Letter from the President
After decades of discovering new therapies, improving quality, and increasing patient access, the FACT community of accredited organizations and expert inspectors has much wisdom to share. Fortunately, several opportunities exist for us to provide advice and direct the future of cellular therapy. It is our responsibility to take advantage of those opportunities.
Over the past several years, FACT has submitted numerous comments to regulatory agencies, participated in multistakeholder groups, and has built relationships with industry. We can therefore assure you that your input is incredibly valued. We also know that our field is one in which we all are open to new ideas for the sake of advancing cellular therapies for the patients. Our unwavering commitment, though, is to safety and quality. To that end, I encourage you to please continue to provide feedback (especially when requested!) and advocate for the importance of accreditation. In this newsletter, we have included several announcements that include requests for comments from the United States Food and Drug Administration (FDA) and the Standards Coordinating Body, as well as updates from the FACT Professional Relations Committee.
Finally, to highlight FACT’s goal to recognize the value of communicating and sharing the knowledge from our accredited organizations and inspectorate within our own network, we are inviting guest authors to contribute to our “Just the FACTs” newsletter. I therefore encourage you to read the piece written by Eunice Kim and Heather Steinmetz on “Qualification and Validation” that is adapted from a well-received presentation from a previous FACT event. If you would like to submit an article or article topic for consideration for inclusion in the newsletter please do not hesitate to reach out to: email@example.com. Once again, I want to thank you for all you do to enhance the cell therapy field to ultimately improve outcomes for the patients we serve!
Catherine Bollard, MD
Eunice Kim, CLS
Stem Cell Laboratory Manager
Heather Steinmetz, MPH
Quality Assurance Manager
Hematologic Malignancies/Stem Cell Transplantation & Cellular Therapy Program
Qualification and validation may be erroneously used interchangeably. Understanding the difference and when to use a qualification or validation will support a robust quality management plan. There is an interdependency between qualifications and validations. Validations are built on the conclusions of qualifications.
When baking a cake, high quality ingredients and a tested recipe combine to make a delicious cake. If inferior ingredients or an inaccurate recipe are used, the cake will not bake or taste as expected.
Similarly, validations, like a recipe, are comprised of qualified elements to produce consistent results. Validation is the “confirmation by examination and provision of objective evidence that particular requirements can consistently be fulfilled. A process is validated by establishing, by objective evidence, that the process consistently produces a cellular therapy product meeting its predetermined specifications” (FACT 8th ed).
Qualification is “the establishment of confidence that equipment, supplies, and reagents function consistently within established limits” (FACT 8th ed). Qualifications may be performed by one or more people. Equipment may have installation and operational qualification performed by the vendor, and the laboratory may complete performance qualification.
New validations and re-validations should include a review of material qualifications prior to implementation. If a validation is amended, materials should be evaluated to ensure they are still used according to the qualified function. In the event of an occurrence, qualified materials and validated processes should both be investigated to determine if materials were used according to the qualified method and the validated process upheld.
Similar to checking ingredients as they are received in the kitchen, it is critical to qualify each supply, reagent and equipment element individually. Validations may then use these qualified elements to test the process for consistency of expected results.
Supplies, reagents, and equipment may be used for multiple procedures; therefore, it is important to understand downstream effects and assess the impact changes may have on multiple validated processes. Verification should be performed when changes to qualified supplies, reagents, or equipment are made. In some cases where significant changes are made, revalidation may be appropriate.
For example, transfer bags may be used in multiple processing procedures. The transfer bag is qualified to consistently function within established limits. The transfer bag may then be used in a validation for each processing procedure.
Use of qualified materials and validated processes consistently produces a cellular therapy product meeting predetermined specifications. A validated process contains qualified materials. Understanding the interdependency between qualifications and validations minimizes risk to cellular therapy products.
For more information on performing a validation, see FACT QM Series, Module 10, Validation Roundtable, a Program Perspective.
Like a fine wine, some Just the FACTs newsletters get better with time. They are useful reminders and references for navigating ongoing requirements, and we are excited to introduce a new feature titled, “From the Archives.” We will re-publish and update articles that address common questions that FACT continues to receive in order to share the knowledge far, wide, and into the future.
Our first featured article is, The X Factor: What is GxP and What Training is Required?” This article was originally published in July 2021 and addresses many questions FACT has recently received.
Enjoy the article!
The X Factor: What is GxP and What Training is Required?
The eighth edition FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration requires that physicians and staff in Marrow Collection Facilities, Apheresis Collection Facilities, and Processing Facilities have annual training in current GxP appropriate to the processes performed in accordance with Applicable Law. (See Standards CM3.3.4, C220.127.116.11, and D18.104.22.168).
