manual of procedures - pact group · the pact group manual of procedures is reviewed and approved...

Manual of Procedures PRODUCTION ASSISTANCE FOR CELLULAR THERAPIES

(PACT)

Prepared and Distributed by:

PACT Coordinating Center (CC)

The Emmes Corporation

Rockville, Maryland

Version 1.0

January 2017

Manual of Procedures Production Assistance for Cellular Therapies (PACT) Version 1.0 - January 2017

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DOCUMENT APPROVAL

The PACT Group Manual of Procedures is reviewed and approved by the PACT Steering Committee. Approval information is on file with the PACT Coordinating Center.


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Table of Contents

1.0 INTRODUCTION ............................................................................................................... 1 1.1 Program Overview ....................................................................................................... 1 1.2 Program Goals .............................................................................................................. 1

2.0 ORGANIZATION AND STRUCTURE ........................................................................... 3 2.1 Introduction .................................................................................................................. 3 2.2 Steering Committee ...................................................................................................... 3

2.2.1 Purpose ............................................................................................................ 3 2.2.2 Membership ..................................................................................................... 4 2.2.3 Steering Committee Chair ............................................................................... 4 2.2.4 Meetings and Teleconferences ........................................................................ 5

2.3 PACT Cell Processing Facilities .................................................................................. 5 2.3.1 Contact Information ......................................................................................... 5 2.3.2 Center for Cell and Gene Therapy, Baylor College of Medicine .................... 5

2.3.2.1 Translational Research ........................................................................... 5 2.3.2.2 cGMP Manufacturing............................................................................. 7

2.3.3 Center for Biomedicine and Genetics, City of Hope ....................................... 9 2.3.3.1 Facilities ............................................................................................... 10 2.3.3.2 Services ................................................................................................ 11 2.3.3.3 Accreditations and Master Files ........................................................... 12

2.3.4 University of Minnesota, Molecular and Cellular Therapeutics ................... 12 2.3.4.1 Facility Description .............................................................................. 13 2.3.4.2 PACT ................................................................................................... 14 2.3.4.3 Facility Accreditations ......................................................................... 15

2.3.5 Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine .......................................... 15

2.3.5.1 Translational Research ......................................................................... 16 2.3.5.2 Facility Overview ................................................................................. 19

2.3.6 Moffitt Cancer Center .................................................................................... 22 2.3.6.1 Moffitt Cell Therapy Facility Description ........................................... 22 2.3.6.2 Moffitt CTF Organizational Chart ....................................................... 24 2.3.6.3 Moffitt CTF Project Management ........................................................ 25 2.3.6.4 Moffitt CTF Services ........................................................................... 26 2.3.6.5 Moffitt CTF Training Program ............................................................ 26 2.3.6.6 Moffitt CTF Quality Management ....................................................... 27 2.3.6.7 Moffitt CTF Accreditation ................................................................... 27 2.3.6.8 Moffitt CTF FDA Approval Process ................................................... 28

2.4 PACT Coordinating Center (CC) ............................................................................... 28


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Continued

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2.5 National Heart, Lung, and Blood Institute (NHLBI) ................................................. 29 2.6 Expert Evaluation Panel (EEP) .................................................................................. 30

2.6.1 Purpose .......................................................................................................... 30 2.6.2 Membership ................................................................................................... 30 2.6.3 Meetings ........................................................................................................ 30 2.6.4 Reports ........................................................................................................... 31

2.7 PACT Working Group and Other Subcommittees ..................................................... 31 2.7.1 Purpose .......................................................................................................... 31 2.7.2 CPF Membership ........................................................................................... 31 2.7.3 Teleconferences ............................................................................................. 31

3.0 POLICIES AND PROCEDURES FOR FACILITIES OPERATIONS ....................... 32 3.1 Process Control .......................................................................................................... 32

3.1.1 Specific Elements of Process Control Policy ................................................ 33 3.1.2 Process Validation ......................................................................................... 33 3.1.3 Assay Design and Validation......................................................................... 34

3.2 Document Control ...................................................................................................... 34 3.2.1 Standard Operating Procedures ..................................................................... 35 3.2.2 Deviations from Standard Operating Procedures .......................................... 35

