Establishing a Game Plan: How Written Agreements and Qualification Develop a Winning Strategy Between FACT-Accredited Programs and Third-Party Manufacturers
Cellular therapy is a team sport. The quality of care that is ultimately provided to a patient depends on everyone working together toward the common goal of safe and effective therapy. Multiple people, and increasingly multiple entities, play a role in patient diagnosis and selection; donor assessments and cell collection; cellular therapy product manufacturing, storage and distribution; and administration and follow up.
Sticking with the team sport analogy, everyone involved in cellular therapy should be working from a common game plan. FACT requires several quality management principles that essentially make up that game plan. Written agreements and vendor qualification are two examples.
In this article, we are clarifying FACT’s position on written agreements and vendor qualification required of FACT-accredited programs who collect, process, or administer cellular therapy products that are manufactured by a third-party manufacturer (“third party”). In short, these activities are used to develop and verify the game plan for how the two entities will interact:
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- The written agreement defines the roles and responsibilities of both the accredited program and the third party.
- The qualification verifies that the third party complies with the relevant Standards with respect to interactions with the accredited program.
FACT does not dictate how roles and responsibilities are defined and verified, or in what type of agreement. These could be achieved via Quality Agreements, Master Services Agreements, or relevant policies and procedures that are referred to in other agreements.
Pharmaceutical and biotechnology companies leading the manufacture of a cellular therapy product must have approved Investigational Device Exemptions (IDEs), Investigational New Drug Applications (INDs), or Biological License Applications (BLAs), or equivalent. When a third party has such documented evidence of regulatory oversight and approval, FACT does not require that the agreement defines how it complies with Applicable Law, required accreditations, quality management, or GTP or GMP processes. FACT considers the regulatory approvals as documented compliance with these requirements.
These regulatory approvals do not, however, define roles and responsibilities between the two entities. Just a few examples of relevant activities include chains of identity and custody, shipping, storage, patient scheduling, and communication. A third party or accredited program may have developed preferred processes to increase consistency; however, the two entities will still need to agree on whose processes will be used. (Again, how these responsibilities are defined in written agreements is not dictated by FACT.)
The accredited program’s qualification process will verify that the defined responsibilities will comply with the Standards. As described above, FACT does not require the qualification process to determine compliance with Applicable Law, required accreditations, quality management, and GTP and GMP processes if it confirms regulatory approval for the relevant cellular therapy product.
FACT also does not dictate how qualifications are performed. Agreements can be utilized as a source of information for qualification; separate qualification processes are not necessary (but are also not forbidden). Existing qualification processes can be adapted to utilize written agreements. Use of agreements for qualification is only possible if the right people at the accredited program have access to them.
FACT recommends a collaborative approach to written agreements and qualification as the field evolves. Accredited programs and companies alike are making considerable effort to minimize the burden of onboarding new cellular therapy products, and we are all teammates trying to improve the process so that more patients are treated with cellular therapies that can be lifesaving and life giving.
Which Comes First: Written Agreements or Qualification?
The two are closely related in this scenario and can be done separately or concurrently. Each accredited program, and likely each third party, has proactively developed a process for managing these and no two entities are exactly alike. Some programs prefer to qualify a company before developing an agreement, and some develop an agreement as part of the qualification process. FACT does not require or prohibit either method so long as the intent is met: that roles and responsibilities are clearly defined and in compliance with the Standards.
Teamwork Between Accredited Programs and Third-Party Manufacturers
Because the safety and efficacy of a cellular therapy administered to a patient depends on the cell collection procedure, the cellular starting material, and the manufacturing process, accredited programs must utilize cell collection and processing facilities that meet the Standards.
As accredited programs participate more in research and commercial cellular therapies, they will likely experience increased interactions with pharmaceutical or biotechnology companies who have approved IDEs, INDs, or BLAs or equivalent. FACT does not require that these companies undergo a FACT inspection; however, the manner in which they and the accredited program interact to manufacture and administer a cellular therapy product must still meet the Standards. The program is responsible for defining and verifying processes that achieve this.
The level of participation of the accredited program in manufacturing research or commercial cellular therapy products varies. Regardless of where a product is collected or manufactured, responsibilities must be clearly defined.
Written Agreements Develop the Game Plan
Written agreements are essential to adequately and appropriately manage each step in the cellular therapy process when two different entities are involved. Written agreements provide direction for how the accredited program and the third-party manufacturer will interact to be sure activities meet the FACT Standards.
