6th Edition FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration Summary of Changes This document summarizes the changes made to the 6th edition of the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration. This summary does not list all changes made to the Standards; refer to the final Cellular Therapy Standards and the acco mpanying Accreditation Manual for all requirements. These documents will be published on March 1, 2015 and become effective on June 1, 2015. Changes made to the 6th edition Cellular Therapy Standards and/or its accompanying Accreditation Manual include: Global Changes 1.

Revised Title a. FACT-JACIE Standards are now called FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration, also referred to as the Hematopoietic Cell Therapy Standards. b. The purpose is to define the scope of these requirements due to an increasing number of accredited facilities that support non-hematopoietic cellular therapies and because FACT now has a separate set of Standards for those services (the Common Standards for Cellular Therapies). The scope of the Hematopoietic Cell Therapy Standards includes: i. Collection, processing, and administration of hematopoietic progenitor cells (HPCs), whether minimally or more than minimally manipulated, for hematopoietic indications. ii. Collection, processing, and administration of cellular therapy products for donor lymphocyte infusion (DLI). c. Facilities pursuing accreditation for hematopoietic services in addition to collection and processing for other clinical specialties (e.g., i mmunology, cardiology, neurology, etc.) may consult the Hematopoietic Cellular Therapy Standards as a single reference point. d. Clinical Programs for other specialties may only share an accreditation with a hematopoietic progenitor cell (HPC) transplant program if the sa me physician group serves the sa me patient population (for example, if an immunology program works with the transplant program to administer CAR-T cells). If a different patient population is served, the program likely will not be able to share an accreditation because of differing directorship and protocols. In these cases,

the Clinical Program will be inspected and accredited under the Common Standards. e. For more details for how the Standards will be applied, reference the Just the FACTs Newsletter, Fall 2014 (Available at: http://factwebsite.org/uploadedFiles/Just_the_FACTs_Newsletter/Fall%202014(1 ).pdf) 2. New Format a. The new format of the Standards visually groups related requirements. b. Standards used solely for organizational purposes, but without specific requirements, were removed to make the document briefer. Header standards that facilitate comprehension remain. 3. Continuing Education (B3.1.6, B3.2.2, B3.8.4, B3.10.2, CM3.1.5, CM3.2.2, C3.1.5, C3.2.5, C3.3.2, D3.1.3, D3.2.3, D3.3.2) a. Hours i. Key personnel (directors, attending physicians, quality managers, and designated pharmacists) must participate in at least 10 hours of continuing education. ii. The number of hours is now specified in response to concerns from applicants and inspectors that “regular participation” is too ambiguous. iii. Because there are many topics related to the required areas of education, and because formally recognized activities (e.g., CME activities) are not necessarily required, this is an achievable amount of activity. b. Required areas of education include: i. Clinical Program Director, attending physicians, and designated pharmacists: Cellular therapy, to include (but not limited to) the field of HPC transplantation. ii. Quality Managers: Cellular therapy and/or quality management, to include (but not limited to) the field of HPC transplantation. 1. Collection quality managers should also have education in cell collection. 2. Processing quality managers should also have education in cellular therapy processing. iii. Marrow Collection Facility Medical Director: Cellular therapy, to include (but not limited to) the field of HPC transplantation and marrow collection.

