FDA Says Shipping Logistics Should Be Priority For Cell Therapy Products

FDA says manufacturers need robust shipping programs to ensure the safety and quality of cell therapies, since there are no ready replacements and a patient’s life can be at risk if problems arise. Kite exec notes that “more than any other biologic, the supply chain of autologous cell therapies reaches really literally end-to-end.”

FDA says that manufacturers should apply the same level of rigor to their storing and distribution programs as their development programs for cell therapy products. These are sensitive products that are highly dependent on cold temperatures for cells to survive and demand careful handling.

A series of speakers discussed some of the logistical challenges involved in distributing autologous cell therapies and the cryogenic conditions required for shipment at a July 10 CASSS meeting on cell and gene therapies in Rockville, Md.

The session’s moderator, Bryan Silvey, Kite Pharma Inc.’s senior director, quality compliance, set the tone for the discussion. He noted that these products need to be manufactured with special care, because if there is a problem with the product, there is not another lot readily available, especially for autologous products where cells are removed from a person, manipulated off-site and administered back to that same person. Kite’s chimeric antigen receptor T cell therapy Yescarta (axicabtagene ciloleucel) was approved in the US for diffuse large B-cell lyphoma just before the company was acquired by Gilead Sciences Inc. in August 2017 for $11.9bn.  (Also see "Gilead Makes Cell Therapy The Base Of Its Oncology Platform With Kite Buy" - Scrip, 29 Aug, 2017.)

Silvey said that “I hope you can all appreciate that more than any other biologic, the supply chain of autologous cell therapies reaches really literally end-to-end. In your typical biologics you’ll have starting material that is either a working cell bank and you make your product and you fill your lots, and your lots could be 10,000 to 20,000 prefilled syringes. If there is a breakdown in supply chain you can just pick another syringe off the shelf and give it to the patient. That absolutely is not the case here in this field that we’re journeying in as an industry. It is one dose and one lot and patient. You don’t have a chance to remake the lot and you don’t have a chance to go through a deviation investigation.”

Distribution Rigor Should Equal Development

FDA’s Richard Health Coates, a reviewer with the Center for Biologics Evaluation and Research, concurred. He said manufacturers need to apply the same rigor to distributing these products as developing them.

“You need to take that same focus and energy in your shipping process otherwise you have ruined all that development work.”

Coats said that the federal Food, Drug and Cosmetic Act as well as the regulations under 21 CFR also recognize the importance of shipping and distributing products to good manufacturing practice standards, and the following regulations apply in this area:

• 211.142(b) warehouse procedures: states that there should be storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality and purity of the drug products are not affected.
• 211.150 distribution procedures: states that written procedures should be established and followed describing the distribution of drug products.
• 211.166(a)(2) stability testing: states that a written program should include storage conditions for samples retained for testing.
• 21 CFR 600.15 temperatures during shipment: states that blood must be 18 degrees Celsius or colder and should be transported in an environment capable of continuously cooling the blood toward a temperature range of 1 to 10 degrees Celsius.
• 21 CFR 640.2: states that blood has to be continually stored at 1 to 6 degrees Celsius.

Coats said that several groups such as USP and the World Health Organization have issued useful guidelines to help manufacturers comply with these shipping and distribution requirements.

Coats said that USP Chapter <1079> “does a very good job of laying out some of the over-arching aspects of shipping and distribution” of cell and gene therapy products. The chapter sets expectations for temperature monitoring and temperature mapping. It states that temperature should be tracked using a monitoring system which should include alert mechanisms to ensure that present ranges are not breached.

Other useful guides include USP <797> on sterile preparations for pharmaceutical compounding, and <USP> 659 for packaging and storage requirements. He also recommended manufacturers consult the World Health Organization’s guideline on good distribution practices for pharmaceutical products.

He said that “the more you know about the shipping process the more robust the process will be.” For example, it is important to know that products will be kept to the same temperature whether “it’s Boston in January or Phoenix in July.”

Coats said that the International Safe Transit Association (ISTA) also offers valuable guidance on procedures for conducting shipping tests. The association targets shippers, carriers, suppliers, testing laboratories, and educational and research institutions focused on the specific concerns of transport packaging, and helps members control costs, damage, and resources during the distribution of packaged-products by publishing laboratory preshipment testing procedures and certifying packaged-products.

Coats further noted that it is also important to know the shipping conditions once the product is in transit.

“Know as much as you can about your process and the shipping logistics. Are you really just taking this material and going down the hallway or are you shipping this across the country? I recently reviewed a shipping validation protocol for a non-cell therapy product. The firm did not have lot of in-depth knowledge of the shipping logistics. Their particular shipment was supposed to be shipped between 2-8 degrees, the shipping container was out of validation even before it got on the truck because there was a three-hour lag time on the loading dock before it was placed onto the truck.”

Unique Challenges Posed By Cryogenic Shipping

Craig Vermeyen, senior manager, packaging engineering at Kite, discussed some of the challenges in dealing with shipping using liquid nitrogen as the packaging method for these products, which is increasingly the shipping method of choice to keep cells cold during transit.

Yet liquid nitrogen poses its own risk if not handled properly. “Because liquid nitrogen is very cold you have to make sure that you do not get burned and there is a lot of processing involved with the liquid nitrogen itself. You have to make sure that you are wearing gloves and aprons.”

Another challenge is finding labels with enough adhesion properties to be able to withstand cryogenic temperatures. He said that “you have to focus on the label, if your product is labeled with an adhesive you have to make sure that it can deal with cryogenic temperatures.”

It is also that “everyone understands how important it is to treat these products with care.”

He said that “everyone involved needs to understand the contents of the shipment. It is important that the courier knows they are not delivering toilet paper from Amazon. It is a product that could save someone’s life, if that product breaks in transit it is very difficult to find a backup in time when a patient doesn’t have any more chances.”

From the editors of The Gold Sheet.