12 Essentials to Setting Up Cold Chains for Biologics
Managing effective transportation of biologics, especially in healthcare, requires rigorous oversight. Logistical plans and intervention protocols need to be comprehensive and easily accessible. Insurance coverage needs to be robust. Compliance must be factored into operational execution, from package labeling to data management.
Depending on the biologic, there can be any number of specifics, from cryogenically freezing Cell & Gene Therapies to safely containing hazardous tissue samples.
Few service providers exist who can execute an end-to-end operation. Should you find yourself responsible for these logistics or curious about workflows, here is a quick run-through of the key operations to be mindful of.
1. Get the Basics
Begin by identifying the fundamentals of your operation.
- What are you shipping?
- Where are you shipping it from?
- Where are you shipping it to?
These are essential components to remember. Every decision in managing your cold chain will flow downstream of the answers to these questions.
2. Compliance
Once you have a clear idea of the product and locations, you will need to become aware of relevant regulations.
If you’re shipping in the US, the FDA will be very important. In Europe, be conscious of the EMA. You’ll likely reference Good Distribution Practice (GDP)/ Good Manufacturing Practice (GMP) regardless of where you are.
Regulation typically applies in two layers:
Logistics Operations:
Depending on the product being shipped, there may be specific requirements for packaging and insulation.
For example, Blood Plasma samples in the USA are subject to FDA Code of Federal Regulations Title 21 (21CFR), which states:
“Immediately after filling, plasma intended for manufacturing into injectable products shall be stored at a temperature not warmer than -20 deg.C” [640.69(b]
In this instance, when assembling our logistics plan, we must ensure that all our physical infrastructure (warehouses, vans, credos, etc.) can secure our plasma sample at -20°C.
While it varies from biologic to biologic, regulation typically applies to the packaging, marking, labeling, storage, transportation, and
2. Document Management
In addition to physical requirements, there will also be paperwork compliance that varies across products and geographies.
For example, if your biologic falls under the Hazardous Material Regulations, there are extensive guidelines for documentation.
Blood plasma samples may require paperwork for separation, filtration, and pathogen reduction treatments.
A potentially infectious tissue sample may require an Infection Control Record.
So on and so forth.
Each regulatory body’s standards will vary substantially depending on the product you are shipping and the jurisdictions of your operations.
3. Assess your Time and Temperature Requirements
Once you’ve investigated the compliance requirements, you will know the temperature constraints in which your biologics can legally rest. There may be circumstances where you decide regulatory requirements are insufficient and want to set higher standards.
For example, suppose you are transporting a “Whole blood” sample back to your lab. The FDA mandates “The blood has been stored continuously at 1 to 6 deg.C and shipped between 1 and 10 deg.C;”.
If you are testing for Hemoglobin, the sample may be stable for 10–12 days without any issues. If you are testing for Circulating Tumor Cells (CTC), however, it is likely better to run expedited shipping to limit transit time to less than 72 hours, from the time of collection.
Now, suppose you are testing for cancer cells in a urine sample. Depending on where you are shipping, there may be no temperature regulations on Urine, but you may opt to store the cells between 1 to 8 deg. C, to better preserve the CTCs in the sample.
Now is the time to understand the nature of the molecules you want to preserve and set hard guidelines for further planning.
4. Monitoring Requirements
Once you know the shipment’s time and temperature limitations, identify the monitoring requirements you would like at each transportation step.
Are passive temperature loggers acceptable, or do you need real-time temperature tracking?
Is GPS important?
Is the shipment live for <24 hours or do you need 24/7 visibility?
If stored in a warehouse, can you monitor the ambient temperature?
Does your software notify you to activate intervention protocols during temperature deviations? If so, what is the threshold?
5. Packaging Solutions
Once you know your shipments’ monitoring requirements and operational constraints, you can pick out the right packaging solutions.
Depending on the sensitivity of your biologics, you will require different equipment. For small and stable shipments, you may be fine with a passive Credo. If you’re moving a Cell and Gene Therapies, you likely need specialized equipment like Cryovials and Liquid Nitrogen Containers.
Depending on your Monitoring requirements [Step 4], you may also need containers with certain types of technology monitoring solutions. Ex. Some Credos offer IoT integration, that livestream data into the cloud.
6. Transportation
Once you know what physical items will be shipped, you can begin to design transportation plans.
You may find it best to structure your transportation exclusively over ground, a combination of ground and air, intermodal or otherwise. If a certain biologic is extremely time-sensitive, such as an organ transplant, you may find it most practical to charter a helicopter.