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 2

iv. Apheresis Collection Facility Director and Medical Director: Cellular therapy, to include (but not limited to) the field of HPC transplantation and apheresis. v. Processing Facility Director and Medical Director: Cellular therapy, to include (but not limited to) the field of HPC transplantation and processing. 4. Annual Review of Quality Management Program (B4.1.2, C4.1.1, D4.1.1) a. Many applicants did not understand the purpose of the annual report on the performance of the Quality Management (QM) Program, which is a longitudinal review of the program. b. The 6th edition more clearly explains this by requiring the Director to annually review the effectiveness of the QM Program, and provide documentation of the review findings to the Clinical Program Director (collection and processing). 5. Outcome Analysis (B4.7, C4.7, D4.7) a. Analysis i. Outcome analysis must include evaluation of individual cellular therapy product data and aggregate data for each type of cellular therapy product and/or recipient type. 1. Products must be safe for individual recipients and any adverse events must be reviewed. 2. Aggregate data will illustrate trends that may need to be addressed. ii. Clinical Programs must compare one-year survival to national or international outcome data, and should achieve survival rates within expected ranges. 1. With the introduction of national and international comparative outcome data, Clinical Programs have additional resources to evaluate their one-year survival rates and improve upon them when they fall below expected ranges. 2. Clinical Programs should begin evaluating their one-year survival rates in comparison with published data soon, before it could have an impact on their accreditation. This new recommendation will also give programs, FACT, and JACIE experience with this type of evaluation before any decisions are made to officially require outcomes within expected ranges in future Standards editions.

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 3

3. In the U.S., the CIBMTR Transplant Center-Specific Outcome Data must be used. a. This report calculates center-specific expected ranges, so all programs should feasibly be able to perform as expected. There is no default number of programs that will fall out of range. 4. Programs in other regions must report which data is used to FACT or JACIE. 5. If expected one-year survival outco me is not met, the Clinical Program must submit a corrective action plan. FACT plans to establish a committee to create tools and resources for performing root cause analysis. b. New required analyses: i. Clinical Programs: 1. Acute GVHD grade within one hundred (100) days after transplantation. 2. Chronic GVHD grade within one (1) year after transplantation. 3. Central venous catheter infection. ii. Apheresis Collection and Processing Facilities: 1. Ti me to engraftment measured by ANC and platelet count. 6. Audits (B4.8, C4.8, D4.8) a. Most required audits must now be performed annually. i. Audits do not need to have the same objective every year. Different points of processes can be audited. 7. Deviation Management (B4.10, B5.7, CM5.7, C4.10, C5.7, D4.10, D5.7) a. There were several disparate comments regarding deviation management requirements, indicating a general lack of clarity. The section was revised to be more concise and streamlined. b. The most significant change to requirements is in regards to planned deviations, or variances. i. Variances always require pre-approval, and that process requires less scrutiny after the occurrence because approval was granted upfront. ii. Pre-approvals for variances are now required in the policies and procedures section and do not need to undergo the exact process as required for serious adverse events, errors and accidents, and biological product deviations in the quality management section.

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 4

c. Documentation of incidents and investigation reports now requires more detail. 8. Qualification and Validation (B4.13, C4.14, D4.14) a. Qualification of critical reagents, supplies, equipment, and facilities used for the marrow collection procedure is now required. b. More specific requirements for validation studies are delineated in response to common deficiencies found during on-site inspections. Such requirements include: i. An approved validation plan, including conditions to be validated. ii. Acceptance criteria. iii. Data collection. iv. Evaluation of data. v. Summary of results. vi. Review and approval of the validation plan, results, and conclusion by the director or designee and Quality Manager or designee. 9. Policies and Procedures (B5, CM5, C5, D5) a. Newly Required Standard Operating Procedures (SOPs) i. Clinical Program: 1. Donor screening, testing, eligibility determination, selection, and management: This was always required per B6 but more explicitly stated in B5 in the 6th edition. 2. Management of donors who require central venous access: Infections are a real risk and must be mini mized. 3. Administration of ABO-incompatible products to include a description of the indication for and processing methods to be used for red cell or plasma reduction: Requirements have been in the processing section, but it is the attending physician that actually writes the order. 4. Duration and conditions of cellular therapy product storage and indications for disposal: This is another requirement that has been in the processing section; however, the attending physician ultimately approves disposal. (See also D12.1.6) 5. Hygiene and use of personal protective equipment: This has always been required to maintain safety of personnel, but is now explicitly stated. ii. Marrow Collection Facility

