C9 CELLULAR THERAPY PRODUCT STORAGE
C9.1 Apheresis Collection Facilities shall control storage areas to prevent mix-ups, deterioration, contamination, cross-contamination, and improper release or distribution of products.
C9.2 Apheresis Collection Facilities shall establish policies for the duration and conditions of storage prior to distribution to a Processing Facility or Clinical Program.
C10 CELLULAR THERAPY PRODUCT TRANSPORTATION AND SHIPPING
C10.1 Procedures for transportation and shipping of the cellular therapy product shall be designed to protect the integrity of the product and the health and safety of facility personnel.
C10.1.1 The primary cellular therapy product container shall be placed in a secondary container that is sealed to prevent leakage.
C10.1.2 The cellular therapy product shall be transported and/or shipped to the Processing Facility at a temperature defined in the Apheresis Collection Facility Standard Operating Procedure Manual.
C10.1.3 Cellular therapy products that are transported and/or shipped from the collection site to any non-contiguous Processing Facility shall be transported and/or shipped in an outer container made of material adequate to withstand leakage of contents, impact shocks, pressure changes, temperature changes, puncture, and other conditions incident
to ordinary handling.
C10.1.4 If the intended recipient has received high-dose therapy, the cellular therapy product shall be transported by a qualified courier.
C10.2 The cellular therapy product shall be transported and/or shipped with required accompanying records as defined in the Apheresis Collection Facility’s Standard Operating Procedure Manual and in compliance with C7.6.
C10.3 There shall be a record of the date and time of cellular therapy product distribution.
C11 RECORDS
C11.1 GENERAL REQUIREMENTS
C11.1.1 A records management system shall be established and maintained to facilitate the review of records.
C11.1.1.1 The records management system shall facilitate tracking of the cellular therapy product from the donor to the recipient or final disposition and tracing from the recipient or final disposition to the donor.
C11.1.1.2 For cellular therapy products that are to be distributed for use at another institution, the receiving institution shall be informed of the tracking system and requirement for tracking the product in writing or electronic format at or before the time of product distribution.
C11.1.2 Records shall be maintained in such a way as to ensure their integrity and preservation.
C11.1.2.1 If records are maintained in more than one location, there shall be a system to ensure prompt identification, location, and retrieval of all records.
C11.1.2.2 Records shall be accurate, legible, and indelible.
C11.1.3 All records and communications between the collection, processing, and transplant facilities, and their patients and donors, shall be regarded as privileged and confidential.
C11.1.3.1 Safeguards to assure this confidentiality shall be established and followed in compliance with applicable laws and regulations.
C11.1.4 Records shall be maintained in one or more forms that are retrievable.
C11.2 Apheresis Collection Facility records related to quality control, personnel training and competency, facility maintenance, facility management, complaints, or other general facility issues shall be retained in accordance with applicable laws and regulations, or a defined program or institution policy, unless otherwise specified in these Standards.
C11.2.1 Employee records shall be maintained in a confidential manner, as required by applicable laws and regulations.
C11.3 Patient and donor records including, but not limited to, consents and records of care shall be maintained in a confidential manner as required by applicable laws and regulations for a minimum of ten (10) years after the administration of the cellular therapy product, or, if not known, ten (10) years after the date of the distribution, disposition, or expiration of the product, whichever is latest.
C11.4 Records to allow tracking and tracing of cellular therapy products shall be maintained for a minimum of ten (10) years after final distribution of the product,
or as required by applicable laws and regulations. These records shall include at a minimum: product identity, unique numeric or alphanumeric identifier, and collection date and time; and donor and recipient identification as far as known.
C11.5 Research records shall be maintained in a confidential manner as required by applicable laws and regulations for a minimum of ten (10) years after the
administration, distribution, disposition, or expiration of the cellular therapy product, whichever is latest.
C11.6 ELECTRONIC RECORDS
C11.6.1 The Apheresis Collection Facility shall establish and maintain a current listing of all critical electronic record systems. Critical electronic record systems shall include at a minimum systems under the control of the Apheresis Collection Facility that are used:
C11.6.1.1 In lieu of paper.
