• Human Resources • Financial – Budget / Billing • Facility Management / Maintenance • Clinical Engineering • Environmental Services • Materials Management • Clinical Lab / Transfusion Service • Pharmacy

Desired Processing Procedures Cryopreservation Incompatible ABO Related CD34 Selection Thaw & Infusion Thaw & Wash Transport / Shipping

Types of Patients Adults Pediatrics Both

Types of HCT/P Therapy Autologous Allogeneic • Related - Matched / Haplo • Unrelated

Types of HCT/P Products Bone Marrow Apheresis Cord Blood

Lab Logistics Days / Hours of operation Types of procedures (procedural times) Associated support logistics (ABO, Micro, Flow) Staffing and experience Distance between associated facilities (collection , patient units)

Program Logistics Desired “Go Live” Date Growth expectations

Collection Logistics Operating Room Schedule Mobilization methods Apheresis – days / hours Collection capacity Collection methods Cell dose goals

Clinical Logistics Inpatient /Outpatient based transplants Inpatient/outpatient capacity Cell dose goals Transplant goals (single, tandem, multiple)

FDA (Food & Drug Administration) Establishment Registration 21 CFR 1271 – GTP Regulations 21 CFR 211 – GMP Regulations 21 CFR Part 11

CLIA (Clinical Laboratory Improvement Amendments) Registration / Compliance / Accreditation CAP (College of American Pathologists) Accreditation – goal for many clinical /testing laboratories Proficiency Testing – obtain access to proficiency testing program ICCBBA/ ISBT (International Council for Commonality in Blood Banking Automation/ Information Standard for Blood & Transplant) Register to obtain facility identification – work towards being ISBT compliant labeling

FACT (Foundation for the Accreditation of Cellular Therapy) FACT Accreditation – goal for most HCT/P programs AABB AABB Accreditation – Cellular Therapy – goal for many HCT/P processing facilities Be The Match® / NMDP (National Marrow Donor Program) / Meet Criteria for Participation – allows for access to “unrelated donors”

LCI BMT Program’s Plans / Goals - Initial Thoughts / Decisions

Types of Patients: Adults only (may work with Peds in future) Types of HCT/P Therapy: Autologous and Allogeneic – related (both matched & haplo) Types of HCT/P Products: Apheresis products only Desired Processing Procedures: Cryopreservation, Incompatible ABO Related , Thaw & Infusion, Transport

Lab Logistics Days / Hours of operation: Weekday – mostly 8AM till done Types of procedures (procedural times): 1 – 3 hours per product Staffing and experience: 1 Manager (experienced) & 2 initial cell processing techs – okay if new to cell processing Distance between associated facilities - Apheresis – next door; Inpatient Unit ~ 200 ft.

Program Logistics Growth expectations: area population may support up to 200 transplants / year

Collection Logistics Mobilization methods: G or G+Plerixafor Apheresis – days / hours: Weekday – mostly 6AM till completed Collection capacity: 2 Optia instruments, 2 – 4 patients per week Collection method: continuous MNC, based on CD34 monitoring, max 8 hrs Cell dose goals: 10 million for Myeloma; otherwise 5 million

Clinical Logistics Expect to do: ~ 20 transplant first year Inpatient based transplants Inpatient capacity = 16 beds

• Facility & Environment – size, design/layout, features, security & safety, future growth

• Equipment – type, vendors, numbers, redundancy • Materials/Supplies – vendors, grade, quantity, storage, documentation • Personnel – qualifications, numbers, training, competency, documentation

• Process Control / Procedures / Policies • Quality Related Issues • Labeling • Records / Tracking / Documentation • Storage Issues - Materials/Supplies , Products, Documents

[GTP Regulations] 21 CFR Part 1271.190 Any facility used in the manufacture of HCT/Ps must be of suitable size, construction & location to prevent contamination of HCT/Ps with communicable disease agents and to ensure orderly handling of HCT/Ps without mix-ups… Must maintain the facility in a good state of repair… Must provide adequate lighting, ventilation, plumbing, drainage and access to sinks and toilets that are adequate to prevent the introduction, transmission or spread of communicable disease.

FACT (6th Ed) Standards : D2.1: …be of adequate space, design, and location, for the intended procedures.

D2.1.1: …provide adequate lighting, ventilation, and access to sinks to prevent the introduction, transmission, or spread of communicable disease

D2.1.2: …oxygen sensors shall be appropriately placed and utilized in areas where LN is present

D2.1.3: … be secure to prevent the entrance of unauthorized personnel.