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 5

1. Donor testing, eligibility determination, and management: In addition to a donor screening SOP, facilities must address donor testing, eligibility determination, and management in SOPs in compliance with CM6. 2. Hygiene and use of personal protective equipment: This has always been required to maintain safety of personnel, but is now explicitly stated. 3. Emergency and disaster plan related to the marrow collection procedure: Although Marrow Collection Facilities work closely with the Clinical Program, there are considerations for emergency and disaster management with respect specifically to the marrow collection procedure. iii. Apheresis Collection Facility 1. Management of donors who require central venous access: Infections are a real risk and must be mini mized. 2. Administration of blood products: Apheresis Collection Facilities often need to administer blood products to donors and this should be performed according to an established procedure. 3. Prevention of mix-ups and cross-contamination: Apheresis Collection Facilities often have more than one cellular therapy product in its possession. 4. Hygiene and use of personal protective equipment: This has always been required to maintain safety of personnel, but is now explicitly stated. iv. Processing Facility 1. Recalls of equipment, supplies, and reagents: Recalls for materials have an effect on resources for future processing, and cellular therapy products processed with defective materials may have been adversely affected. b. Other changes i. The SOP manual’s listing of current SOPs must include the title, identifier, and version for completeness and control. ii. Age-specific issues are now a required element of SOPs, which is believed to assist programs to remember to consider these issues when developing procedures.

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 6

iii. In addition to staff training, competency must be documented before a staff member performs a new or revised procedure, if appropriate. 10. Donor Selection, Evaluation, and Management (B6, CM6, C6) a. The Clinical Program must have written criteria for selection of allogeneic donors who are elderly in addition to those who are minors. b. Interpretation and translation must be performed by individuals qualified to provide these services in the clinical setting. i. The Standards reco mmend that family members and legally authorized representatives not serve as interpreters or translators. It is expected that every effort be made to avoid this situation, but it is also understood that many centers treat patients who speak uncommon languages. c. Informed consent and donor evaluation now must be obtained by a health care professional who is not the primary health care professional overseeing care of the recipient. This was only a recommendation in the 5th edition. d. The informed consent process must inform the donor of the policy for cellular therapy product discard or disposal. e. Pregnancy tests are now required. i. Previous editions only required a pregnancy assessment for female donors with childbearing potential, which was often misinterpreted. ii. Tests must be performed within seven (7) days prior to starting the donor mobilization regimen and, as applicable, within seven (7) days prior to the initiation of the recipient’s preparative regimen. This is particularly important when the recipient is on a long-term (for example, 21-day) preparative regimen. f. The requirement for a written order from a physician specifying the timing and goals of collection and processing is now also included in the clinical standards. g. The requirement for verification typing of the selected donor, with results confirmed prior to administration of the preparative regi men, is more explicitly stated in response to many questions. h. Clinical Programs must have a policy for anti-HLA antibody testing for mis matched donors and recipients. i. Records required for donor eligibility determination must be in English or translated into English when crossing international borders. j. Standards throughout the document explicitly reference requirements for incomplete donor eligibility determination in addition to ineligible donors. 11. Cord Blood Administration

