produced by Chinese hamster ovary (CHO) cell culture and purified by Protein A affinity capture followed by orthogonal polishing chromatography. It is presented as a sterile, preservative-free liquid for subcutaneous (SC) injection. One antigen-binding arm antagonizes TL1A (TNFSF15), dampening TH1/TH17-driven mucosal inflammation and fibrosis; the second arm is an agonist of the IL-22 receptor, promoting epithelial regeneration and mucosal-barrier repair. TILA-278 and its matching placebo are supplied as investigational medicinal product (IMP) manufactured, labeled, packaged, and released in accordance with GMP Annex 13. The chemistry, manufacturing, and controls basis for the product — including specifications (ICH Q6B), viral safety (ICH Q5A(R2)), and the stability program that establishes the storage conditions and shelf life referenced in this manual (ICH Q5C) — is documented in Module 3, consistent with the intended marketing application as a biologic under 21 CFR Part 601. Nonclinical characterization was conducted per ICH S6(R1).

Study TILA278-201 is a randomized, double-blind, placebo-controlled, parallel-group, 12-week induction study in subjects with moderate-to-severe ulcerative colitis (UC). Of 1700 subjects screened, 900 were randomized 1:1:1 to TILA-278 High (n=299), TILA-278 Low (n=300), or Placebo (n=301). The pharmacy is responsible for managing the blinded IMP supply across all three assignment groups without compromising the treatment blind. In the event of any conflict between this manual and the clinical study protocol regarding a subject's treatment, the protocol prevails, and the discrepancy is escalated to the sponsor for reconciliation.

This manual is a controlled Trial Master File (TMF) document and is read in conjunction with the protocol, the IMP label, the Investigator's Brochure (IB), the Randomization/IWRS Plan (TMF-012), and the Laboratory Manual (TMF-011, for the coordination of pharmacokinetic [PK] and anti-drug antibody [ADA] sampling around dosing). Site handling is additionally governed by applicable pharmacy standards for sterile compounding (e.g., USP General Chapter <797>) and cold-chain custody (e.g., USP General Chapter <1079>), and by local regulation where more stringent.

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1. Roles, Responsibilities, and Access Control

1.1 Accountability at the site

The Principal Investigator (PI) is ultimately accountable for the receipt, storage, dispensing, administration, reconciliation, and return/destruction of IMP at the site. The PI may delegate IMP-handling tasks to a qualified pharmacist or appropriately trained designee, with each delegation documented on the site Delegation of Authority log and supported by current GCP and protocol training filed in the Investigator Site File (ISF).

1.2 Preservation of the blind

TILA-278 High, TILA-278 Low, and Placebo are managed under a double-blind design. Where the presentations are fully indistinguishable in the container as supplied, all pharmacy and clinical staff may remain blinded throughout. Where preparation of the assigned dose could reveal treatment identity (for example, a difference in fill volume, concentration, or number of injections between the High, Low, and Placebo assignments), an unblinded pharmacist — functionally separated from the blinded study team and from outcome assessment — performs preparation and masking so that the syringe(s) delivered to the blinded administrator are identical in appearance across all assignments. The unblinded pharmacist does not communicate treatment identity to any blinded team member and does not participate in efficacy or safety assessment.

1.3 Access control

IMP and the Interactive Response Technology (IRT/IWRS) are maintained under restricted, auditable access. Only delegated staff may enter the storage area, transact in the IRT, or perform preparation. Access credentials, keys, and the temperature-monitoring records are controlled to prevent unauthorized dispensing and to protect the blind. The sponsor, the sponsor's clinical supply organization, and the central depot support receipt, resupply, temperature-excursion disposition, and returns/destruction as described below.

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2. Investigational Medicinal Product Description

2.1 Presentation

Attribute	Description
Active substance	TILA-278, recombinant humanized IgG1 bispecific monoclonal antibody (anti-TL1A antagonist / IL-22 receptor agonist), CHO cell culture-derived
Dosage form	Sterile, preservative-free solution for subcutaneous injection
Assignments	TILA-278 High, TILA-278 Low, matching Placebo (vehicle only)
Container-closure	Single-use unit as supplied and labeled (per the IMP label and Module 3), for single-dose administration
Appearance	Colorless to pale yellow solution; a slight opalescence may be present owing to the protein content; free of visible foreign particulate matter

The formulation vehicle is a buffered protein-stabilizing matrix (for example, a histidine-buffered solution containing a stabilizing sugar and a low concentration of polysorbate surfactant), as specified in Module 3. The matching Placebo is the identical vehicle without active substance. Each unit is single-use; any product remaining after preparation of the assigned dose is discarded and is not pooled or retained for a subsequent administration.

