This article summarizes the content of a presentation given at the Arena Clinical Trial Supply Southeast conference in July 2015. The presentation, entitled "Management of Multiple Service Providers for Importation of a Cell Bank," told the story of GeoVax ‘s experience in importing frozen cells from Europe to the United States. As the owner of the cell banks (vials of frozen cells, which are used in vaccine manufacturing), GeoVax had the responsibility to coordinate the work of four vendors in compliance with regulatory requirements. The presentation discussed the challenges of managing the importation process and lessons learned from the experience. The cell banks are not clinical trial supplies per se; however, the challenges that GeoVax faced in importing them are both comparable and relevant to the hurdles that a small company faces when importing an investigational biotech drug with strict temperature requirements.
GeoVax is a clinical-stage biotechnology company developing vaccines against HIV and Ebola. Our lead candidate is GOVX-B11, a vaccine for prevention of HIV/AIDS. GOVX-B11 is designed to be effective against HIV-1 Clade B, which is the version of the HIV-1 virus that is most common in the Americas and Western Europe. Vaccines against HIV-1 Clade C (the most widespread version of HIV-1, responsible for the HIV/AIDS epidemic in Africa and India), Ebola, and Marburg (a virus similar to Ebola) are in preclinical testing. One of GeoVax’s core technologies is recombinant Modified Vaccinia Ankara (MVA), which is a very safe and potent platform technology. Recombinant MVA vaccines have traditionally been manufactured in primary Chick Embryo Fibroblast (CEF) cells. Primary CEFs are prepared from chicken eggs and have a number of disadvantages including limited egg supply and the sterility risk inherent in processing large numbers of eggs. Replacement of CEFs with a continuous cell line would address these issues and enable more consistent and scalable production of recombinant MVA vaccines.
GeoVax recognized the benefits of a continuous cell line for recombinant MVA production and licensed the EB66? cell line from Valneva SE, the French company that developed the line. GeoVax then outsourced production of a Master Cell Bank (MCB ), a Working Cell Bank (WCB), and an End-of-Production Cell Bank (EoPCB) to a European contract manufacturer. Upon completion of cell banking, GeoVax needed to import all three banks to the United States. Samples of the EoPCB were needed immediately for an animal study, and the remainder of the cell bank vials were to be stored at an American facility in the vapor phase of liquid nitrogen for future use in cGMP manufacturing.
Like many biotech companies in Phase 1 and 2 clinical trials, GeoVax is a small organization. We have deep expertise in the science behind our products, and we are highly competent in overseeing the manufacture and testing of our vaccines. We are not, however, experts in logistics. The importation of these cell bank vials was much more complicated than any previous importation project and required us to learn very quickly how to handle a number of different challenges.
GeoVax developed an initial plan for importation of the cell banks, based on our previous experience in importing drug products from European contract manufacturers. The plan, illustrated in Figure 1, was relatively simple. GeoVax would contact a shipper (Courier) and our insurance company, approve quotes from both companies, ensure that all paperwork was in place, and then authorize the shipment. To preserve the quality of the cell banks, it was necessary to transport them in dry shippers, which are containers that use liquid nitrogen vapor to hold products at very cold temperatures (approximately -150 °C).
Figure 1. Initial plan for importation of the cell banks
We learned very quickly that the task was not as simple as it appeared. Several factors materialized, making the project much more complicated and extending the timelines:
- The contract manufacturer of the cell banks (CMO) insisted on signing agreements with the contract research organization performing the animal testing (Testing Lab) and the cold storage facility (Storage Facility). These agreements were redundant with other contracts and completely unnecessary from a legal perspective; however, GeoVax had no choice but to wait until they were completed. Execution of these agreements lengthened the timeline and delayed the shipments.
- The shipping company (Courier) initially indicated to GeoVax that it could provide dry shippers for transport of the cell banks. However, after weeks of searching, the Courier determined that it could not locate any of its dry shippers. GeoVax was then obligated to find a different company to provide dry shippers.
- GeoVax identified a company that could provide an end-to-end service including dry shipper rental and shipping logistics. However, when GeoVax presented this option to our insurance company, the insurance company refused to provide coverage for the shipment because of the logistics company’s use of common carriers rather than airlines. This issue with insurance coverage led GeoVax to determine that two companies (Courier and Dry Shipper Provider) must be used.
- The use of both Courier and Dry Shipper Provider created the need for GeoVax to coordinate efforts between the two vendors. Though simple in principle, this coordination of efforts became much more complicated when GeoVax realized that the two companies did not communicate well with each other. GeoVax then became the "go-between" transferring information between the Courier and the Dry Shipper Provider to ensure that the shipments occurred on time.
The final process, illustrated in Figure 2, is significantly more complicated than the original plan. The number of process steps had doubled, increasing the amount of work to be performed by GeoVax and adding a number of potential failure modes.
Figure 2. Final plan for importation of the cell banks
In addition to the increases in complexity, various miscellaneous delays and difficulties occurred. Last-minute requests for documentation appeared, documents were lost, customs paperwork sometimes was not transferred, delays occurred in customs clearance, and contractors’ internal processes delayed approval of certain steps, and documentation errors occurred. Ultimately, the cell banks were transported safely and on time. All vials arrived safely in the United States at their intended locations. No temperature excursions occurred, and the shipments did not exceed the validated range of the dry shippers. Most importantly, nothing in the shipping process violated cGMP regulations, and the conditions of the shipment were fully compatible with the future use of these cell banks for manufacturing of vaccines under cGMP compliance. The animal study was initiated on time, and the MCB and WCB vials are now stored safely at the cGMP-compliant storage facility.
The cell bank importation project provided several lessons for GeoVax, listed below.
- Determine and address regulatory and stakeholder requirements early. Three entities (GeoVax, Testing Lab, and Storage Facility) were required to apply for USDA import permits for the cell bank. Application review time varied, even though the applications were essentially identical. Had GeoVax not addressed the need for import permits early, the shipment could have been delayed. Similarly, our insurance company, a key stakeholder, had specific requirements for the shipping method. Had GeoVax not been flexible on choice of shipping company, we could have encountered difficulty in insuring the shipment.
- Become an expert on logistics. Though each of the vendors in this process was very competent, no vendor was invested in the safety of the cell bank to the same extent as GeoVax. For this reason, it was necessary for us to learn the shipping process well to ensure that the cell banks were imported safely and as rapidly as possible. Ultimately, the safety of the product is the responsibility of its owner, and it is to the owner’s advantage to develop a comprehensive understanding of the process, the players, the alternatives, and the risks.
- Engage multiple specialists. The use of separate vendors for shipping and dry shipper rental was inefficient and inconvenient; however, it was highly effective and gave GeoVax a great degree of control over the process.
- Stay on top of everyone. Had GeoVax not watched the timeline and the critical path carefully, and facilitated communication both between vendors and between business units of a single vendor, the shipments would not have occurred on time. It is essential to keep track of the timeline and not simply to trust that contractors will perform their process steps according to the original schedule.
- Do not assume that people will talk to each other. We found that, within a single vendor organization, American employees were not communicating with their European colleagues. GeoVax needed to transfer information between American and European employees of the same company. Had GeoVax not stepped in and communicated this information, shipments could have been delayed.
- Don’t overreact to small errors, and don’t blame. Numerous small errors and delays occurred in this process. None of them led to a crisis, however, and the smooth and friendly handling of each of these incidents was essential to the success of the process.
The process of importing the cell bank, much more difficult and complicated than originally thought, provided valuable lessons to GeoVax. We recommend that other small companies in similar situations plan ahead and consider the lessons listed in this article.