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 7

a. Clinical Programs and Processing Facilities must have a procedure to confir m the identity of cord blood units if verification typing cannot be performed on attached segments, given Clinical Programs’ experiences with too few segments to perform verification typing. (B6.4.12.3, D8.13) b. Clinical Programs must consult with the Processing Facility regarding cord blood preparation for administration. Cord blood units that have not been red cell reduced prior to cryopreservation are now required to be washed. (B7.6.3) c. Requirements for cord blood washing (which is required for units that were not red cell reduced prior to cryopreservation) were intentionally duplicated in the processing section in recognition of the relationship between clinical and processing: physicians order the preparation and processing personnel perform the task. (D8.4.3, D8.4.4) 12. Control of Facility Parameters (CM2.3, C2.4, D2.3) a. Facility parameters that may affect cellular therapy product viability, integrity, contamination, sterility, or cross-conta mination during collection, including temperature and humidity at a minimum, must be assessed for risk to the cellular therapy product. b. Parameters identified to be a risk must be controlled, monitored, and recorded. c. Applicants and inspectors often questioned what parameters must be controlled, and their opinions sometimes differed. These revisions are intended to ensure applicants assess risks of facility parameters and document that assessment. Such information will help inspectors make a judgment call on the adequacy of facility controls. 13. Backup Coverage of Staff (CM3.3.2, C3.4.1, D3.4.1) a. Facilities were often found to have minimal staff that was only sufficient should no staff members be absent. b. To provide sufficient coverage should staff members become unavailable, facilities must have a minimum of one designated trained individual with an identified trained backup. 14. Labeling (CM7, C7, D7, Appendix II, Appendix III) a. The 5th edition required organizations to have a plan for ISBT 128 coding and labeling technology implementation. The proposed sixth edition requires that organizations be actively imple menting ISBT 128 coding and labeling technologies.

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 8

i. “Actively implementing” could be demonstrated by registration with ICCBBA, identification or creation of appropriate product codes, label designs, label validation, and/or use of scanned information. ii. ISBT 128 does not need to be i mplemented at the bedside since many medical record systems are not compatible and significant time and resources would be required to enable compatibility. b. Barcoding may negate the need for verification of label information by two people. The verification now may be conducted by two qualified people or by one qualified person using a validated process. c. Label Content i. Product attributes and recipient name no longer need to be affixed when using partial labels. ii. Name and quantity of anticoagulant and other additives, and expiration date and time may now accompany the product rather than be attached. iii. The statements “Properly Identify Recipient and Product” and “For Use by Intended Recipient Only” are no longer required. iv. The statement “For Nonclinical Use Only” is no longer in the appendix since the table applies to products for clinical use; however, the requirement remains. It is now stated in the text as Standards CM7.4.6, C7.4.6, and D7.4.7. v. Date and time of distribution no longer need to be affixed to the outer container label during shipping and transport on public roads. vi. If labels are generated by ISBT 128 technologies or are approved under an Investigational New Drug (IND) application, those requirements must be used. d. Requirements for Warning Labels On and Documents Accompanying Autologous Cellular Therapy Products i. Although United States FDA donor eligibility requirements do not apply to autologous products, the following warning statements and accompanying documentation do apply: 1. The statement, “FOR AUTOLOGOUS USE ONLY”. 2. The statement “NOT EVALUATED FOR INFECTIOUS SUBSTANCES” unless screening and testing is performed in accordance with all FDA donor eligibility requirements. 3. The statement “WARNING: Reactive Test Results for [name of disease agent or disease]” if there are any identified risk factors or

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 9

reactive test results. Note that if identified risks/results were a result of screening and testing that do not meet all FDA donor eligibility requirements, this statement must be used in addition to the statements in points 1 and 2 above. 4. Instructions for product use to prevent the introduction, transmission, or spread of communicable diseases and for reporting serious adverse reactions or events to the distributing facility. 5. Documents related to identified risk factors or reactive test results if any donor screening or testing is performed, whether or not all FDA requirements are met. 15. Liquid Nitrogen Safety (B2.15, B2.1.2, B2.8, D2.1.2, D2.8) a. The number of deficiencies in regards to safety of liquid nitrogen handling and oxygen sensors (or lack thereof) prompted more explicit requirements. b. Clinical Program personnel are in the immediate vicinity of liquid nitrogen when a cryopreserved cellular therapy product is brought to the clinical unit. The written safety manual must include action in case of exposure to liquid nitrogen. c. Processing Facilities must have oxygen sensors that are appropriately placed and utilized in areas where liquid nitrogen is present and must also specifically address liquid nitrogen exposure in the written safety manual. Changes Specifically to Clinical Program Requirements 16. Clinical Program Location (B1.1 and B1.1.1) a. Rather than specifying that clinical sites be housed in geographically contiguous or proxi mate space, the Standards now state that an integrated medical team and Clinical Program Director must be housed in a defined location and demonstrate common activities among all sites. b. Rationale i. The change more clearly describes the underlining intent of the requirement, which is that all clinical sites must have regular, documented interaction and consistent protocols to be considered a single program. ii. Improvements in technology (e.g., medical records and document management systems) and infrastructure (travel opportunities) have enabled clinical sites across greater distances to cohesively interact.