C11.6.1.2 To make decisions.
C11.6.1.3 To perform calculations.
C11.6.1.4 To create and/or store information used in critical procedures.
C11.6.2 For all critical electronic record systems, there shall be policies, procedures, and system elements to ensure the accuracy, integrity, and confidentiality of all records.
C11.6.3 There shall be a means by which access to electronic records is limited to authorized individuals.
C11.6.4 The critical electronic record system shall ensure that all donor, cellular therapy product, and recipient identifiers are unique.
C11.6.5 For all critical electronic record systems, there shall be an alternative system for all electronic records that ensures continuous operation in the event that critical electronic record systems are not available. The alternative system shall be validated and Apheresis Collection Facility staff shall be trained in its use.
C11.6.6 For all critical electronic record systems, there shall be written procedures for record entry, verification, and revision.
C11.6.6.1 A method shall be established or the system shall provide for review of data before final acceptance.
C11.6.6.2 A method shall be established or the system shall provide for the unambiguous identification of the individual responsible for each record entry.
C11.6.7 For all critical electronic record systems, there shall be the ability to generate true copies of the records in both human readable and electronic format suitable for inspection and review.
C11.6.8 For all critical electronic record systems, there shall be validated procedures for and documentation of:
C11.6.8.1 Training and continuing competency of personnel in the use of the system.
C11.6.8.2 Monitoring of data integrity.
C11.6.8.3 Back-up of the electronic records system on a regular schedule.
C11.7 RECORDS IN CASE OF DIVIDED RESPONSIBILTY
C11.7.1 If two (2) or more facilities participate in the collection, processing, or administration of the cellular therapy product, the records of each facility shall show plainly the extent of its responsibility.
C11.7.2 The Apheresis Collection Facility shall furnish to the facility of final disposition a copy of all records relating to the collection procedures performed in so far as they concern the safety, purity, or potency of the cellular therapy product involved.
C12 DIRECT DISTRIBUTION TO CLINICAL PROGRAM
C12.1 Where cellular therapy products are distributed directly from the Apheresis Collection Facility to the Clinical Program for administration or subsequent processing, the Standards related to labeling, documentation, distribution, transportation, and recordkeeping in Sections D7, D8, D10, D12, and the Appendices apply.
PART D: PROCESSING FACILITY STANDARDS
D1 General
D2 Processing Facility
D3 Personnel
D4 Quality Management
D5 Policies and Procedures
D6 Process Controls
D7 Coding and Labeling of Cellular Therapy Products
D8 Distribution
D9 Storage
D10 Transportation, Shipping, and Receipt
D11 Disposal
D12 Records
PART D: PROCESSING FACILITY STANDARDS
D1 GENERAL
D1.1 These Standards apply to all processing, storage, and distribution activities performed in the Processing Facility on cellular therapy products obtained from
living donors.
D1.2 The Processing Facility shall abide by all applicable laws and regulations.
D1.2.1 The Processing Facility shall be licensed, registered, and/or accredited with the appropriate governmental authority for the activities performed.
D1.3 The Processing Facility, including a Processing Facility Director, a Processing Facility Medical Director, and at least one staff member, shall have been in place and performing cellular therapy product processing for at least twelve (12) months preceding initial accreditation.
D2 PROCESSING FACILITY
D2.1 The Processing Facility shall be of adequate space, design, and location for the intended procedures.
D2.1.1 The Processing Facility shall be divided into defined areas of adequate size to prevent improper labeling, mix-ups, contamination, or crosscontamination of cellular therapy products.
D2.1.2 There shall be a process to control storage areas to prevent mix-ups, contamination, and cross-contamination of all cellular therapy products
prior to release or distribution.
D2.1.3 The Processing Facility shall be secure to prevent the entrance of unauthorized personnel.
D2.1.4 The Processing Facility shall provide adequate lighting, ventilation, access to sinks, and air quality where applicable to prevent the introduction, transmission, or spread of communicable disease.
