Atara Biotherapeutics



Background
Atara Biotherapeutics (Atara) www.atarabio.com is in clinical development of a new biotherapeutic protein. The drug product is filled at a contract manufacturing operator (CMO) and shipped to the labeling site on the east coast of the US for subsequent clinical trials. Release samples are sent from the CMO to a third-party for analysis.

Atara was seeking to identify and implement a revised frozen logistics process to transport the next shipment of palletized clinical trial material. As part of this process, Modality Solutions was tasked to execute a ‘turnkey’ packaging solution that:
  • Targeted clinical material to maintain frozen condition (temperature target range of -20°C) for a minimum of 48 hours
  • Maintained shipment integrity during handling and transit
  • Eliminated vial breakage
  • Provided proper data logger placement during transit for monitoring
  • Executed training on standard operating procedures with CMO
After providing a short-term frozen shipping solution (Phase 1), Atara also wanted to evaluate a liquid formulation that would ship at refrigerated (2° to 8°C) temperatures (Phase 2). The previous combination of transportation mode and deep frozen conditions had been identified as a potential cause for broken vial incidents. Modality Solutions provided a path forward (timelines, cost estimates, and risks) for developing liquid formulation studies for distribution.

Objectives
The objectives of our consulting assistance included:
Phase 1
  • Designing and implementing triage shipping plan
  • Identifying and sourcing required packaging materials (thermal packaging, refrigerants, and secondary packaging) for planned shipments of release samples and production volumes of drug product
  • Qualifying packaging in a package testing lab
  • Creating training documentation for pack out
  • Providing on-site training to CMO personnel to ensure proper pack out
  • Identifying logistics service provider to ensure successful shipment according critical-to-quality attributes (e.g. temperature within indicated range, no physical damage, proper documents delivered, etc.)

Phase 2
  • Creating profile development for testing (thermal plus shock/vibration)
  • Developing engineering study test plan and protocol
  • Writing technical report on engineering study results for the formulation change

Value to Atara Biotherapeutics
The value of this project included:
  • Access to FDA and other regulatory agency experience for multiple products, presentations, and jurisdictions
  • Ensuring filing documentation had the best opportunity for positive FDA response during Phase 2B meeting
  • Learning opportunity across organization to better understand current best practices to transportation studies for formulation changes

Methodology
The assistance we provided Atara included:
  • Coordinating triage shipping plan. Two shipments of clinical trial material was coordinated according to a ‘triage’ shipping plan. An effective shipping process (passive shipping air freight, over the road dedicated truck, etc.) with all appropriate procedural controls, training, and monitoring was implemented immediately with a competent third-party logistics (3PL) provider.
  • Identifying, selecting, and sourcing secondary packaging and shipping systems. A secondary packaging, insulated shipper, inner corrugated box, phase change material (PCM) refrigerant, and data monitors were selected and sourced to meet user requirements. This shipper system offered a range of sizes to accommodate:
    • Release samples to the release testing lab in quantities of 100 to 500 vials
    • Production vials sent to labeling facility in quantities of 7,000 to 10,000 vials
  • Qualifying shipping system. The shipping system was tested in a calibrated testing lab to confirm performance. The performance in the lab environment was documented with a signed protocol with acceptance criteria prior to testing. Results were summarized in a performance report.
  • Creating pack out instructions. GDP-compliant pack out instructions for the insulated shipper were created. The instructions were integrated by the CMO into their training systems. After integration, a review and approval process was facilitated between all partners (Atara, CMO, and freight forwarder) to ensure compliance to all user requirements.
  • Training CMO personnel. Atara staff and CMO operators were trained on site and were able to demonstrate proficiency on pack out instructions prior to shipment.
  • Selecting logistics provider. The selected logistics provider provided a range of services required in User Requirements Specification (URS). The provider delivered all required packaging material to CMO on a just-in-time basis and offered a range of expedited and deferred delivery alternatives.
  • Procuring shipping system. The selected shipping system was procured by Modality Solutions, stored at selected logistics provider, and delivered to CMO site when needed for shipment preparation.
  • Coordinating ‘first article’ shipment. The first lot of unlabeled vials was coordinated between CMO and the logistics provider. Tracking, temperature data, and delivery receipt were also provided.
  • Creating testing program for liquid formulation. A detailed program of testing program for liquid formulation was then designed. The testing program focused on simulated transportation hazards needed to test product formulation, container closure integrity, and a combination of physical and chemical stability. The testing program focused on methods, expected results, timelines, and costs to test a change to a liquid formulation stored and shipped at refrigerated temperatures from a current frozen formulation.
  • Implementing testing program (Phase 2). The detailed testing program for liquid formulation was completed, and the technical report was written.

Results
For Phase 1, progress was measured by the acceptance of the following deliverables and accomplishments:
  • ‘Triage’ shipping plan creation and coordination
  • Risk assessment and mitigation plan
  • Approved URS document
  • Selection of proper packaging materials, refrigerants, and data loggers
  • Qualification protocol and report for selected packaging
  • Compliant packaging instructions and personnel trained on procedures
  • Selection of logistics provider to provide just-in-time packaging and delivery services
  • Procurement of packaging systems and coordination with logistics provider for first article shipment
  • Approved approach, timeline, and budgetary estimates for liquid formulation testing

For Phase 2, progress was measured by the acceptance of the following deliverables and accomplishments:
  • Profile development for transition from frozen formulation (≤ -20°C) to a refrigerated formulation (2° to 8°C)
  • Protocol and technical report

The two phases of this project were successful. Atara reported on December 3, 2016 a response rate (RR) of 73.3% and 6-month Overall Survival (OS) > 70% in their Phase 2 trial at the American Society of Hematology (ASH) Annual Meeting 2016. They announced on December 12, 2016 that an agreement has been reached with the U.S. Food and Drug Administration (FDA) on the designs of two Phase 3 trials intended to support approval in the treatment of rituximab-refractory EBV-Associated Post Transplant Lymphoproliferative Disorder (EBV-PTLD) after hematopoietic cell transplant (HCT) or solid organ transplant (SOT). These two Phase 3 trials will support potential approvals in two separate indications.