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 10

iii. When several clinical sites apply for accreditation as a single Clinical Program, the burden is on the applicant to demonstrate compliance with this requirement. Early consultation with FACT or JACIE is encouraged. 17. Provision of Care in Ambulatory Settings (B2.3) a. Important services in the transplant process may be provided in ambulatory settings, such as outpatient units, depending on the region or delivery model. b. When the preparative regimen, cellular therapy product administration, or initial post-transplant care is provided in an ambulatory setting, there must be a designated area with appropriate location and adequate space and design to mini mize the risk of airborne microbial contamination. 18. Accreditation of HLA Typing Laboratories (B2.11) a. Clinical Programs may now use HLA typing laboratories that are accredited by an organization other than ASHI or EFI, so long as those accreditation programs are appropriate for the care of HPC transplant recipients. b. A joint FACT and NMDP consultative committee of HLA experts established guidelines for what constitutes appropriate standards and accreditation. c. For an accreditation organization to be recognized as appropriate, it must work directly with FACT or JACIE to submit documentation and answer questions related to those guidelines. d. Clinical Programs are strongly encouraged to confirm appropriateness prior to discontinuing receipt of services for ASHI- or EFI-accredited HLA typing laboratories. Determination of appropriateness prior to accreditation expiration dates is not guaranteed. e. The Guidelines for Histoco mpatibility Typing Standards and Accreditation Programs will be available on the FACT website. 19. Accreditation of Techniques Used For Chi merism Testing (B2.12) a. Rationale i. Clinical decisions regarding the pace of withdrawal of post-transplant immunosuppression and/or subsequent administration of donor lymphocytes based on chimerism results may have potentially lifethreatening consequences with respect to GVHD, relapse risk, or graft failure. ii. Chimerism testing may be performed with a variety of methods and interlaboratory variability may be significant. b. The draft standard available for public comment described this requirement as accreditation specifically for chi merism testing. There was little disagreement that

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 11

laboratory accreditation for chimerism testing is ideal; however, there were many questions regarding what accreditation is available. The standard was revised to require accreditation of the techniques used in chi merism. c. EFI and other organizations provide external laboratory accreditation and quality assurance in chimerism testing. 20. Clinical Program Director Verification of Knowledge and Skills of Transplant Team (B3.1.5.1) a. The Clinical Program Director has been required to verify knowledge and skills of transplant team in previous editions. b. The 6th edition requires that such verification occurs at least once per accreditation cycle. 21. Training for Clinical Program Directors and Attending Physicians (B3.3) a. New requirements for specific clinical training and co mpetency include: i. Administration of ABO incompatible cellular therapy products. ii. Monitoring of pain. b. New requirement for additional specific clinical training and competency for programs requesting accreditation for allogeneic transplantation: diagnosis of opportunistic infections (which includes cytomegalovirus (CMV) infection). c. New requirement for knowledge: washing and diluting of cellular therapy products. 22. Clinical Program Personnel (B3) a. New sections were added to B3 Personnel to include all key providers in a Clinical Program. i. Physicians-in-Training (B3.4) 1. Physicians-in-training must be licensed to practice and limited to a scope of practice within the parameters of their licensure. They must also be appropriately supervised. 2. Physicians-in-training must receive specific training and develop competency in transplant-related skills, which include those listed for attending physicians. ii. Pharmacists (B3.8) 1. Pharmacist requirements relate to those who perform services for the transplant program. 2. Pharmacists must be licensed to practice and limited to a scope of practice within the parameters of their training and licensure.