Although written agreements have been required for several editions of FACT Standards, the need for written agreements for commercialized or research cellular therapy products became abundantly clear over recent years. As an intentionally simple example to illustrate this point, one of the earliest experiences for Clinical Programs was the need to contact a company when a patient’s status changed. When a Clinical Program is in control of the entire cellular therapy process for its patients, it can manage and direct the timing of cell collection and processing. Once those processes are dependent on a separate company, Clinical Programs need to know who to call to develop a plan for how they will need to adjust treatments and reschedule cellular therapy if a patient unexpectedly cannot undergo a cell collection procedure or therapy administration.
It is worth repeating here that, for companies with regulatory approval via IDEs, INDs, and BLAs, FACT does not require agreements to define how the third party will comply with Applicable Law, required accreditations, quality management, and GTP and GMP processes because this is confirmed by the regulatory agency.
The Standards require that agreements include defined responsibilities for critical tasks between the accredited program and the third party. As listed in the Standards, these include collection, processing, testing, storage, distribution and administration and the relevant processes that support these activities. The Standards apply to the Clinical Programs, their collection and processing facilities, and any other entity that performs tasks related to the cellular therapy product, even if that facility only briefly handles the product.
Traditionally, Clinical Programs that have a Cellular Processing Facility receive final cellular therapy products via that facility in compliance with the Part D Processing Facility Standards. Recognizing that Clinical Programs and the intermediaries who receive cellular therapy products are becoming more diverse to meet a growing patient demand, the Standards account for situations when the final product is received directly by the program or an intermediary facility. Intermediary facilities include pharmacies, blood banks, or external storage facilities. These requirements must also be considered when developing written agreements.
What is the Required Format for Written Agreements?
The intent of the Standards is to define the minimal elements to be included in written agreements, but not to define the format of the agreement. Agreements meeting this standard could stand alone or be part of a larger document(s) that exists between the entities such as relevant policies and SOPs, a contract, or a Master Service or Quality Agreement. Examples of ways to manage written agreements with third parties include:
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- A third-party manufacturer may distribute a licensed or regulatory-approved cellular therapy product to a Clinical Program the day prior to expected administration. A policy and SOP shared by the Clinical Program describes the responsibilities and the process for receipt by the institutional blood bank and short-term secured storage at that location.
- A third-party manufacturer maintains a comprehensive Quality Agreement with the institution housing an IEC Clinical Program that includes responsibilities for collection and shipping of the cellular starting material collected by apheresis, and receipt and short-term storage of the finished product at the clinical site.
Some programs have adopted Quality Agreements as a method of defining responsibilities with third parties, and some manufacturers have proactively included quality responsibilities within existing documents such as Master Service Agreements. Neither of these approaches is required by the Standards, but both are permitted. FACT receives many inquiries regarding its requirements for Quality Agreements, and notes that the Standards do not specify this type of agreement and neither requires nor forbids them.
What is the Required Format for Qualification of Third-Party Providers?
FACT does not prescribe a specific form or method for conducting supplier qualification of third parties. It is the responsibility of the accredited program to determine the appropriate approach, whether through a formal supplier qualification process, documented agreements, or other mechanisms that demonstrate the supplier meets the necessary standards. FACT recommends a collaborative approach given the evolving cell and gene therapy landscape and continued efforts to identify efficient and streamlined ways of performing qualification.
Qualification via verifying compliance with regulatory and quality standards through written agreements is acceptable. This is only possible if the appropriate personnel in the accredited program have access to any agreements that may have been established at a higher level in the institution. Programs may need to request the agreements from institutional leaders or the manufacturer if this approach is taken.
Qualification of third parties can be performed in a variety of ways, including but not limited to:
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- Documented verification that pre-determined requirements are addressed via the approved IND, BLA, and written agreements with the institution.
- Questionnaire outlining the established procedures of the third-party. It is acceptable to adapt a Clinical Program’s established questionnaire to allow verification of compliance with requirements via agreements. For example, an existing qualification form could be modified to identify the predetermined requirements for a third-party manufacturer, reference the existing relevant agreement, and document requirements verified via the agreements using the form. This would maintain the effectiveness of the qualification process while reducing the need to perform duplicative work or introduce multiple qualification methods.