D2.2 Critical facility parameters that may affect cellular therapy product processing, storage, or distribution shall be controlled, monitored, and recorded to
demonstrate ongoing compliance.
D2.3 When using processing methods that may result in contamination or crosscontamination of cellular therapy products, critical environmental conditions shall be controlled where appropriate for temperature, humidity, ventilation, air quality, and surface contaminates.
D2.3.1 Where appropriate, the Processing Facility shall provide environmental monitoring for microorganisms.
D2.4 The Processing Facility shall be maintained in a clean, sanitary, and orderly manner.
D2.5 There shall be documentation of facility cleaning and sanitation to ensure adequate conditions for proper operations.
D2.6 There shall be adequate equipment and materials for the procedures performed.
D2.7 SAFETY REQUIREMENTS
D2.7.1 The Processing Facility shall be operated in a manner designed to minimize risks to the health and safety of employees, patients, donors,
visitors, and volunteers.
D2.7.2 The Processing Facility shall have a written safety manual that includes instructions for action in case of exposure to communicable disease or to chemical, biological, or radiological hazards, where applicable.
D2.7.3 All waste generated by the Processing Facility activities shall be disposed of in a manner that minimizes any hazard to facility personnel and to the environment in accordance with applicable laws and regulations.
D2.7.4 Gloves and protective clothing shall be worn while handling biological specimens. Such protective clothing shall not be worn outside the work
area.
D3 PERSONNEL
D3.1 PROCESSING FACILITY DIRECTOR
D3.1.1 There shall be a Processing Facility Director who is an individual with a medical degree or doctoral degree in a relevant science, qualified by training or experience for the scope of activities carried out in the Processing Facility. The Processing Facility Director may also serve as the Processing Facility Medical Director, if appropriately credentialed.
D3.1.2 The Processing Facility Director shall be responsible for all procedures, administrative operations, and the Quality Management Program of the Processing Facility, including compliance with these Standards and other applicable laws and regulations.
D3.1.3 The Processing Facility Director shall participate regularly in educational activities related to the field of cellular processing and/or transplantation.
D3.2 PROCESSING FACILITY MEDICAL DIRECTOR
D3.2.1 There shall be a Processing Facility Medical Director who is a licensed or certified physician with postgraduate training and at least one year practical and relevant experience in the preparation and clinical use of cellular therapy products. The Medical Director may also serve as the Processing Facility Director, if appropriately credentialed.
D3.2.2 The Processing Facility Medical Director or designee shall be directly responsible for all medical aspects related to the Processing Facility.
D3.2.3 The Processing Facility Medical Director shall participate regularly in educational activities related to the field of cellular processing and/or transplantation.
D3.3 QUALITY MANAGEMENT SUPERVISOR
D3.3.1 There shall be a Processing Facility Quality Management Supervisor approved by the Processing Facility Director to establish and maintain systems to review, modify, and approve all policies and procedures intended to monitor compliance with these Standards and/or the performance of the Processing Facility.
D3.3.2 The Processing Facility Quality Management Supervisor shall participate regularly in educational activities related to the field of cellular processing and/or quality management.
D3.4 STAFF
D3.4.1 The Processing Facility shall have an adequate number of trained staff for the volume and complexity of all operations.
D4 QUALITY MANAGEMENT
D4.1 The Processing Facility shall establish and maintain a written Quality Management Plan.
D4.2 The Quality Management Plan shall include an organizational chart of key positions, personnel, and functions within the Processing Facility.
D4.2.1 The Quality Management Plan shall include a description of how these key personnel interact to implement the quality management activities.
D4.2.2 The Processing Facility Director or designee shall be responsible for the Quality Management Plan as it pertains to the Processing Facility.
D4.2.2.1 The Processing Facility Director or designee shall have authority over and responsibility for ensuring that the Quality Management Program is effectively established and maintained.
D4.2.2.2 The Processing Facility Director or designee shall not have oversight of his/her own work if this person also performs other
tasks in the Processing Facility.
D4.2.2.3 The Processing Facility Director or designee shall report on quality management activities, at a minimum, quarterly.