2.2 Product handling characteristics

As a therapeutic protein, TILA-278 is sensitive to freezing, mechanical stress, heat, and prolonged light exposure, each of which can promote aggregation or subvisible particle formation. The product must not be frozen or shaken, and must be protected from light in its original carton until immediately before use. TILA-278 is not a cytotoxic or otherwise hazardous drug; routine aseptic technique and standard universal precautions are sufficient, and specialized hazardous-drug (e.g., NIOSH-listed) containment is not required.

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3. Receipt of Shipments

IMP is shipped under validated cold-chain (2 °C to 8 °C) with a temperature-monitoring device (data logger) in each shipment. On arrival, the delegated pharmacist:

1. Confirms the shipment against the packing list and IRT shipment record;
2. Reads and stops the temperature monitor, records the result, and retains the device/record;
3. Inspects the cartons for damage, tampering, or signs of freezing;
4. Immediately transfers acceptable product to 2 °C–8 °C monitored storage;
5. Acknowledges receipt in the IRT within the timeframe defined by the sponsor (target within 24 hours of receipt).

Any shipment arriving with a temperature-monitor alarm, evidence of freezing, or physical damage is placed in a segregated, clearly labeled quarantine area, marked "Do Not Use," and reported to the sponsor/depot. Quarantined product is not dispensed until the sponsor provides a documented usability disposition (Section 5).

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4. Storage Conditions and Environmental Monitoring

4.1 Conditions

TILA-278 and Placebo are stored refrigerated at 2 °C to 8 °C, in the original carton to protect from light, in a secure, limited-access, IMP-dedicated location. Do not freeze. Do not shake. IMP is segregated from routine clinical stock to prevent inadvertent use.

4.2 Monitoring

The storage unit is temperature-monitored with a calibrated device providing continuous or minimum/maximum recording. Temperatures are checked and documented on each working day, including current, minimum, and maximum readings since the last check. Calibration of monitoring devices is current and documented. A contingency plan (backup refrigerator or alarmed system) is in place to protect stock during power interruption or equipment failure. All temperature records are retained in the pharmacy file.

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5. Temperature Excursion Management

Any reading outside 2 °C to 8 °C — including any evidence of freezing — is a reportable excursion. On detection, the pharmacist:

1. Immediately segregates and quarantines the affected product with a "Do Not Use" label;
2. Records the minimum/maximum temperature reached and the total duration outside range;
3. Notifies the sponsor/depot without delay and supplies the excursion data.

The sponsor performs a stability-based usability assessment against the approved conditions and the mean-kinetic-temperature allowances defined in the Module 3 stability program (ICH Q5C) and returns a written disposition (release to use or destroy). Excursion product remains quarantined and is not dispensed until a documented release is received. Frozen product is not to be used.

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6. Randomization, Blinding, and IRT

Treatment assignment and kit allocation are managed through the IRT/IWRS in accordance with the Randomization/IWRS Plan (TMF-012). At each dosing visit the IRT identifies the kit(s) to be dispensed for the subject. The pharmacy dispenses strictly the IRT-designated kit(s) and does not substitute. Where preparation could reveal assignment, the unblinded pharmacist masks the prepared syringe(s) so that appearance is identical across High, Low, and Placebo (Section 1.2). Emergency code-break/unblinding is performed only through the controlled mechanism described in TMF-012, is restricted to circumstances where knowledge of the assignment is essential to the subject's clinical management, and is documented (who, when, why). Individual emergency unblinding does not unblind the study team beyond what is strictly necessary.

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7. Preparation

Preparation is performed by delegated staff using aseptic technique consistent with USP <797> in a clean, dedicated preparation area, and follows the exact steps below:

1. Verify the IRT-assigned kit number(s), subject identifier, visit, and expiry; confirm the kit has not been quarantined or recalled.
2. Equilibrate the product to room temperature by removing it from refrigeration in its original carton for approximately 30 minutes. Do not apply external heat and do not use a water bath, microwave, or other forced-warming method.
3. Inspect the solution visually. It should be colorless to pale yellow and may be slightly opalescent. Do not use product that is cloudy, discolored, or contains visible foreign particulates, or that shows a compromised container-closure.
4. Do not shake. Mix, if directed, only by gentle handling to avoid foaming and aggregation.
5. Prepare a single dose from a single-use unit using aseptic technique. TILA-278 is supplied ready for SC administration; no reconstitution is required. Where the assigned dose is drawn into a syringe, the unblinded pharmacist prepares and masks it so that the delivered injection(s) are indistinguishable across assignments.
6. Label and hand off. Label the prepared dose with the protected subject/kit identifiers required by the blind. Once removed from refrigeration, administer within 2 hours; do not return an equilibrated or prepared dose to the refrigerator for later use, and discard any prepared dose not administered within that period.