D2.1.4: …be divided into defined areas of adequate size to prevent improper labeling, mix-ups, contamination, or cross-contamination of cellular therapy products.

D2.1.5: …process to control storage areas to prevent mix-ups, contamination, and cross-contamination of all cellular therapy products prior to release or distribution.

Space/ Size: equipment size & #s; # personnel; storage needs; account for workflow, # procedures, building codes, growth Design / Work Areas: consider workflow (efficiency); storage, office areas, safety Location: proximity to associated areas, consider environment for impact, security/traffic, access to LN source, access to support services; access to areas for personal hygiene & breaks Lighting , Ventilation, Sinks: refer to builders/architects - building codes and specifications Security: who should have access, how accessed, primary & secondary levels of access, line of sight Safety: refer to builders/architects – local building codes / regulations / specifications; oxygen sensor(s), facility alerts, line of sight

LCI Facility – Initial Thoughts / Decisions Space/ Size: • Equipment: 2 BSC, 2 Cfg, 2CRF, 2 LN Storage Bank, Refrig., -80 Freezer, COBE 2991, CliniMACS • 1 Manager and 2 processing staff • Products Storage - 2 LN banks with individual LN supply – room for 2 more • Materials Storage - Storage room with racks; Cabinets with drawers/shelving • Documentation Storage – file cabinets in Staff and Manager Office • Separate breakroom shared by Stem Cell Processing and Apheresis staff

Design / Work Areas: • Linoleum floor and Corian like countertops. Wood cabinets. • Work flow considered – semi-circular / linear • Separation between products – some duplication of equipment/space – allows for concurrent processing. • Movable work surfaces with shelving.

Location: • Apheresis is directly next door, Inpatient Unit is around the corner ~200 feet distance • Transfusion service – near Inpatient Unit. • Flow cytometry is ½ mile away – use courier for sample transport [will eventually do ourselves for timely turnaround

as flow cytometry moves further (~9 miles) away]. • Staff restroom available in Apheresis and/or hallway.

• Location across from Nuclear Medicine, minimal walk through traffic

LCI Facility – Initial Thoughts / Decisions

Lighting , Ventilation, Sinks: • Lightning – builder/architect defined. Safety lights (always on), storage areas – “auto on” for safety. • Ventilation – builder/architect defined. Extra vent near Flow Cytometer. Air handling is semi-dedicated. • 3 sinks provided – 2 by entrance, 1 by Apheresis entrance with eyewash.

Security: • Access to lab space via personnel badge only – for both entrance (main, Apheresis) • Access to main lab space is limited to a select number of BMT Program faculty and staff. • Access to essential facility personnel (Example: maintenance, security, safety) • Storage areas – can be locked and then key access only • Product storage – individual Banks will be kept locked • Line of sight – view window at main door.

Safety: • Safety lighting, exit signs, fire alerts, fire extinguisher, etc. per building codes • Safety related items (PPE; spill kits; biohazardous waste & sharps containers) • Oxygen sensor in LN Bank Storage room • Line of sight – view window at main door.

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LCI Facility Work / Product Flow

1. Product transfer from Apheresis, to Accession/Labeling Area – log in

2. Product goes to assigned BSC, paperwork goes to associated work space

3. Product remains in processing area and assigned centrifuge (CFG).

4. Test sample goes to Testing Area and AcT or outside for ABO and Micro

5. Cryopreservation – product transferred to assigned controlled rate freezer (CRF)

6. Cryopreserved product transferred to LN Storage Banks.

7. Transfer cryopreserved products into Cryoshippers and prepare Waterbath carts - transport to inpatient unit.

8. Product leave Lab via entrance/exit.

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[GTP Regulations] 21 CFR Part 1271.200 To prevent the introduction, transmission, or spread of communicable diseases, equipment used in the manufacture of HCT/Ps must be of appropriate design for its use and must be suitably located and installed to facilitate operations, including cleaning and maintenance. …must establish and maintain procedures for cleaning, sanitizing and maintaining equipment to prevent malfunctions, contamination or cross-contamination, accidental exposure of HCT/Ps to communicable disease agents… …where appropriate, you must routinely calibrate… …must routinely inspect equipment for cleanliness, sanitation… …must document and maintain records of all equipment maintenance, cleaning, sanitizing, calibration…