D4.2.2.4 The Processing Facility Director or designee shall report on the performance of the Quality Management Plan, at a minimum, annually. This report shall be provided to the Clinical Program Director, as applicable.
D4.3 The Quality Management Plan shall include, or summarize and reference, personnel education, experience, and training requirements for each key position in the Processing Facility. Personnel requirements shall include at a minimum:
D4.3.1 Current job description for all staff.
D4.3.2 A system to document the following for each staff member:
D4.3.2.1 Initial qualifications.
D4.3.2.2 Orientation.
D4.3.2.3 Initial training.
D4.3.2.4 Competency for each critical function performed.
D4.3.2.5 Continued competency at least annually.
D4.3.2.6 Training and retraining.
D4.3.2.7 Provisions for continuing education.
D4.3.3 A description of minimal trainer qualifications and a uniform plan for staff training.
D4.4 The Quality Management Plan shall include, or summarize and reference, policies and procedures for development, approval, validation, implementation, review, revision, and archival of all critical processes, policies, and procedures.
D4.5 The Quality Management Plan shall include, or summarize and reference, a system for document control. The document control system shall include at a minimum the following elements:
D4.5.1 Listing of all active critical documents that shall adhere to the document control system requirements. Controlled documents shall include at a
minimum:
D4.5.1.1 Policies.
D4.5.1.2 Standard Operating Procedures.
D4.5.1.3 Worksheets.
D4.5.1.4 Forms.
D4.5.1.5 Labels.
D4.5.2 A procedure for preparation, approval, implementation, review, revision, and archival of all policies and procedures.
D4.5.2.1 Archived policies and procedures, the inclusive dates of use, and their historical sequence shall be maintained for a minimum of ten (10) years from archival or according to governmental or institutional policy, whichever is longer.
D4.5.3 A standardized format for policies, procedures, worksheets, forms, and labels.
D4.5.4 Assignment of a numeric or alphanumeric identifier and title to each document and document version regulated within the system.
D4.5.5 A procedure for document approval, including the approval date, signature of approving individual(s), and the effective date.
D4.5.6 A system to ensure that controlled documents cannot undergo accidental or unauthorized modification.
D4.5.7 A system for document change control that includes a description of the change, the signature of approving individual(s), approval date(s), and
effective date.
D4.5.8 A system for the retraction of obsolete documents to prevent unintended use.
D4.5.9 A system for record creation, assembly, review, storage, archival, and retrieval.
D4.6 The Quality Management Plan shall include, or summarize and reference, policies and procedures for establishment and maintenance of written agreements with third parties whose services impact the cellular therapy product.
D4.6.1 Agreements shall include the responsibility of the facility performing any step in processing, testing, or storage to comply with applicable laws and regulations and these Standards.
D4.6.2 Agreements shall be dated, reviewed, and renewed on a regular basis.
D4.7 The Quality Management Plan shall include, or summarize and reference, policies and procedures for documentation and review of cellular therapy product efficacy and/or outcome analysis, as appropriate, including at least:
D4.7.1 For HPC products intended for hematopoietic reconstitution, a process for documentation and review of time to engraftment following cellular
therapy product administration.
D4.7.2 For other cellular therapy products, the criteria for product efficacy and/or the clinical outcome shall be determined and shall be reviewed at regular time intervals.
D4.8 The Quality Management Plan shall include, or summarize and reference, policies, procedures, and a timetable for conducting, reviewing, and reporting audits of the Processing Facility’s activities to verify compliance with elements of the Quality Management Program and operational policies and procedures.
D4.8.1 Audits shall be conducted on a regular basis by an individual with sufficient expertise to identify problems, but who is not solely responsible for the process being audited.
D4.8.2 The results of audits shall be used to recognize problems, detect trends, identify improvement opportunities, and implement corrective actions when necessary.
D4.8.3 Audits shall include documentation that external facilities performing critical contracted services have met the requirements of the written
agreements.