What is GxP?
The Standards define GxP as, “Good practice following various quality standards and regulations. The “x” is variable, with further definition of good practices defined by different Applicable Law and industry standards. The type of work that is being performed will define which GxPs should be followed.”
Different facilities will follow different GxPs based on the activities they perform. These may include, but are not limited to, Good Manufacturing Practices (GMPs), Good Tissue Practices (GTPs), Good Documentation Practices (GDPs), Good Clinical Practices (GCPs), and Good Laboratory Practices (GLPs).
What GxPs require annual training per the Standards?
FACT requires training in all GxPs that are required by law. Accredited facilities must determine which GxPs apply to the activities they perform and for the types of cellular therapy products for which the cells will be used. Facilities must:
- Perform an assessment of all activities and determine which GxPs are required by law for each of those activities.
- Document this assessment so 1) the program has a defined list of GxPs that require training and 2) inspectors can verify appropriate training is performed.
- Develop training for each GxP identified as applicable to the activities performed. It can be within existing training or separate.
- Document completion of the training by each relevant physician or staff member.
There are some GxPs that will most likely always apply to certain situations. All Apheresis Collection and Processing Facilities will have activities applicable to GTPs and GDPs. All Marrow Collection Facilities will have activities applicable to GDPs, but may also perform activities related to GTPs depending on the type of cellular therapy products for which they are collecting. Collection and Processing Facilities may also need to follow GCPs or GLPs.
The extent and level of GMPs implemented in Collection or Processing Facilities is dependent on the type of manufacturing that is performed and for whom. For example, Collection Facilities may need to follow GMP requirements related to the transportation of starting material to a third-party manufacturer of a more-than-minimally manipulated cellular therapy product. Often, such processes would be dictated by the manufacturer. Processing Facilities manufacturing investigational and licensed cellular therapy products that are more-than-minimally manipulated or for non-homologous use will need to follow GMPs.
How much training is required each year?
Comprehensive training on every aspect of GxPs each year is not expected; rather, there must annually be some training based on a GxP topic.
Many of the procedures performed by personnel already require training in GxPs to perform the work; therefore, GxP training is not required to be separate. However, documentation must provide evidence that the GxPs were included. For example, training in environmental control could include an overview of GTPs or GMPs, the relevant requirements based on the work to be performed, and the specific tasks performed by personnel.
Training resources for GxPs from reputable sources are plentiful online via the websites of regulatory agencies, quality management societies, and professional societies. It is also acceptable to share training resources among the clinical, collection, and processing functions of an integrated cellular therapy program. Some organizations have asked if training required as part of Risk Evaluation and Mitigation Strategies (REMS) implemented by manufacturers of commercially available cellular therapy products (such as CAR-T products) would suffice for GMP training. GMP training would not be expected in REMS programs because they address specific risks associated with a final product ready for administration rather than the manufacturing of the product (for example, cytokine release syndrome following CAR-T administration).
Addressing Shortages; An Update from the FACT Professional Relations Committee on Fludarabine and Cord Blood Processing Device Shortages
Drug and supply shortages have been frequently plaguing cellular therapy programs. Current shortages include, but are likely not limited to, Fludarabine, Albumin, marrow collection kits, and apheresis circuits. Such shortages have been topics of discussion by the FACT Professional Relations Committee. Professional societies and registries advocate for solutions to the operational, regulatory, and quality challenges these shortages cause.
The American Society for Transplantation and Cellular Therapy (ASTCT) and the National Marrow Donor Program (NMDP)/Be the Match have been reporting their efforts to the FACT Professional Relations Committee regarding the Fludarabine Phosphate Injection shortage in the United States. This shortage is forcing centers to use non-FDA approved lymphodepleting regimens that may negatively influence the outcome of blood and marrow transplantation and CAR-T cell therapy. In June 2022, the two organizations submitted a letter to the U.S. Food and Drug Administration (FDA) outlining the issue, the negative impact on patients, and potential solutions. ASTCT and NMDP/Be the Match are continuing to advocate for solutions and work with the FDA to alleviate the issue. During the most recent committee meeting in October 2022, updates included reports of current availability from Teva Pharmaceuticals and expected availability from Fresenius Kabi and Areva Pharmaceuticals in late October.
