Requirements for Qualifying Third-Party Manufacturers of Cellular Therapy Products Regulated Under U.S. INDs or BLAs
In light of the recent licensing of immune effector cell (IEC) products in the United States, this is an opportune time to continue education regarding third-party manufacturers in general. The manufacturing process for many novel cellular therapy products, including research and licensed cellular therapy products, involves multiple entities: holders of Investigational New Drug (IND) applications for research or Biological License Applications (BLA) for licensure, collection facilities, and processing facilities. Clinical units may be involved with one or more of these facilities.
There are three main responsibilities when third-parties are involved in the manufacture of a research or licensed product: verify regulatory oversight, qualify the vendor or service provider, and define responsibilities.
Though many questions from organizations regarding these requirements are specific to IEC processes, the information below can also be used as guidelines for other types of cellular therapy products.
Verify Regulatory Oversight
- The participating manufacturer (e.g., collection or processing facility) is responsible for verifying that the contracting entity for whom it performs services possesses an approved IND or BLA.
- The Clinical Program is responsible for verifying the manufacturer responsible for the entire manufacturing process (e.g., a commercial manufacturer) possesses an approved IND or BLA.
Qualify the Third-Party Manufacturer
- The IND or BLA holder is responsible for verifying that any facility performing a step of manufacturing complies with GMP and GTP requirements as applicable (see 21 CFR 1271.150(c)(1)(iii)).
- If the IND or BLA is held internally by a FACT-accredited facility, then the facility must perform this qualification and provide documentation to FACT inspectors.
- If the IND or BLA is external, i.e., held by a third-party investigator or manufacturer, this qualification is outside the scope of FACT accreditation and the FACT-accredited facility is not required to provide documentation of this type of qualification to FACT inspectors.
The participating manufacturer must participate in site visits from the IND or BLA holder and provide the level of service required of that entity, including compliance with GMP and GTP requirements as applicable. FACT-accredited facilities that participate in manufacturing for external IND or BLA holders must provide FACT inspectors evidence of complying with these requirements as required by applicable laws and regulations.
- The Clinical Program must perform vendor qualification of the IND or BLA holder. It is the FDA that monitors regulatory compliance, and the Clinical Program only needs to perform vendor qualification. Programs must verify the IND or BLA holder meets its needs in regards to many areas of cellular therapy, including labeling processes (label content applied by whom and how), level of service (turnaround times, customer inquiries), and other metrics defined by the program. Documentation of this qualification must be provided to the FACT inspection team.
- It is acceptable to delegate this activity to the Processing Facility so long as there is robust communication between the program and facility, which should be obvious in documentation.
- The level of participation of the clinical service in manufacturing an immune effector cell product varies. Regardless of where the product is collected or manufactured, responsibilities must be clearly defined.
- If a Clinical Program is responsible for collecting cells or preparing the IEC product for administration, or if independently FACT-accredited cell collection and processing facilities contract with a manufacturer, FACT Standards for collection and processing apply to the steps performed.
- If products are received directly by the Clinical Program or intermediary facility (e.g., blood bank, pharmacy) from a third-party manufacturer, the following responsibilities must be defined at a minimum: chain of custody, product storage, verification of product identity, and management of adverse events. Additional responsibilities will be included in the new edition of FACT Standards to be published in March 2018.