3.3 Audits ......................................................................................................................... 35 3.4 Equipment .................................................................................................................. 35 3.5 Reagents and Supplies ................................................................................................ 36 3.6 Inspection and Testing of Incoming Materials ........................................................... 38 3.7 Product and Sample Identification and Traceability .................................................. 38 3.8 Log-In and Sample Processing ................................................................................... 38 3.9 Inspection of Products During Processing, Prior to Distribution,

and Before Administration ......................................................................................... 39 3.10 Requirements for Testing and Controls ..................................................................... 39 3.11 Product Release Requirements ................................................................................... 40 3.12 Requirements for Packaging, Labeling, and Shipping Procedures ............................ 40

3.12.1 Labeling and Labeling Controls .................................................................... 41 3.12.2 Storage and Preservation ............................................................................... 41 3.12.3 Storage Conditions ......................................................................................... 41 3.12.4 Storage Devices ............................................................................................. 41 3.12.5 Distribution and Transportation ..................................................................... 41 3.12.6 Product Shipping Receipt Confirmation Form .............................................. 42

3.13 Sample Repository ..................................................................................................... 42


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Continued

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4.0 REGULATORY REQUIREMENTS .............................................................................. 43 4.1 Master Files for Facilities’ Information ..................................................................... 43 4.2 IND/IDE Applications ............................................................................................... 44

4.2.1 CMC Section Development ........................................................................... 44 4.2.2 FDA IND Meetings ....................................................................................... 44

4.3 Quality Monitoring Program ...................................................................................... 44 4.3.1 QA Monitoring Policy ................................................................................... 45 4.3.2 Quality Monitoring Plan ................................................................................ 46 4.3.3 CPF QA Monitoring ...................................................................................... 46

4.3.3.1 Audits ................................................................................................... 47 4.3.4 Corrective and Preventative Action Plans ..................................................... 47

5.0 POLICIES AND PROCEDURES FOR REQUEST FOR SERVICES APPLICATIONS (RSA) ................................................................................................... 49 5.1 Cell Processing Facilities Product Experience ........................................................... 49 5.2 Scope of Product or Service Request ......................................................................... 51

5.2.1 Areas of Shared Interest ................................................................................. 52 5.3 Request for Services Application (RSA) ................................................................... 53 5.4 NHLBI Initial Scope Review ..................................................................................... 54 5.5 Scientific Review Board Review ............................................................................... 54 5.6 NHLBI Final Review ................................................................................................. 54

5.6.1 Task Order Request for Proposal ................................................................... 55 5.6.2 Task Order Award ......................................................................................... 55

5.7 Project Progress Reports ............................................................................................ 57

6.0 CONFIDENTIALITY ....................................................................................................... 58 6.1 Confidential Information ............................................................................................ 58

6.1.1 Responsibility ................................................................................................ 58 6.1.2 Records .......................................................................................................... 58

6.2 NIH Policy ................................................................................................................. 58 6.3 PACT Steering Committee and Expert Evaluation Panel .......................................... 59 6.4 Scientific Review Board and Expert Evaluation Panel:

Confidentiality and Conflict of Interest ..................................................................... 59 6.5 PACT Website ........................................................................................................... 59

7.0 POLICIES AND PROCEDURES FOR COORDINATING CENTER ....................... 61 7.1 Introduction ................................................................................................................ 61 7.2 Communications ........................................................................................................ 61

7.2.1 Teleconferences ............................................................................................. 61


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Continued

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7.2.2 Email .............................................................................................................. 61 7.2.3 Meetings ........................................................................................................ 62 7.2.4 Web Communications ................................................................................... 62

7.3 Website ....................................................................................................................... 62 7.4 Roster ......................................................................................................................... 63 7.5 Logistical Support for Meetings ................................................................................. 63 7.6 Documentation Support ............................................................................................. 64 7.7 Metrics ........................................................................................................................ 64 7.8 Customer Satisfaction Questionnaires ....................................................................... 65

8.0 PUBLICATION POLICY ................................................................................................ 66 8.1 Publication Classification ........................................................................................... 66

8.1.1 Peer-reviewed Publications of Studies Utilizing PACT Product .................. 66 8.1.2 PACT Non-peer Reviewed Publications ....................................................... 66 8.1.3 Investigator or PACT-Developed Slide Presentations .................................. 66 8.1.4 Outreach Materials ......................................................................................... 67

8.2 Intellectual Property ................................................................................................... 67 8.3 Archive ....................................................................................................................... 67


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List of Abbreviations/Acronyms