Preparative regimens must be documented within Standard Operating Procedures or clinical guidelines per FACT Standards. If Fludarabine is specifically used as part of a preparative regimen but other drugs must be used due to the shortage, then this is a deviation and must comply with established deviation processes as outlined in an accredited organization’s Quality Management Plan. For ongoing situations such as Fludarabine shortages, guidelines could also include alternative protocols when the main protocol is not possible due to shortages. Since this would be an established and approved approach to handling shortages, then it would not be a deviation every time one occurs.
An additional shortage of processing technology that is impacting cell processing at cord blood banks and transplant programs results from the exit of Cytiva (formerly GE/BioSafe) from the medical device market. Banks and programs must identify new processing technology and, if applicable, submit pre-approval supplements to the FDA. Collaboration among cord blood banks to share validation protocols could ease the burden on individual banks and result in standardized processes. For more information on how you can help, please reach out to Donna Regan at firstname.lastname@example.org.
Free On-Demand Recordings Provided by Organizational Members of the FACT Professional Relations Committee
The FACT Professional Relations Committee shared and discussed many important topics during its quarterly meeting in October 2022. Included during this meeting were several videos that can be accessed free of charge. These sessions can be used to inform future directions of organizations and to train personnel.
- ISCT webinar, “Implementing a New Clinical CAR T Program: Manufacturing Your Own!”
- NMDP Donor Leave Policy Forum to allow more donors to answer the call to be a donor. (Once registered, the on-demand video will be available.)
- Cord Blood Connect presentation by Dr. Peter Marks, Director of the FDA Center for Biologics Evaluation and Research (CBER) on Regulatory Pathways for the Development of Gene and Cell Therapies for Rare Diseases, made available by the CBA.
- ASGCT bipartisan briefing with the House Cancer Caucus on innovative approaches to cancer care including the basics of gene and cell therapy, the patient experience, access considerations, and the future outlook and pipeline of CAR-T cell treatments.
Input Needed for Next Phase of NIST Flow Cytometry Consortium Interlaboratory Studies; Comments Due October 31
The Standards Coordinating Body (SCB) is collecting data for the NIST Flow Cytometry Consortium and requests your input. The next phase of interlaboratory studies will focus on antigen-specific T Cells or CAR T cells, and your input is valuable to guide the direction of the studies. The SCB is reaching out to members of the regenerative medicine therapy community, including cellular therapy facilities, for input on needs and perceived gaps in flow cytometry methodologies. The goal is to perform studies that will be valuable to the stakeholders in this space.
The short, six-question survey can be found at https://www.surveymonkey.com/r/FC-TCell and responses are due by October 31, 2022. Questions can be directed to Katie Zander, Ph.D. at CZander@regenmedscb.org.
Provide the Food and Drug Administration Feedback on Distributed and Point-of-Care Manufacturing; Comments Due December 13, 2022
The U.S. Food and Drug Administration (FDA) is seeking input on distributed manufacturing (DM) and point-of-care (POC) manufacturing because of their potential to enable rapid, localized, and timely response to demands for therapies. Although no such manufacturing is currently approved by the FDA, the agency has already seen interest by several technology developers. The FDA Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER) formed the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative to determine whether an application using an advanced manufacturing technology can fit within the existing regulatory framework. Findings from this initiative would inform potential future policy development.
The FDA has identified areas of consideration in a discussion paper titled, Distributed Manufacturing and Point-of-Care Manufacturing of Drugs, and is asking for public feedback on key questions identified in the paper, such as:
- How often might a DM unit move to a new location and what might an applicant report to the agency when doing so?
- What locations are envisioned for POC unit operation?
- How might a centralized quality system (i.e., at a “parent location”) ensure each manufacturing unit complies with regulatory requirements and quality standards?
- What type of business relationships are envisioned between companies developing POC manufacturing platforms and health care facilities?
Stakeholders can provide input in various ways:
- Attend the public workshop on November 14-16.
- Submit comments to the public docket under docket number FDA-2022-N-2316.
- If developing direct manufacturing or point-of-care technology, contact CDER’s Emerging Technology Program at CDER-ETT@fda.hhs.gov or CBER’s Advanced Technologies Team at Biologics@fda.hhs.gov (add “CATT” to the subject line).
ISCT and CMaT Announce Upcoming Course Dates for Successful Workforce Development in Biomanufacturing
The International Society for Cell & Gene Therapy (ISCT) and the NSF Engineering Research Center for Cell Manufacturing Technologies (CMaT) developed the Workforce Development in Biomanufacturing course to address workforce shortages in cellular therapies. Workforce shortages was a major topic of discussion at the 2022 FACT Regenerative Medicine InterCHANGE, and this program was highlighted as a potential solution.