D4.9 The Quality Management Plan shall include, or summarize and reference, policies and procedures on the management of cellular therapy products with positive microbial culture results that address at a minimum:
D4.9.1 Documentation and product labeling.
D4.9.2 Product quarantine.
D4.9.3 Release of the product, including identification of authorized individuals and criteria for product release.
D4.9.4 Investigation of cause.
D4.9.5 Notification of the recipient’s physician, collection facility, and/or any other facility in receipt of the product, as applicable.
D4.9.6 Reporting to regulatory agencies if appropriate.
D4.10 The Quality Management Plan shall include, or summarize and reference, policies and procedures for errors, accidents, adverse events, biological product deviations, variances, and complaints.
D4.10.1 Policies and procedures shall include methods for:
D4.10.1.1 Detection.
D4.10.1.2 Investigation.
D4.10.1.3 Evaluation.
D4.10.1.4 Documentation.
D4.10.1.5 Reporting.
D4.10.1.6 Corrective action.
D4.10.1.7 Follow-up for effectiveness of corrective action.
D4.10.2 Documentation of each adverse event associated with a cellular therapy product shall be reviewed in a timely manner by the Processing Facility Director and/or Processing Facility Medical Director, as appropriate.
D4.10.3 A written description of adverse events shall be made available to the recipient’s physician and the collection facility, if appropriate.
D4.10.4 When applicable, adverse events shall be reported to appropriate regulatory agencies within the required timeframes.
D4.10.5 Deviations from Standard Operating Procedures shall be documented.
D4.10.5.1 Planned deviations shall be pre-approved by the Processing Facility Director or designee and if medically relevant, by the Processing Facility Medical Director or designee.
D4.10.5.2 Unplanned deviations and associated corrective actions shall be reviewed by the Processing Facility Director or designee, or Processing Facility Medical Director or designee, as appropriate.
D4.10.6 There shall be a defined process improvement plan that includes policies or procedures for the recognition and investigation of the cause of all issues that require corrective action.
D4.10.6.1 The implementation of corrective actions shall include both short-term action to address the immediate problem and long-term action to prevent the problem’s recurrence.
D4.10.6.2 Follow-up activities shall be conducted to determine if the corrective actions were effective.
D4.11 The Quality Management Plan shall include, or summarize and reference, policies and procedures for cellular therapy product tracking and tracing that allow tracking from the donor to the recipient or final disposition and tracing from the recipient or final disposition to the donor.
D4.12 The Quality Management Plan shall include, or summarize and reference, policies and procedures for actions to take in the event the Processing Facility’s
operations are interrupted.
D4.13 The Quality Management Plan shall include, or summarize and reference, policies and procedures for qualification of critical supplies, reagents, equipment, and facilities.
D4.13.1 Suppliers of critical supplies, reagents, services, and equipment shall be qualified by a method that ensures they are compliant with applicable laws and regulations and these Standards.
D4.13.2 Reagents that are not the appropriate grade shall undergo qualification for the intended use.
D4.14 The Quality Management Plan shall include, or summarize and reference, policies and procedures for validation and/or verification of critical procedures.
D4.14.1 Critical procedures to be validated or verified shall include at least the following: processing techniques, cryopreservation procedures, labeling, storage, and distribution.
D4.14.2 There shall be documentation of review and acceptance of validation studies by the appropriate individual from Quality Management.
D4.14.3 Changes to a process shall be verified or validated to ensure that they do not create an adverse impact anywhere in the operation.
D4.14.4 Procedures for manufacturing reagents in-house shall be validated.
D5 POLICIES AND PROCEDURES
D5.1 The Processing Facility shall establish and maintain policies and/or procedures addressing critical aspects of operations and management in addition to those required in D4. These documents shall include all elements required by these Standards and shall address at a minimum:
D5.1.1 Donor and recipient confidentiality.
D5.1.2 Product receipt.
D5.1.3 Processing and process control.
D5.1.4 Prevention of mix-ups and cross-contamination.
D5.1.5 Red cell compatibility testing and processing of ABO-incompatible products to include a description of the indication for and processing methods to be used for red cell and plasma depletion.