Abbreviation Definition

AHC Academic Health Center BK BK virus BLA Biologics License Application BM Bone Marrow BMT Bone Marrow Transplant BRB Biomedical Research Building BPR Batch Production Record CAGT Center for Cell and Gene Therapy CAR Chimeric Antigen Receptor CBG Center for Biomedicine and Genetics CAP College of American Pathologists CAPA Corrective and Preventive Action CC Coordinating Center CFR Code of Federal Regulations cGLP Current Good Laboratory Practices cGMP Current Good Manufacturing Practices cGTP Current Good Tissue Practices CLIA Clinical Laboratory Improvement Amendments CMC Chemistry, Manufacturing, and Controls CMP Cell Manufacturing Program COH City of Hope COI Conflict of Interest COR Contracting Officer Representatives C of A Certificate of Analysis CP Clinical program CPF Cell Processing Facilities CTF Cell Therapy Facility DC Dendritic Cell DMF Drug Master File DNA Deoxyribonucleic Acid EEP Expert Evaluation Panel EBV Epstein Barr Virus


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EBV-LMP Epstein Barr Virus Latent Membrane Protein FACT Foundation for the Accreditation of Cellular Therapy FDA Food and Drug Administration GCP Good Clinical Practice HCT Hematopoietic Cell Transplantation HCT/P Human Cells, Tissues, and Cellular and Tissue-Based Products HEPA High-Efficiency Particulate Air hESC Human Embryonic Stem Cells HIV Human Immunodeficiency Virus HHV-6 Human Herpesvirus-6 HPC Hematopoietic Progenitor Cells HVAC Heating, Ventilation, and Air Conditioning IBC Institutional Biosafety Committee ICH International Council of Harmonisation ICRC Islet Cell Resource Center ID/IQ Indefinite Delivery/ Indefinite Quantity IND Investigational New Drug IDE Investigational Device Exemption iPSC Induced Pluripotent Stem Cells IQ Installation Qualification IRB Institutional Review Board ISCI Interdisciplinary Stem Cell Institute ISO International Organization for Standardization LCL Lymphoblastoid Cell Lines LMI Large Multivalent Immunogen MCB Master Cell Bank MCC Moffitt Cancer Center MCT Minnesota Molecular and Cellular Therapeutics Facility MOP Manual of Procedures MSC Mesenchymal Stem Cells NCI National Cancer Institute NDA New Drug Application NGVL National Gene Vector Laboratory


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NHLBI National Heart, Lung, and Blood Institute NIAID National Institute of Allergy and Infectious Diseases NIDDK National Institute of Diabetes and Digestive and Kidney Diseases NIH National Institutes of Health NINDS National Institute of Neurological Disorders and Stroke NK Natural Killer OBA Office of Biotechnology Activities OQ Operation Qualification PACT Production Assistance for Cellular Therapies PB Peripheral Blood PCP Preclinical Program PI Principal Investigator PQ Performance Qualification QA Quality Assurance QC Quality Control RAC Recombinant DNA Advisory Council RO/DI Reverse Osmosis/ Deionization RSA Request for Services Application SC Steering Committee SME Subject Matter Experts SOP Standard Operating Procedure SRB Scientific Review Board SRC Scientific Review Committee TCH Texas Children’s Hospital TIL Tumor Infiltrating Lymphocytes TO Task Order TORFP Task Order Request for Proposal Treg T regulatory cells UCB Umbilical Cord Blood UM University Of Miami Miller School Of Medicine UMMC University of Minnesota Medical Center UPS Uninterruptible Power Supplies URL Uniform Research Locator


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VPF Vector Production Facility VSV Vesicular Stomatitis Virus VZV Varicella Zoster Virus WCB Working Cell Bank WG Working Group


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1.0 INTRODUCTION

The purpose of this Manual of Procedures (MOP) is to describe the Production Assistance for Cellular Therapies (PACT) program’s organization, responsibilities of each participating institution, and the policies and procedures that govern the program’s efforts.