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 12

3. Training must include an overview of hematology/oncology patient care, therapeutic drug monitoring, monitoring for and recognizing drug/drug and drug/food interactions and making necessary modifications, and recognition of medications that require adjustment for organ dysfunction. 4. Pharmacists should be involved in the development of guidelines or SOPs related to pharmaceutical management of transplant recipients. 5. Designated transplant pharmacists (i.e., those who have a leadership role or routine involvement in the care of transplant recipients) must meet continuing education requirements. b. Mid-level practitioners are now referred to as Advanced Practice Providers/Professionals, or APPs. (B3.5) c. Consulting specialists must now also include ophthalmology, obstetrics/gynecology, and dermatology. (B3.9) 23. Clinical Program Document Control (B4.5) a. Clinical Program document control requirements were expanded in the 6th edition and are similar to the requirements in the collection and processing sections. b. The document control system must include: i. Policies, protocols, and Standard Operating Procedures; worksheets; forms; and labels. ii. Elements listed in B4.5.3. iii. Process for regular review and assessment of records to identify recurring problems, potential points of failure, or need for process improve ment. 24. Recipient Care (B7) a. This section was previously titled, “Therapy Administration,” but now contains all requirements related to the care of the transplant recipient. b. Recipient informed consent must be obtained and documented by a licensed health care professional familiar with the proposed therapy, and this process must provide information regarding the risks and benefits. c. Records must be made concurrently with each step of recipient care in such a way that all steps may be accurately traced, and must identify the person immediately responsible for each significant step (including dates and ti mes). d. Specific references to “chemotherapy” were replaced with references to the “preparative regi men” to encompass all regi mens.

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 13

e. Barcoding has beco me more prevalent in Clinical Programs and may negate the need for verification of the drug and dose and recipient identity by two people. The verification now may be conducted by two qualified people or by one qualified person using a validated process. f. The recipient’s medical record of the administered cellular therapy product must include the product’s unique identifier, initiation and completion times of administration, and any adverse events related to administration. g. Standard of care has evolved in the assessment of recipients for evidence of acute and chronic GVHD, need for vaccinations, and post-transplant late effects. i. Allogeneic recipients must be assessed regularly for evidence of acute and chronic GVHD using an established staging and grading system. ii. There must be policies and procedures in place for allogeneic recipient post-transplant vaccination schedules and indications. 25. Data Management (B9.1) a. The Standards now recommend that both allogeneic and autologous data are submitted to a national or international database even if not required by applicable laws and regulations. b. Collection of data necessary to complete the CIBMTR Transplant Essential Data Forms or the EBMT Minimum Essential Data-A forms for at least one year following administration of the cellular therapy product is recommended. Changes Specifically to Marrow and Apheresis Collection Facility Requirements 26. Mini mum Number of Marrow Collection Procedures (CM1.5) a. The mini mum number remains at a minimum average of one (1) collection procedure per year within the accreditation cycle. b. This requirement applies to a single team of collectors and support staff. When different teams are used at different sites, the minimum number of procedures must be performed at each of those sites. c. The guidance also emphasizes that marrow collectors with little experience must be supervised appropriately to build and maintain competency. 27. Apheresis Equipment (C8.3) a. Must be inspected for cleanliness prior to each use and verified daily to be in compliance with the maintenance schedule prior to use. b. Calibration must be performed according to a traceable standard and, when out of calibration, there must be a defined process for action for cellular therapy products collected since the last calibration. This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 14