D5.1.6 Cryopreservation and thawing.
D5.1.7 Labeling (including labeling of associated forms and samples).
D5.1.8 Product expiration dates.
D5.1.9 Product storage to include alternative storage if the primary storage device fails.
D5.1.10 Release and exceptional release.
D5.1.11 Cellular therapy product recall to include a description of responsibilities and actions to be taken, including notification of appropriate regulatory agencies.
D5.1.12 Transportation and shipping, including methods and conditions within the Processing Facility and to and from external facilities.
D5.1.13 Product disposal.
D5.1.14 Reagent and supply management.
D5.1.15 Equipment operation, maintenance, and monitoring, to include corrective actions in the event of failure.
D5.1.16 Cleaning and sanitation procedures to include identification of the individuals responsible for the activities.
D5.1.17 Environmental control to include a description of environmental monitoring plan.
D5.1.18 Hygiene and use of personal protective attire.
D5.1.19 Infection control, biosafety, and chemical and radiological safety.
D5.1.20 Facility management.
D5.1.21 Decontamination and disposal of medical and biohazard waste to include Processing Facility-specific requirements where these differ from institutional requirements.
D5.1.22 Emergency and disaster plan, including the Processing Facility response.
D5.2 The Processing Facility shall maintain a detailed Standard Operating Procedures Manual.
D5.2.1 The Standard Operating Procedures Manual shall include a listing of all current Standard Operating Procedures.
D5.3 Standard Operating Procedures shall be sufficiently detailed and unambiguous to allow qualified technical staff to follow and complete the procedures successfully.
Each individual procedure shall include:
D5.3.1 A clearly written description of the objectives.
D5.3.2 A description of equipment and supplies used.
D5.3.3 Acceptable end-points and the range of expected results, where applicable.
D5.3.4 A stepwise description of the procedure.
D5.3.5 Reference to other Standard Operating Procedures or policies required to perform the procedure.
D5.3.6 A reference section listing appropriate literature, if applicable.
D5.3.7 Documented approval of each procedure by the Processing Facility Director or Medical Director, as appropriate, prior to implementation and every two years thereafter.
D5.3.8 Documented approval of each procedural modification by the Processing Facility Director or Medical Director, as appropriate, prior to implementation.
D5.3.9 A current version of orders, worksheets, reports, labels, and forms, where applicable.
D5.4 Copies of Standard Operating Procedures relevant to processes being performed shall be readily available to the facility staff.
D5.5 All personnel in the Processing Facility shall follow the Standard Operating Procedures related to their positions.
D5.6 Review and/or training by a staff member shall be documented before the staff member is allowed to perform new and revised policies and procedures.
D6 PROCESS CONTROLS
D6.1 There shall be a process for controlling and monitoring the manufacturing of cellular therapy products to ensure products meet predetermined release
specifications.
D6.1.1 The Processing Facility Director shall define tests and procedures for measuring and assaying cellular therapy products to ensure their safety, viability, and integrity and to document that products meet predetermined release specifications. Results of all such tests and procedures shall become part of the permanent record of the product processed.
D6.1.2 There shall be a documented system for the identification and handling of test samples so that they are accurately related to the corresponding cellular therapy product, donor, or recipient, as applicable.
D6.1.2.1 There shall be a mechanism to identify the individual obtaining the sample, the date, the time (if appropriate), and the sample source.
D6.1.2.2 Samples obtained for testing shall be representative of the cellular therapy product to be evaluated.
D6.1.3 There shall be the establishment of appropriate and validated assays and test procedures for the evaluation of cellular therapy products.
D6.1.3.1 For all cellular therapy products, a total nucleated cell count and viability measurement shall be performed.
D6.1.3.2 For HPC products, a CD34 assay shall be performed.
D6.1.3.3 For cellular therapy products undergoing manipulation that alters the final cell population, a relevant and validated assay, where available, shall be employed for evaluation of the target cell population before and after the processing procedures.