This MOP addresses the structure and role of the Coordinating Center (CC), the National Heart, Lung, and Blood Institute (NHLBI), the Cell Processing Facilities (CPF), the Steering Committee (SC) the Expert Evaluation Panel (EEP), and the Scientific Review Board (SRB). It describes the operational structure within which standards are developed and requests for cell processing are evaluated. The membership, scope, and objectives of the PACT subcommittees are described. The general requirements and expectations for current good manufacturing practices (cGMP) and current good tissue practices (cGTP), testing, and product standards are addressed. The plans for PACT facility information, standard operating procedures (SOP), equipment and process validation, testing and results are described. Principles and practices are provided as the basis for development of each product including the process for consideration of requests from investigators for cell products. The plans are addressed for preparation of materials for Investigational New Drug (IND) application submissions. The MOP describes procedures to facilitate communication and collaboration among the involved groups.

1.1 Program Overview

There is a growing need in the translational research community to obtain clinical grade cellular products manufactured under cGMP conditions This production assistance will facilitate transition of laboratory research developments into clinical grade products for use in IND-enabling studies. This program, sponsored by NHLBI, will provide assistance with the manufacture of cellular therapy products and regulatory expertise to address all aspects of the translational process. NHLBI coordinated jointly with the CC, will review requests for cell product manufacture. A product approved by NHLBI for manufacture will be produced by the designated facility according to the applicable regulatory requirements.

1.2 Program Goals

The establishment of CPF where consulting, manufacturing, and regulatory activities are combined facilitates the development of novel cellular therapies manufactured in compliance with all regulatory requirements. Each CPF brings unique expertise with specific cellular products. The combined experience of the program groups, especially regarding the current individual facility expertise with specific cellular products, will create a coordinated effort and a highly qualified program dedicated to providing support in areas ranging from translational development to the scale-up of a product to the manufacture and delivery of clinical grade cellular therapy products for animal safety studies. The research and development production support provided by PACT will assist in the translation of laboratory protocols to clinical grade large-scale product manufacturing SOPs.


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An investigator will submit a request for Services Application (RSA) for evaluation to PACT. When a RSA is approved, the NHLBI will solicit proposals via a Task Order Request for Proposal (TO-RFP) from the PACT CPFs. The CPFs will competitively bid to perform the work by submitting a task order proposal to NHLBI. NHLBI will evaluate proposals against the requirements of the TO-RFP and the award will be issued to the CPF in accordance with the requirements stated in the TO-RFP. It is the responsibility of the designated facility to manufacture the cell product under cGMP conditions and if necessary, generate the required data in support of an IND application.

As a part of this process, the CPF provide the required infrastructure for operation under current good laboratory and manufacturing practices (cGLP and cGMP) with appropriate expertise at each stage of the process.


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2.0 ORGANIZATION AND STRUCTURE

2.1 Introduction

The Production Assistance for Cellular Therapies (PACT) program is supported by the National Heart, Lung, and Blood Institute (NHLBI) and managed by the program Steering Committee (SC). The SC establishes subgroups as needed. Participants in the program include a Coordinating Center (CC) and five Cell Processing Facilities (CPF). An Expert Evaluation Panel (EEP) provides oversight for the program.

2.2 Steering Committee

2.2.1 Purpose

The SC formulates and implements all policy decisions related to the conduct of the PACT group.

The functions of the SC include:

• Guide the development and oversees the operations of the PACT program

• Monitor the progress on approved and funded projects

• Ratify major changes in the Manual of Procedures (MOP)

• Advise and assist the CC and working groups on operational matters

• Monitor performance of participating CPF including assessment of compliance with current Good Manufacturing Practices (cGMP), current Good Laboratory Practices (cGLP), current Good Tissue Practices (cGTP), and other regulations as appropriate


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• Evaluate and review recommendations of the EEP

• Assist in implementing education objectives

2.2.2 Membership

The SC consists of:

• Chair appointed by NHLBI

• Principal Investigators (PI) from each of the participating CPF

• CC PI

• NHLBI Contracting Officer Representatives (COR)

The following observers may attend SC teleconferences/meetings with NHLBI approval:

• NHLBI program staff

• CPF key Co-Investigator(s), key technical staff

• CC program staff

• Other relevant consultants

The terms of the SC members and Chair are:

• SC membership is indefinite

• Chair term is for five years or as determined by the NHLBI

2.2.3 Steering Committee Chair

NHLBI appoints a Chair who is primarily responsible for the scientific direction and administration of PACT. The Chair remains informed of all operational aspects of the program. The Chair:

• Leads the SC to formulate policy and takes necessary action to ensure smooth operation

• Advises the CC on scientific, technical, regulatory, data management and other issues of importance to the overall conduct of the program

• Advises on subcommittee formation

• Presides over SC face-to-face meetings

• Presides over SC conference calls or assigns the responsibility to the CC PI and/or NHLBI COR

• Participates in other meetings as appropriate

• Functions as liaison between the SC and the EEP


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2.2.4 Meetings and Teleconferences

The CC coordinates SC meetings and schedules teleconferences. SC teleconferences are held monthly. Ad hoc teleconferences are arranged as needed and as agreed by the SC.