FACT (6th Ed) Standards : D6.1 …used to process cellular therapy products shall be used in a manner that maintains product function and integrity and prevents product mix-ups, contamination, and cross-contamination. D6.3: System to uniquely identify & track all critical equipment used in the processing of cellular therapy product… D.6.4: Equipment used in processing, testing, cryopreservation, storage, and distribution shall be maintained in a clean and orderly manner and located to facilitate cleaning, sanitation, calibration and maintenance according to established schedules. D6.5: …Shall be inspected for cleanliness prior to each use and verified to be in compliance with the maintenance schedule daily prior to use D6.6: …shall be standardized and calibrated on a regularly scheduled basis… D.6.7: …actions to take in the event of equipment malfunction or failure.

Prior History / Experience: comfort with specific equipment / vendor; institutional contractual issues Appropriate Design for Use: specifications – size, power, function, ease of cleaning, maintenance, safety, visual appeal Location/Installation: size, workflow, function, minimize interference, safety, ease of access for use, maintenance, cleaning, visual appeal Redundancy: consider workflow; concurrent processes; impact of equipment failure; back up Qualification required

LCI Equipment – Initial Thoughts/Decision Prior History / Experience: • Many selected based on prior experience with equipment by original planners (NuAire, Hettich, Helmer, Forma, CBS,

Thermo Scientific, Mettler, Terumo, Genesis, Miltenyi. Beckman Coulter is a preferred vendor (AcT Diff 2 and FC500)

Appropriate Design for Use: • All equipment selected are designed/intended for the specific use • Size was not a concern for most equipment due to size of facility • 6 ft.. BSC planned for with spacing of cabinetry (note: A 3rd BSC purchased within 1 year of start up) • Most items selected use standard power (110-120 V) • Hettich Rotixa centrifuge outfitted with rotor and buckets specific for centrifuging blood bags. • CBS LN Storage Banks – model V3000 selected specifically for LN vapor phase storage (LN inside walls)

Location/Installation: • Equipment located for workflow • Adequate space allowance between equipment and structure – allows for cleaning, maintenance

Redundancy: • Some equipment in duplicate – allows for concurrent processing & minimizes down-time due to equipment failure • Plan – have a empty LN Bank available in the event of LN Bank failures/issues.

Qualification required: • Qualify equipment, as applicable, in this new environment and for the procedures

LCI Equipment – Initial Thoughts/Decision Current List of Equipment: • Biological Safety Cabinet • Centrifuge • Controlled Rate Freezers • Tubing Welder • Tubing Heat Sealers • Electronic Balance • Hematology Analyzer • Flow Cytometer • TQ Prep – flow cytometry • LN Switching System • LN Storage Banks • Cryoshippers • Water Baths • Water Bath Carts • Refrigerator • -80C Freezer • COBE 2991 • CliniMACS • Microscope • Bag Heat Sealer • Plasma Expressors

Other Minor Equipment: • Inventory System for LN Banks

• Racks • Canisters • Dividers

• Pipettes – different sizes • Pipet-Aid • Tube Rotator • Vortex • Bag Press (cryopreservation) • Flammables Cabinet • LN Transfer System • Carts • Step Stool/Ladder • Printers – labels • Printers – paper • PCs – for ordering tests, labels, worksheets • Label maker • Test tube / Cryotube racks • Hemacytometers • Tally Counters

[GTP Regulations] 21 CFR Part 1271.210 a) Verification – must not use supplies and

reagents until they have been verified to meet specifications designed to prevent circumstances that increase the risk of introduction, transmission or spread of communicable diseases (by user of by vendor).

b) Reagents used in processing…must be sterile, where appropriate.

c) Validate /verify the processes used in the production of in-house reagents.

d) Maintain records … 1. of receipt – type, quantity, manufacturer,

lot #, date of receipt / expiration 2. of verification of each supply / reagent / if

vendor (certificate of analysis) 3. of supply/reagents used in the

manufacture of each HCT/P.