D6.1.4 For tests required by these Standards performed within the Processing Facility:
D6.1.4.1 There shall be a process for monitoring the reliability, accuracy, precision, and performance of laboratory test procedures and instruments.
D6.1.4.2 New reagent lots shall be verified to provide comparable results to current lots or to give results in agreement with suitable reference material before or concurrently with being placed into service.
D6.1.4.3 Where available, reference material shall be used each day of testing and shown to give results within the defined range established for that material.
D6.1.4.4 Function checks shall be performed for testing instruments, as appropriate, prior to testing donor, recipient, or cellular therapy product samples.
D6.1.4.5 For tests performed within the Processing Facility, there shall be documentation of ongoing proficiency testing as designated by the Processing Facility Director. The results shall be reviewed by the Processing Facility Director or designee and outcomes reviewed with the staff.
D6.1.5 Tests required by these Standards, not performed by the Processing Facility, shall be performed by a laboratory certified or accredited by the appropriate laboratory regulatory agency.
D6.1.6 Communicable disease testing required by these Standards shall be performed using test reagents or kits approved by the appropriate regulatory authority and performed in an appropriately registered laboratory that is accredited or licensed in accordance with applicable laws and regulations.
D6.1.7 Cellular therapy products that do not meet allogeneic donor eligibility requirements shall be distributed only if there is documented urgent medical need for the product. Documentation shall include, at a minimum, the approval of the recipient’s physician and the Processing Facility Medical Director or other designated physician.
D6.1.8 Notification of the transplant physician of nonconforming cellular therapy products and approval for their release shall be documented.
D6.2 There shall be a written request from the recipient’s physician before processing is initiated specifying the cellular therapy product type, recipient and donor identifiers, the type of processing that is to be performed, and the anticipated date of processing.
D6.3 For allogeneic cellular therapy products, information required by the Processing Facility prior to distribution of the product shall include:
D6.3.1 A statement of donor eligibility.
D6.3.2 For ineligible donors, the reason for their ineligibility.
D6.3.3 Documentation of urgent medical need and physician approval for use, if applicable.
D6.4 For cryopreserved products received from another facility, the Processing Facility shall ensure availability of adequate storage space at the appropriate temperature.
D6.5 Processing procedures shall be validated in the Processing Facility and documented to result in acceptable target cell viability and recovery.
D6.5.1 Published validated processes shall be verified within the Processing Facility prior to implementation.
D6.5.2 The Processing Facility shall use validated methods for preparation of cellular therapy products for administration.
D6.5.2.1 If the Processing Facility lacks experience with the type of cellular therapy product requested for a recipient, personnel shall obtain the manufacturer’s instructions and follow these instructions to the extent possible.
D6.5.2.2 The Processing Facility should verify the processing procedures utilizing practice units similar to the cellular therapy product intended for administration when feasible.
D6.6 Critical control points and associated assays shall be identified and performed on each cellular therapy product as defined in Standard Operating Procedures.
D6.7 Methods for processing shall employ aseptic technique and cellular therapy products shall be processed in a manner that minimizes the risk of crosscontamination.
D6.7.1 Where processing of tissues and cells involves exposure to the environment, processing shall take place in an environment with specified
air quality and cleanliness.
D6.7.2 The effectiveness of measures to avoid contamination and crosscontamination shall be verified and monitored.
D6.8 Equipment, supplies, and reagents used to process cellular therapy products shall be used in a manner that prevents product mix-ups, contamination, and
cross-contamination, and that does not compromise product function and integrity.
D6.9 Supplies and reagents used in processing, testing, cryopreservation, and storage shall be controlled by a materials management system that includes
requirements for:
D6.9.1 Visual examination of each supply and reagent used to manufacture cellular therapy products for damage or evidence of contamination upon receipt and acceptance into inventory.
D6.9.2 Records of receipt that shall include the supply or reagent type, quantity, manufacturer, lot number, date of receipt, acceptability, and, as applicable, the expiration date.
D6.9.3 Storage of materials under the appropriate environmental conditions in a secure, sanitary, and orderly manner to prevent mix up or unintended
use.