28. Other Marrow and Apheresis Collection Facility Changes a. Marrow and Apheresis Collection Facility records must identify the person immediately responsible for each significant step (including dates and ti mes). (CM8.15.1, C8.16.1) b. Marrow Collection Facilities must also control storage areas to prevent mix-ups, deterioration, conta mination, cross-contamination, and improper release or distribution of products. (CM9.1) i. Cellular therapy products are always undergoing some process, and temporary holding until they are picked up by another facility is considered storage. c. Cellular therapy products must be transported or shipped to the Processing Facility in a validated container. (CM10.3, C10.3) d. Apheresis collection that is performed in outpatient units must be in a designated area with appropriate location and adequate space and design to minimize the risk of airborne microbial contamination. (C2.1.2) e. Apheresis Collection Facility Directors and Medical Directors must have performed or supervised a mini mum of 5- previously 4- collection procedures in the 12 months preceding initial accreditation and a minimum average of 5 collection procedures per year within the accreditation cycle. (C3.1.4, C3.2.4) f. Extracorporeal photopheresis (ECP) requirements are now also included in the apheresis section based on apheresis professionals’ request for more specific guidelines. A written therapy plan from a physician, SOPs, and a final report of ECP administered are required. (C8.17) Changes Made Specifically to Processing Facility Requirements 29. Processing Facility Standards (Part D) a. Part D was reorganized to separate the Process Controls section into more manageable sections of like requirements. b. New sections are named Equipment, Supplies, and Reagents; Cellular Therapy Product Transportation and Shipping; and Distribution and Receipt. 30. More than Minimal Manipulation a. Processing Facilities must qualify environmental control systems and validate cleaning and sanitation procedures appropriate for the environmental classification and degree of manipulation performed. (D2.4.1) b. Processing Facilities must adhere to good manufacturing practices (GMP) appropriate for the degree of cellular therapy product manipulation. (D8.11.1) This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 15

31. Assays (D8.1.3.2, D8.1.3.3) a. For HPC products intended for restoration of hematopoiesis, an assay measuring viable CD34 must be performed. (D8.1.3.2) b. When manipulation alters the final cell population, a validated assay must be employed for evaluation of the viable target cell population before and after processing. (D8.1.3.3) 32. Cellular Therapy Product Receipt (D11.4) a. Processing Facilities must review and verify the product specifications for cellular therapy products received by an external facility. There must be documented evidence of donor eligibility screening and testing in accordance with applicable laws and regulations for these products. b. When cellular therapy products are returned to the Processing Facility after distribution for administration and approved for return to the inventory, documentation must include the events requiring return, the temporary storage temperature when at the clinical facility, the results of inspection upon return, and subsequent action taken to protect product safety and viability. 33. Other Processing Facility Changes a. Processing Facility Directors and Medical Directors must have a minimum of two years of postgraduate training and practical and relevant experience for the scope of activities carried out in the facility. Some regions of the world may have degrees that are equivalent to the doctoral degree. If a Processing Facility Director has such a degree, significant and co mpelling information regarding the degree requirements must be submitted to demonstrate equivalency. (D3.1.1, D3.2.1). b. Policies and procedures on the management of cellular therapy products with positive microbial culture results must also address the identification of individuals authorized to approve release, including the Processing Facility Medical Director at a mini mum. (D4.9.4) c. Records of identification codes of personnel with methods to link the name and/or signature to the identification codes is no longer required because of improvements in recordkeeping. d. Processing Facilities must have a written stability program that evaluates the viability and potency of cryopreserved cellular therapy products at a minimum annually. (D9.2.2)

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 16

i. There were many questions surrounding how stability studies must be performed and how they could be applied to early phase cellular therapy products. ii. The Standards Committee felt that this requirement is appropriate, but added guidance that includes examples of how to perform stability studies and clarification that stability studies can be in development for early phase products that do not yet have a definitive potency marker. e. Cellular therapy product inventory records no longer need to include the proper product or specimen name since the unique identifier is the ultimate identifier. (D9.8.1) f. The outer container for cellular therapy product transportation or shipping must be secured. (D10.5.3)

This outline provides a summary of the 6th edition Hematopoietic Cellular Therapy Standards and does not include all changes or requirements. See the FACT-JACIE International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration for all current requirements. The 6th edition is effective June 1, 2015. 17