Developed by academic, regulatory, clinical, and commercial experts, this program upskills key personnel for roles across the cell and gene therapy sector with modules including:
- Module 1: Stem Cell and Immune Cell Engineering and Therapies
- Module 2: Quality Assurance and Regulatory Framework
- Module 3: Cell Bioprocessing and Manufacturing
- Module 4: Cell Product Characterization and Importance of Standards
The inaugural course received positive reviews and attendees indicated that they would recommend the course to colleagues. Visit the ISCT website for detailed information on course dates, format, registration, and fee discounts.
From Orlando to Paris, Minneapolis to Houston, FACT invites you to come with us on the 2023 Education Events Tour! Our 2023 education offerings include accreditation workshops, inspector training courses, and quality boot camps. These events are open to current and aspiring accreditation programs, FACT inspectors and trainees, quality personnel, and industry representatives. No matter your interests or where you are in your accreditation journey, we have an event that’s right for you!
The first stop is Orlando, Florida at the 2023 Tandem Meetings!
FACT Cellular Therapy Accreditation Workshop
We invite you to attend the Cellular Therapy Accreditation Workshop in conjunction with the 2023 Tandem Meetings on Tuesday, February 14, from 8:00 am to 5:00 pm, at the World Center Marriott in Orlando, Florida. FACT’s accreditation workshops make learning about the accreditation process and related FACT Standards an up-close and personal experience. Accreditation workshops are collaborative events where you will be able to work through a series of scenario-based case studies supplemented with presentations facilitated by experienced FACT instructors.
The Cellular Therapy Accreditation Workshop provides a high-level overview of topics including requirements and expectations for accreditation, how to position your organization to pursue accreditation, and the most commonly cited standards. Additional areas of discussion include manufacturer audits and corrective action plans and audits to improve outcomes and data management.
FACT Clinical Inspector Training Course
We invite you to attend the FACT Clinical Inspector Training Course in conjunction with the 2023 Tandem Meetings on Tuesday, February 14, from 8:00 am to 5:00 pm, at the World Center Marriott in Orlando, Florida. FACT’s inspector training courses make learning about the inspection process an up-close and personal experience with practical, hands-on sessions simulating performing an inspection supplemented with presentations facilitated by experienced FACT inspectors.
The FACT Inspector Training Course is for clinical inspector trainees only. Trainees must complete all pre-training course requirements before attending. The training course is a collaborative event where the trainee will work with an experienced FACT inspector to review the entire inspection process from beginning to end.
FACT instructors will educate inspector trainees on the following topics during the inspector training course:
- Inspection preparation essentials
- Important technology tools
- Advance review of documents
- Clinical program tour
- Facility documents
- Patient record review
- Post-inspection requirements
FACT – ASTCT Quality Boot Camp
We invite you to attend the FACT – ASTCT Quality Boot Camp on Wednesday February 15, from 8:00 am to 5:00 pm, at the World Center Marriott in Orlando, FL. This is a collaborative event where you will participate in a series of roundtable activities supplemented with presentations facilitated by experienced FACT inspectors and quality personnel.
The theme of the FACT – ASTCT Quality Boot Camp is: Strengthen your Quality Management Program through the Effective Use of Quality Tools. Using the right quality tool can help reduce errors, improve communication, help maintain compliance, and save programs time and resources while improving the overall quality of your program and processes.
During the quality boot camp, FACT instructors will discuss tools and techniques most commonly used in quality management and process improvement including:
- SWOT Analysis (Strengths, Weaknesses, Opportunities, and Threats)
- Risk Assessment and Failure Mode and Effects Analysis (FMEA)
- The Five Whys
- Fishbone/Ishikawa Diagram
If you cannot join us in Orlando, future stops include:
FACT Virtual Apheresis Collection and Processing Accreditation Workshop
Virtual, Wednesday, April 19, 2023
8:00 am – 5:00 pm CT
FACT Apheresis Collection Inspector Training Course
Minneapolis, MN April 2023
8:00 am – 5:00 pm CT
Registration Open Soon!
FACT Cord Blood Accreditation Workshop
Paris, France, May 30, 2023
8:00 am – 5:00 pm CT
FACT Cord Blood Inspector Training Course
Paris, France, May 30, 2023
8:00 am – 5:00 pm CT
FACT Collection, Processing, and Cord Blood Virtual Quality Boot Camp
Virtual, June 23, 2023
8:00 am – 5:00 pm
FACT Accreditation and Quality Principles Workshop
Perth, Australia, August 7, 2023
8:00 am – 5:00 pm
Registration Open Soon!
FACT Processing Inspector Training Course
Houston, TX, September 7, 2023
8:00 am – 5:00 pm