D6.9.4 The use of supplies and reagents coming into contact with cellular therapy products during processing, storage, and/or administration that are sterile and of the appropriate grade for the intended use.
D6.9.4.1 Non-disposable supplies or instruments shall be cleaned and sterilized using a procedure verified to remove infectious agents.
D6.9.5 The use of supplies and reagents in a manner consistent with instructions provided by the manufacturer.
D6.9.6 A process to prevent the use of expired reagents and supplies.
D6.10 There shall be a system to uniquely identify and track all critical equipment used in the processing of cellular therapy products.
D6.10.1 The system shall identify each cellular therapy product for which the equipment was used.
D6.11 Equipment used in cellular therapy product processing, testing, cryopreservation, storage, and distribution shall be maintained in a clean and orderly manner and located to facilitate cleaning, disinfection, calibration, and maintenance at prescribed intervals.
D6.11.1 The equipment shall be inspected for cleanliness prior to each use and verified to be in compliance with the maintenance schedule daily prior to use.
D6.12 The equipment shall be standardized and calibrated on a regularly scheduled basis as described in Standard Operating Procedures and in accordance with the manufacturer’s recommendations.
D6.12.1 All equipment with a critical measuring function shall be calibrated against a traceable standard, if available. Where no traceable standard is available, the basis for calibration shall be described and documented.
D6.12.2 When equipment is found to be out of calibration or specification, there shall be a defined process for action required for cellular therapy products manufactured during the period of uncertainty.
D6.13 There shall be a procedure that addresses the actions to take in the event of equipment malfunction or failure.
D6.14 Equipment shall conform to applicable laws and regulations.
D6.15 The Processing Facility shall monitor and document microbial contamination of cellular therapy products after processing, as specified in Standard Operating Procedures.
D6.15.1 The results of microbial cultures shall be reviewed by the Processing Facility Director or designee in a timely manner.
D6.15.2 The recipient’s physician shall be notified in a timely manner of any positive microbial cultures.
D6.16 Records shall be made concurrently with each step of the processing, testing, cryopreservation, storage, and administration or disposal/disposition/distribution of each cellular therapy product in such a way that all steps may be accurately traced.
D6.16.1 Records shall identify the person immediately responsible for each significant step, including dates and times of various steps, where appropriate.
D6.16.1.1 The Processing Facility shall maintain records of identification codes of personnel including methods to link the name and/or signature to the initials or other identification codes used in other documents and records. These records shall include dates of employment.
D6.16.2 Records shall show the test results and the interpretation of each result, where appropriate.
D6.17 Lot numbers, expiration dates, and manufacturers of critical reagents and supplies and identification of key equipment used in each procedure shall be documented.
D6.18 The Processing Facility Director or designee shall review the processing record for each cellular therapy product prior to release or distribution.
D6.18.1 The recipient’s physician and the Processing Facility Medical Director shall be notified when the clinically relevant processing end-points are not met.
D6.18.2 Notification and appropriate remedial actions, if taken, shall be documented in the processing record.
D6.19 Processing using more-than-minimal manipulation shall only be performed with Institutional Review Board or Ethics Committee approval, with the written
informed consent of the recipient of the cellular therapy product, and in compliance with applicable laws and regulations.
D6.20 For allogeneic cellular therapy products containing red blood cells at the time of administration:
D6.20.1 Results for ABO group and Rh type testing shall be available from two independently collected samples. Discrepancies shall be resolved and documented prior to issue of the cellular therapy product.
D6.20.2 Results for a red cell antibody screen shall be available. D6.21 One or more aliquots representing the cryopreserved cellular therapy product shall be stored.
D6.21.1 Aliquot(s) from cryopreserved cellular therapy products shall be stored under conditions that ensure a valid representation of the clinical product.
D6.21.2 For cryopreserved cellular therapy products with low volume and/or low cellular content when the storage of product aliquots is not feasible, a cryopreserved sample representing the final steps of processing shall be stored and available for future testing.
D6.21.3 Cryopreserved aliquots shall be retained according to institutional Standard Operating Procedures.