2.3 PACT Cell Processing Facilities

2.3.1 Contact Information

Cell Processing Facility Principal Investigator

Center for Cell and Gene Therapy, Baylor College of Medicine

Adrian Gee, MI Biol, PhD [email protected] (832) 824-4214

Center for Biomedicine and Genetics, City of Hope

Joseph Gold, PhD [email protected] (626) 218-0554

Moffitt Cancer Center Linda Kelley, PhD

[email protected] (813) 745-3028

Interdisciplinary Stem Cell Institute, University of Miami,

Miller School of Medicine

Joshua Hare, MD [email protected]

(305) 243-5579

University of Minnesota Molecular and Cellular Therapeutics

David H. McKenna, Jr., MD [email protected]

(612) 624-5736

2.3.2 Center for Cell and Gene Therapy, Baylor College of Medicine

The Baylor College of Medicine Center for Cell and Gene Therapy (CAGT) opened in 1998 as a partnership between Baylor College of Medicine in Houston, Texas Children’s Hospital (TCH) and Houston Methodist Hospital. PACT activities will utilize the Translational Research Laboratories, the GMP Manufacturing Facilities, and the Quality Control and Quality Assurance Groups at CAGT.

2.3.2.1 Translational Research The Translational Research Laboratories (Figure 1) occupy approximately 19,000 square feet on the 17th floor of the Feigin Center at TCH. Major equipment includes Real Time PCR, Millipore™ Luminex®, Perkin Elmer Tri-CARB® and Quantum scintillation counters, Beckman Coulter Gallios, Becton Dickinson and FACsCaliber flow cytometers, Sony SH80 cell sorter, Beckman Optima™ ultracentrifuge, Kodak Gel Logic 200 imaging system, hypoxic incubator,

mailto:[email protected]






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Nikon Eclipse fluorescent microscope, Amaxa and Neon nucleofectors, Miltenyi MACS® immunomagnetic cell separator, and an AmpliGrid Advalytix thermal cycler.

The translational research program consists of clinical and basic science researchers who work together with cGMP manufacturing staff and regulatory professionals to address all aspects of the translational process. Physician researchers work at the bench with basic scientists to ensure mutual appreciation of the challenges that must be met and the processes and resources that are available to address them.

Figure 1: View of the CAGT Translational Research Laboratories

These challenges include selection of an appropriate target patient population, realistic cell doses and production times, regulatory issues that impact choice of reagents and materials, limitations on cell procurement, cell quality issues, appropriate tissue culture methods, selection of suitable animal models, development of associated tests for potency, purity and identity, as well as mechanisms that can be used to assess the safety and potential efficacy of the therapy. The integration of multiple disciplines early in the translational process leads to timely identification and resolution of potential difficulties and greatly reduces the cost and time required to generate the pre-clinical data required for an Investigational New Drug (IND) submission. Using a re-iterative bench to bedside and back to bench approach, new strategies to overcome the limitations of cell therapies have been developed and tested in the clinic, from gene modification of T cells and dendritic cells to evaluation of novel cell culture technologies. This approach has been successfully used to initiate more than 30 CAGT investigator-initiated INDs in cell and gene therapy and to generate manufacturing protocols for the preparation of a variety of cellular products and ancillary reagents. Some of the services available to PACT clients are shown in Table 1.


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Table 1: Services Available through the CAGT Translational Research Laboratories

Available through the CAGT Translational Research Laboratories Tissue culture of primary human cells and cell lines Optimization of media and culture conditions Development of methods for cellular activation Evaluation of biological response modifiers Use of bioreactor systems Cell separation technologies Scale-up of culture techniques Design and production of plasmids and vectors* Evaluation of gene transfer strategies (viral vectors, transfection and transposons) Transduction and transfection of cells Development of animal models for cell-based therapies Use of imaging to track therapeutic cells Ex vivo monitoring of immune responses Monitoring immune reconstitution Assessment of in vivo persistence of therapeutic cells (preclinical and clinical) Optimization of methods for cryopreservation and thawing Optimization of shipping cells

*Vector production is independent of PACT

2.3.2.2 cGMP Manufacturing The CAGT cGMP facility (Figure 2 and Figure 3) is located on the 16th floor of the Feigin Tower, immediately below the Translational Research Laboratories. This floor houses both the Cell Processing Facility (CPF) and Vector Production Facility (VPF) clean room manufacturing areas, and support facilities (materials management, flow cytometry and the quality control laboratory) in addition to some CAGT faculty offices and the Quality Assurance Group.

