Preventing patients from receiving “counterfeit, diverted, sub-potent, substandard, adulterated, misbranded, or expired drugs” is a critical element of the mission of the US Food and Drug Administration (FDA). The protection of the pharmaceutical supply chain is one of the FDA’s highest priorities, and chain of custody is one of the FDA’s primary tools in this mission. Chain of custody, when correctly executed, allows determination of “who, what, and when” with a high level of confidence. For advanced therapies—those derived or generated through biotechnology—chain of custody not only includes verification of “who, what, and when,” but also “at what temperature.”
Manufacturers of advanced large-molecule therapies have determined that the efficacy of a drug can deteriorate with increasing exposure to time out of temperature, and this data is often included in regulatory filings. For this reason, chain of custody for genetic and cell therapies differs and is more complex than for traditional pharmaceuticals, and the requirements for documentation vary as well.
For instance, the rules governing the single numerical identifiers (SNI), which allow a drug to be traced back to the manufacturer is defined by 21 CFR Part 207 for traditional small molecule prescription drugs, while SNIs for biologics and cell-based therapies typically must include the Donor Identification Number (DIN) as well as the manufacturing establishment registration number, and may follow the ISBT* 128 Standard. ISBT 128 is a global standard for identification, labeling, tracking, and data transfer regarding medical products of human origin, set out by the International Council of Commonality in Blood Banking Automation (ICCBBA), and is recognized by the FDA.
Chain of custody documentation involves creating some form of paper or secure electronic audit trail linking a therapy point to point by the SNI, ISBT 128, or other applicable identifier, in chronological order, along all the critical steps from initial manufacture through administration to a patient. To be FDA-compliant, chain of custody documentation in our industry typically includes the date, time, temperature, activity, and who performed the activity, in some systematic fashion, for every event in the path between the manufacturer and the patient. Note that the FDA does not specify how this should be done, only that the system used by any given organization must work in a reliable manner.
For instance, chain of custody documentation could include the following:
- Signature on paper (with date and time), verifying receipt of an incoming shipment;
- Signature on paper (with date and time), verifying courier acceptance of an outbound shipment;
- The corresponding electronic temperature data (with date and time) saved to a server by the temperature monitoring system or a temperature data logger included in a shipment of therapeutic agent;
- Electronic transactions in the inventory management system noting the date, time, and technician who performed an inventory activity (placing an item in storage or retrieving a vial for shipment;
- Batch records in production, which require a signature on paper verifying a step performed, usually accompanied by the date and time; and
- QC inspection and sign-off, on paper as well as verified by PIN in an electronic system, by QC staff (Including date and time) at critical steps in the process.
When working with and handling an advanced therapy, we often have to pause and document the time, date, temperature, and identity of the ‘handler’ on specific forms that we create in tandem with our customized work instructions.
When shipping these materials to a clinical site for patient administration, we hand off the package to a courier, who signs our documents as receiving the shipment. The courier then has to get a sign-off from the TSA screener at the airport as well as a sign-off when the package comes off the plane and a sign-off when the shipment is again handed off to a courier. The courier gets a sign-off when the package is delivered to the dosing or clinical center loading dock, and the dosing center staff requires a sign off when the shipment is delivered to the pharmacy staff, who documents time/date/temperature of placement of the therapy in storage in the pharmacy.
When receipt at the dosing site is positively confirmed by Fisher BioServices, our part of the chain of custody is done; the clinical site takes chain of custody from the moment the therapy is received until it is administered to the patient.
Our industry faces ever-greater and more stringent documentation of “events” or chronological steps in the cold chain life cycle of a drug substance, for the protection of patients. As challenging as this may be, we all benefit from our collective efforts to meet requirements for chain of custody.
Are you thinking about your critical cold chain distribution and storage equipment? Are you making sure your equipment is designed, constructed and maintained to suit the operations to be carried out? To learn more about temperature management throughout cold chain logistics activities, please read my eBook Cold Chain Qualification: 5 Questions You Must Ask When Shipping Biologics!
*The acronym “ISBT” originally referred to ‘International Society of Blood Transfusion,’ but today means ‘Information Standard for Blood and Transplant,’ a sign of how much has changed—and continues to change. Note that the FDA does not require ISBT 128. However, it does require that certain information on the label [unique facility identifier, lot number relating to the donor (called Donation Identification Number in this document), ABO/Rh of the donor, and Product Code] be machine readable, and ISBT 128 data structures can be used by machine-readable technologies, including Code 128 and 2D barcodes, RSS (reduced space symbology) bar codes, RFID, and EDI.