It is recommended to make multiple transportation plans for expected variability (ex. common weather patterns, delays in collection, availability of assets, etc.)
7. Logistics/Coordination
Now that you know the basics of your operation, you can contact specific carriers to set up and coordinate the specific dates/times you will send and receive packages.
Limit your carrier options to those with the necessary certifications to move your products (ex. Hazmat endorsements, Dangerous Goods Certifications, Infectious Substance Shipping Training, Medical Waste Transporter Certification, etc.).
If using multiple carriers for the same shipment, make sure that you leave time for each carrier’s intake process. You don’t want your biologics to be left at an airport terminal because they couldn’t be processed in time to make their flight.
8. Contingency Plans/Intervention Protocols
A critical part of any biologics distribution system is planning for failure. If certain steps of your supply chain fail, you should have contingency plans and intervention protocols on hand.
These protocols should be specific to the challenges you anticipate in your supply chain. For example:
- If weather is particularly volatile in your geography, plan alternative routes or transportation modes.
- If a vehicle has a defect, set up a protocol to dispatch a backup vehicle.
- If a hazardous biologic begins to contaminate the environment, coordinate the right equipment and personnel.
It is advised that for every anticipated failure, there should be specific, step-by-step protocols to respond swiftly and rectify the situation.
9. Documentation
Depending on the biologics you are shipping, you will need to keep some documents on hand. This will vary significantly, depending on the regulatory agencies, insurance companies, transportation providers, or company SOPs specific to your operations.
The two most important mandatory documents are likely your Chain of Custody (COC) and your source paperwork (ex. Chain of Identity, Cell Line Information Sheet, etc.). Depending on the biologic, you may also need documents like Biosafety and Risk Assessment Forms, Cryopreservation Documents, Import and Export Permits, IATA Dangerous Goods form, etc.
Once you have laid out all the necessary and desired forms of documentation, you can begin to organize them into a centralized store to minimize your operational overhead.
10. Risk management
Now that you have a clear idea of the specific operations, you can begin to do a holistic analysis of the risks of your transportation networks and take steps to mitigate them. These will be more high-level than the specific contingency plans. For example:
- If you anticipate a shortage of storage containers, start building relationships with alternative providers.
- If air freight capacity is tightening, it may be wise to identify alternative road transportation providers to cover the same distance.
- If a warehouse is particularly vulnerable to natural disasters, how quickly can your products be relocated to another site for safe storage?
11. Technology
Once you understand all functions and protocols in your operations, you can look for a technology stack to unify and manage your operations.
An essential part of your technology stack is software that can connect into your logistics provider, ERP, cold storage containers, and any other relevant data streams, directly. It is recommended to keep centralized stores of files, documents, and transportation-specific information.
While Google’s G-Suite can likely service as a centralized store of information, you may opt for a more specific software company or a custom software solution. For many biologics, there are existing software companies who may specialize in your operations (e.g., TrackCell for Managing Cell & Gene Therapeutics).
12. Define proposer SOPs + QC Throughout the Process
Last, assemble your standard operating procedures (SOPs) and Quality Control (QC) protocols for continuous improvement.
SOPs should be handbooks that you can use to onboard future transportation team members or explain operations to other people in the organization. They should have step-by-step protocols for every function someone may need to perform in orchestrating the transportation of biologics. Given the complexity of moving biologics, the more specific you can be, the better. As your organization matures, you may also want to reassess your SOPs and modify them to ensure they best serve your demands.
Your QC process should regularly audit your operations to maintain consistent standards. If a certain standard fails (e.g., 24% of samples are spoiled upon arrival when the maximum acceptable threshold is 15%), the responsible stakeholders should be identified, and steps should be taken to mitigate further incidents. Your QC process may also find that while no standard is explicitly failed, there are still large opportunities for improvement. For example, you may find if you shave 2 hours of transportation time off of the average biologic, you could reduce spoilage by 7%. In this case, exploring different service providers, transportation modes, or scheduling may be worthwhile to reduce your transportation time.
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That concludes the basics of managing cold-chains for healthcare biologics. These operations are tremendously complex but getting them right can be foundational to your business, especially in terms of your company reputation, rejection rates, testing accuracy, and, as a result, your bottom line.
If you have any thoughts or questions, feel free to reach out to satvikagnihotri12@gmail.com. Thank you for reading!
— Satvik Agnihotri