Preparation of each dose is documented, and preparation records are retained in the pharmacy file.

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8. Dose and Subcutaneous Administration

8.1 Administration

TILA-278 is administered subcutaneously only, by trained and delegated site personnel, at the scheduled dosing visits during the 12-week induction period. Recommended injection sites are the abdomen (avoiding the area immediately around the navel), the anterior thigh, or the upper arm. Rotate injection sites between doses and avoid skin that is tender, bruised, erythematous, indurated, or scarred, or areas of active dermatologic disease. Where more than one injection is required to deliver the assigned dose, injections are given at separated sites; to preserve the blind, all subjects receive the same number and appearance of injections regardless of assignment. Individual SC injection volume is kept within the volume appropriate for the site (generally not exceeding 2 mL per injection). Do not administer product that is expired, damaged, quarantined, or under an unresolved temperature excursion.

8.2 Post-dose observation

Because hypersensitivity (including anaphylaxis) and immunogenicity are recognized risks for therapeutic proteins, subjects are observed after dosing for signs of hypersensitivity or injection-site reaction — for at least 30 minutes following the first administration and per protocol thereafter. Emergency medications and equipment for the management of an acute hypersensitivity reaction are available at the point of administration. Injection-site reactions and any hypersensitivity signs are reported to the investigator for adverse-event handling.

8.3 Coordination with PK/ADA sampling

Dosing is coordinated with the pharmacokinetic and anti-drug antibody sampling schedule (Laboratory Manual, TMF-011). Because exposure of this antibody is governed by target-mediated drug disposition and ADA formation may alter exposure and safety, the timing of dose administration relative to sample collection is documented so that pre-dose and post-dose samples are correctly attributed.

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9. Drug Accountability and Reconciliation

The pharmacy maintains complete, contemporaneous accountability for every unit of IMP received, dispensed, administered, partially used, unused, returned, or destroyed. For each transaction the record captures the kit/lot number, subject and visit, date, quantity, the responsible individual, and the corresponding IRT transaction. Used, unused, and partially used units are retained under the required conditions until reconciled. The clinical monitor reviews accountability and reconciles the pharmacy records against the IRT and source at monitoring visits and before site closeout; discrepancies are investigated, documented, and resolved. Resupply is triggered through the IRT to maintain adequate, in-date stock without over-supply.

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10. Returns and Destruction

Used containers, unused kits, and expired or quarantined stock are handled per the sponsor's returns and destruction procedure. On-site destruction is permitted only where authorized in writing by the sponsor and performed by a validated method that maintains the blind and complies with local requirements; otherwise, product is returned to the sponsor-designated depot. Accountability reconciliation is completed before any destruction, and certificates of destruction (or return records) are retained in the pharmacy file. No IMP is destroyed until the sponsor has confirmed that reconciliation is complete.

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11. Spills, Waste, and Occupational Safety

TILA-278 is a non-cytotoxic therapeutic protein; specialized hazardous-drug containment is not required. Minor spills are cleaned using standard aseptic and universal-precaution measures, with absorbent material and appropriate surface decontamination, and the event documented. Sharps and biological waste are disposed of in designated containers in accordance with local occupational-health and waste-management requirements.

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12. Documentation, Training, and Retention

Site pharmacy staff are trained on this manual, the IMP label, the IRT, blinding and preparation procedures, and accountability requirements before handling IMP and on material updates, with training documented in the ISF/TMF. The pharmacy file — including this manual, the delegation records, shipment and receipt records, temperature-monitoring logs and excursion dispositions, preparation and accountability records, IRT confirmations, and return/destruction records — is maintained and retained in accordance with ICH E6(R3) and applicable regional record-retention requirements.

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13. Study Contacts

Sponsor (Virtual Biopharma Inc.) clinical-supply, medical-monitor, and IRT/IWRS help-desk contacts, and the central depot, are listed on the current study contact list distributed to the site. Sites direct questions on IMP receipt, storage, temperature excursions, preparation, accountability, and returns/destruction to the corresponding contact, and route any question affecting a subject's clinical management to the medical monitor.