Relevant Standards
Clinical Programs
FACT-JACIE HCT / FACT IEC / FACT Common Standards: B1.2 The Clinical Program shall use cell collection and processing facilities that meet FACT [-JACIE] Standards with respect to their interactions with the Clinical Program.
B1.2.1 If the Clinical Program or an intermediary facility receives cellular therapy products directly from a third-party provider, the following responsibilities shall be defined by a written agreement:
B1.2.1.1 Traceability and chain of custody of cellular therapy products.
B1.2.1.2 Cellular therapy product storage and distribution.
B1.2.1.3 Verification of cellular therapy product identity.
B1.2.1.4 Review and verification of product specifications provided by the manufacturer, if applicable.
B1.2.1.5 Readily available access to a summary of documents used to determine allogeneic donor eligibility.
B1.2.1.6 Documented evidence of allogeneic donor eligibility screening and testing in accordance with Applicable Law.
FACT-JACIE HCT / FACT IEC / FACT Common Standards: B4.6 The Quality Management Plan shall include, or summarize and reference, policies and Standard Operating Procedures for the establishment and maintenance of written agreements.
B4.6.1 Agreements shall be established with external parties providing critical services that could affect the quality and safety of the cellular therapy product or health and safety of the donor or recipient.
B4.6.2 Agreements shall include the responsibility of the external party performing any step in collection, processing, testing, storage, distribution, or administration to maintain required accreditations and to comply with Applicable Law and these Standards.
B4.6.2.1 Agreements should include the responsibility of the external parties to provide clinically relevant information related to products or services.
B4.6.3 Agreements shall be dated and reviewed on a regular basis, at a minimum every two (2) years.
FACT-JACIE HCT / FACT IEC / FACT Common Standards: B4.13 The Quality Management Plan shall include, or summarize and reference, policies and Standard Operating Procedures for qualification of critical manufacturers, vendors, equipment, software, supplies, reagents, facilities, and services.
Collection Facilities
FACT-JACIE CM1.2 The Marrow Collection Facility shall use cell processing facilities that meet FACT-JACIE Standards with respect to their interactions with the Marrow Collection Facility.
FACT-JACIE C1.2 The Apheresis Collection Facility shall use cell processing facilities that meet FACT-JACIE Standards with respect to their interactions with the Apheresis Collection Facility.
FACT IEC / FACT Common C1.2 Collected cellular therapy products shall be distributed to facilities that meet the FACT Standards with respect to their role in the therapy.
FACT-JACIE HCT / FACT IEC / FACT Common C4.6 The Quality Management Plan shall include, or summarize and reference, policies and Standard Operating Procedures for the establishment and maintenance of written agreements.
C4.6.1 Agreements shall be established with external parties providing critical services that could affect the quality and safety of the cellular therapy product or health and safety of the donor or recipient.
C4.6.2 Agreements shall include the responsibility of the external party performing any step in collection, processing, testing, storage, distribution, or administration to maintain required accreditations and to comply with Applicable Law and these Standards.
C4.6.3 Agreements shall be established when the Apheresis Collection Facility provides critical services to external parties.
C4.6.4 Agreements shall be dated and reviewed on a regular basis, at a minimum every two (2) years.
FACT-JACIE HCT / FACT IEC / FACT Common C4.13 The Quality Management Plan shall include, or summarize and reference, policies and Standard Operating Procedures for qualification of critical manufacturers, vendors, equipment, software, supplies, reagents, facilities, and services.
Processing Facilities
FACT-JACIE HCT / FACT IEC / FACT Common D4.6 The Quality Management Plan shall include, or summarize and reference, policies and Standard Operating Procedures for the establishment and maintenance of written agreements.
D4.6.1 Agreements shall be established with external parties providing critical services that could affect the quality and safety of the cellular therapy product or health and safety of the donor or recipient.
D4.6.2 Agreements shall include the responsibility of the external party performing any step in collection, processing, testing, storage, distribution, or administration to maintain required accreditations, and to comply with Applicable Law and these Standards.
D4.6.3 Agreements shall be established when the Processing Facility provides critical services to external parties.
D4.6.4 Agreements shall be dated and reviewed on a regular basis, at a minimum every two (2) years.
FACT-JACIE HCT / FACT IEC / FACT Common D4.13 The Quality Management Plan shall include, or summarize and reference, policies and Standard Operating Procedures for qualification of critical manufacturers, vendors, equipment, software, supplies, reagents, facilities, and services.