FACT (6th Ed) Standards : D.6.1 …Supplies, and reagents used to process cellular therapy products shall be used in a manner that maintains product function and integrity and prevents product mix-ups, contamination, and cross-contamination. D.6.2: Supplies and reagents used… shall be controlled by a materials management system that includes requirements for the following, at a minimum: D.6.2.1: Visual examination for damage, evidence of contamination… D.6.2.2: Record of receipt (type, quantity, manufacturer, lot #, receipt date, acceptability, expiration date D.6.2.3: Storage under appropriate environmental conditions in a secure, sanitary, and orderly manner D.6.2.4: Supplies & reagents coming in contact with cellular therapy products… are sterile & appropriate grade D.6.2.5: Cleaning and sterilizing of non-disposables using a procedure verified to remove contaminants D.6.2.6: Use supplies and reagents in a manner consistent with manufacturer’s instructions D.6.2.7: Process to prevent use of expired reagents /supplies.

Prior History / Experience: comfort with specific materials /supply and /or vendors; institutional contractual issues Appropriate Design for Use: as applicable – nonpyrogenic, sterile, intended for human use Institutional Constraints: preferred (contractual) vendors; efficiency of purchasing process Management: how document receipt and use; storage system and control use. Qualification required

LCI Materials/Supplies – Initial Thoughts/Decision Prior History / Experience: • Many selected based on prior experience by Lab Manager, for example: Origen bags, Protide DMSO. • Others based on the requirements due to equipment.

Appropriate Design for Use: • All materials that will touch HCT/P product will be sterile • Fluids will be “intended for human use” grade (exception with DMSO – USP – certificate of analysis) • Certificate of analysis – verification (documentation) by vendor

Institutional Constraints: • Specific vendors are preferred – easier ordering of commonly/frequently used items. • Non-preferred vendors – requires more “red tape” • Increase “stock par” due to inefficiency or variability of purchasing process

Management: • Paper based documentation of:

• Materials receipt • Materials usage in processing

Qualification required • Qualify key materials/supplies, as applicable, , in this new environment and its use in procedures

Documentation of Use Documentation of Receipt

Storage of Materials / Supplies • Labeled (defined) location • Orderly • Identify “ New Lot” – FIFO

[GTP Regulations] 21 CFR Part 1271.170 Must have personnel sufficient to ensure compliance with requirements of this part. Competent performance of functions …have necessary education, experience & training. Must perform only those activities for which qualified, authorized. Training… must train all personnel, and retrain as necessary to perform their assigned responsibilities adequately.

FACT (6th Ed) Standards : D.3 Personnel D.3.1: Processing Facility Director D.3.2: Processing Facility Medical Director D.3.3: Quality Manager D.3.4: Staff …the # of trained processing personnel… adequate for the # of procedures performed… include a minimum of one designated trained individual with an identified trained backup to maintain sufficient coverage. D5.5 Staff training and, if appropriate, competency shall be documented before performing a new or revised procedure. D8.8: Records shall identify the person immediately responsible for each significant step, including dates and times, where appropriate.

Work with BMT Program / Administration / Human Resources • define hierarchy / organizational chart • personnel budget – # staff and staff role • define position (job titles/job description) for processing staff • define recruitment parameters

• local regulations • availability in local area • scope of search • new / experienced

• develop training & competency process / documentation

LCI Personnel – Initial Thoughts/Decisions

Work with BMT Program / Administration / Human Resources • Medical Director serves as Facility Director • Quality/Accreditation Coordinator serves as Quality Manager • Budgeted for 1 Manager & 2 Cell Processing Staff

• Meets minimum FACT requirement of 2 • Cell Processing Staff – Job titles – Medical Technologist • Internal & Local Recruitment primarily • New (no prior cell processing experience) okay – will train • Qualifications – looking for prior experience working with cells, cell

culturing and aseptic processes. • Background: blood banking, microbiology, immunology, hematology

• Lab math / skills assessment Quiz – used to determine applicants knowledge

Lessons Learned: • Earlier involvement in design

• some unused (wasted) space • some equipment’s placement – harder to

maintain/service • Better workflow/ergonomics

• Earlier involvement in equipment choices • Some equipment purchased – not in use • Some equipment not efficient

• Inadequate Space for Product Storage/Growth • space for LN banks did not account for

rapid growth • space for LN banks did not consider need

for back up supply tanks

• Space for storage of documentation • Did not account for rapid growth – need

more storage space for product folders • Staff office

• Did not account for rapid growth – more staff needed. Office space/setup needed

• Flooring & LN • Initial planners did not consider the effects of

LN on linoleum flooring • Ventilation (Airflow) in LN Storage Room

• Initial planners did not consider amount of venting due to LN Bank fill.

• Location of exhaust vents not effective in removing LN gas – resulting in low oxygen alarms.

Thank You