St. Renatus



Background
St. Renatus, LLC (St. Renatus) was founded to develop a revolutionary and innovative dental anesthetic administered through the nasal cavity. This Investigative New Drug (IND) has completed the U.S. Food and Drug Administration (FDA) Phase 3 clinical trials and gained FDA approval in July 2016. St. Renatus believes the benefits of its product will provide a better experience for doctors and qualifying patients. These benefits include an accurate and sophisticated method to anesthetize the upper teeth topically, without the risk, fear, and pain of an injection. Patients would not experience the uncomfortable cheek or "fat lip" numbness associated with the needle.

As the approval date approached, significant issues around the commercial supply chain existed. Decisions on the channel of distribution partners, warehouse and storage, and network design were still in a state of flux. They needed to distribute a cold chain product in a supply chain that does not traditionally handle a strict 2°C to 8°C product. This compounded an already complex issue. The cold chain management issues needed to be addressed as part of a larger supply chain design -- for both the immediate launch and to support future commercial activities. For these reasons, St. Renatus requested assistance with its cold chain management for the commercial release of its new pre-filled dental anesthetic syringes.

Objectives
The focus of the engagement was to:
  • Conduct cold chain capability assessments of current and proposed supply chain partners
  • Participate in strategic network design decisions for cold chain operations
  • Provide recommendations for a 3PL provider based on cold chain requirements for commercial drug product distribution in the US
  • Assess GDP compliance at selected 3PL provider and thermal packaging supplier(s).
  • Prepare a quality agreement and service level agreement for inclusion in the contract negotiations with both the 3PL and transportation providers
  • Select ‘off the shelf’ thermal packaging configuration(s) to support the commercial launch.
  • Assess thermal packaging operational qualification (OQ) and report to support use of thermal packaging in commercial distribution
  • Author and execute transport validation (shock/vibration study) protocol and report to support suitability of pre-filled syringe for distribution
  • Author thermal packaging performance qualification (PQ) protocol and report for execution by 3PL operations
  • Select proper thermal monitoring technology and approach
  • Prepare the management team for FDA pre-approval inspection (PAI) meeting to discuss cold chain management approach

Value to St. Renatus
Specifically, Modality Solutions was able to:
  • Engage in the strategic network design of cold chain logistics operations
  • Recommend a third-party logistics (3PL) facility to store and ship commercial drug product to wholesalers and distributors
  • Assess GDP compliance of key supply chain partners
  • Qualify thermal packaging for the final proposed commercial packaging format to maintain the recommended storage temperature (2°C to 8°C) at the anticipated minimum and maximum load for the worst-case anticipated shipping route and duration
  • Provide experience in development of cold chain management approach for FDA review and approval
  • Offer deep market knowledge of 3PL providers, thermal packaging suppliers, and compliant monitoring approach and technologies
Methodology
The detailed approach on the assistance we provided St. Renatus for assessing drug product quality during shipment in the US included the steps listed below.
Network Design and Implementation
Explored cold chain capabilities of contract manufacturer, contract packager and national and regional wholesale/distributors. The cold chain capabilities of identified supply chain partners were assessed to inform the strategic design network discussion. Their capabilities directly impacted their potential role in the cold chain network design and helped determine the alternatives to review.

Engaged in strategic design network. A review of proposed supply chain and process flow coupled with a GDP assessment of identified distribution partners allowed for input of strategic network design. Gaps, risk, and mitigation strategies were collaboratively reviewed and discussed to inform the role and recommendation of 3PL provider.

Mapped US supply chain and created process flow diagram. The US supply chain map was used to create the process flow diagram. The process flow diagram shows the detailed steps in the US supply chain that were designed into the thermal packaging qualification protocol.

Recommended 3PL supplier in selected geography. The US supply chain map identified the most likely location of a US distribution center (single site only) for commercial distribution. Prequalification of suppliers in the geographic location were conducted to determine which partners were best suited to support planned distribution process.

Conducted GDP assessment of cold chain management partners. Once the 3PL was selected and the network design was approved, Modality Solutions conducted a GDP assessment of cold chain operations for all partners in the network that manage inventory on behalf of St. Renatus. The GDP assessment determined if any quality or regulatory gaps existed and presented a mitigation plan for all critical and major gaps.

Authored quality agreement and service level agreement for 3PL and transportation providers. The GDP assessment informed the critical-to-quality attributes and gaps in GDP compliance at the selected 3PL. The quality and service level agreements were authored to set clear requirements for maintaining a compliant and effective 3PL operation to support US commercial distribution.

Cold Chain Management
Created validation master plan. The process flow diagram was translated into thermal test profiles for small parcel thermal packaging and lane qualification approach for palletized active refrigeration. Once the thermal profile and lane qualification approach were established, a physical integrity test plan using ISTA methods was created for the small parcel test plan. A parallel approach was outlined for qualification of active refrigeration equipment and lane qualification. The steps and timing to execute for both approaches was documented in the validation master plan for review at PAI.

Authored and executed transport validation study for pre-filled syringe. Modality Solutions designed a test plan and executed a shock/vibration study to confirm pre-filled syringe and associated packaging was suitable for distribution. The study focused on confirming container closure integrity (CCI), device functionality, and packaging elegance during simulated transportation for proposed commercial distribution routes.

Assessed passive thermal packaging OQ package. The data package was reviewed against acceptance criteria and an assessment report detailing the adequacy of thermal and physical testing, qualified temperature range, and duration for thermal packaging was written.

Created pack out instructions. Pack out instructions for the selected and qualified thermal packaging were created. These instructions were based on the qualified pack out instruction used during passive thermal packaging OQ protocol execution.

Authored thermal packaging performance qualification (PQ) protocol and report for execution by 3PL operations. A performance qualification (PQ) protocol for the 3PL was written. The 3PL is currently executing the protocol and will report results. These results will be included in the PQ report.

Authored lane and active refrigeration qualification assessment report. An IQ/OQ assessment report was authored to explain lane routing, pallet build, load plan, and appropriate active refrigeration equipment needed in the network.

Created pallet build work instructions and load out procedures for active refrigeration. The work instructions and procedures informed contract manufacturers, contract packagers, and 3PLs on how to properly build a pallet and load active refrigeration equipment. These processes were designed based on the qualification assessment report.

Selected thermal monitoring approach and technology. The thermal monitoring approach was documented in a standard operating procedure and included in the pack out instructions for the thermal packaging. A recommendation of appropriate monitoring technology was made. This technology was recommended based on the thermal packaging qualification results, monitoring approach, and pack out instructions.

Prepared the management team for FDA pre-approval inspection (PAI) meeting. Modality Solutions ensured understanding of all aspects prior to the St. Renatus management team’s discussion on this cold chain management approach at the PAI meeting.

Results
This project included the following results:
Network Design and Implementation
  • Cold chain capability evaluation of current and proposed supply chain partners
  • Recommendations on network design and role of 3PL for cold chain activities
  • US supply chain map and process flow diagram
  • GDP assessment at selected 3PL provider and thermal packaging supplier(s)
  • Quality Agreement and Service Level Agreement for 3PL and transportation providers
Cold Chain Management
  • Transport validation master plan for commercial cold chain operations
  • Transport validation shock/vibration study protocol and report
  • Small parcel passive thermal packaging OQ assessment report
  • Small parcel passive thermal packaging PQ protocol and report
  • Small parcel thermal packaging pack out instructions
  • Active refrigeration pallet builds and load out instructions
  • Recommended thermal monitoring technology and approach
  • Presentation and training to review approach to gain approval during PAI