Figure 2: Floor Plan of CAGT cGMP Facilities


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The CPF and VPF are separated by three manufacturing suites (swing rooms) that can be allocated to either facility depending on workload. During normal operations, there is no traffic between the facilities. Each is designed to operate independently with its own gowning/degowning areas and supply rooms. The entire facility is rated at Class 10,000 and major equipment is on continuous monitoring with all data backed up off-site.

The CPF is of a single corridor design and consists of 15 manufacturing suites, an internally accessible low temperature storage facility (linked via a pass-through to a similar facility that can be accessed from non-classified space), a cold room, and a released supply room linked via a pass-through to a larger external supply storage area. There is a pass-through from the central corridor to the flow cytometry facility. The Quality Control Laboratory and Quality Assurance offices are located on the same floor.

Figure 3: View of New CAGT cGMP Facilities

Left Panel: Feigin Tower; Upper Middle: Manufacturing Suite; Upper Right: Materials Management; Lower Left: Flow Cytometry; Lower Right: Quality Control Laboratory

Production is organized (Figure 4) by manufacturing groups (e.g., Vaccines, Cytotoxic Lymphocytes, etc.). Cell banks and cell lines are manufactured in the VPF.


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Figure 4: Organizational Chart for the CAGT cGMP Cell Processing Facility

The Cell Processing Facility is Clinical Laboratory Improvement Amendments (CLIA) licensed, accredited by the Foundation for the Accreditation of Cellular Therapy (FACT) and the College of American Pathologists (CAP), and has a current Food and Drug Administration (FDA) establishment registration certificate. The CPF and VPF have maintained separate facility master files with the FDA for the last 13 years.

2.3.3 Center for Biomedicine and Genetics, City of Hope

The Center for Biomedicine and Genetics (CBG) at City of Hope (COH) is a 20,000 sq. ft. biologics manufacturing facility and is capable of simultaneously producing viral and non-viral vectors, vaccines, recombinant proteins, cell therapeutics, bacterial products, and monoclonal antibodies (Figure 5). CBG is supported by systems developed by COH for development and the production of clinical materials. The CBG operates under the requirements of cGMP for Biologics, Drugs and Pharmaceuticals as set out in the Code of Federal Regulations Title 21 (21CFR); nearly all members of the CBG staff were recruited from the biopharmaceutical industry to ensure that all manufacturing is accomplished with the level of safety, proficiency and competence expected by the FDA and our clinical investigators.


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Figure 5: The Center for Biomedicine and Genetics

COH established the CBG to be not only a facilitating core for COH researchers and their collaborators, but as a regional and national resource to facilitate the rapid translation of new ideas that could benefit patients everywhere. To this end, the CBG served for 6 years as a designated National Gene Vector Laboratory (NGVL), served from 2010 - 2015 as a designated PACT cell processing facility for the NHLBI, and has served since 2001 as an Islet Cell Resource Center (ICRC), serving most of the western portion of the U.S. The CBG has been inspected by the FDA and is licensed by the state of California.

2.3.3.1 Facilities The first floor of the building accommodates administrative offices document and record control areas. The first floor also houses an area for quarantined incoming materials and Quality Control (QC) laboratories for testing incoming materials and process development work. The cryogenic storage requirements of the pilot facility are maintained on this floor. Storage is strictly segregated and access to materials associated with projects subject to cGMP regulations is subject to Quality Assurance (QA) control and provided only to authorize production or QC personnel. Access to this section of the first floor of the building is controlled by an electronic card access system.

All manufacturing and fill operations occur on the second floor of the facility; refer to Figure 6 for a layout of the CBG 2nd floor. The facility is expressly designed to meet cGMP facility requirements according to CFR 21 Section 210, 211. The facility was specifically designed to accommodate the simultaneous manufacturing of multiple biological products. To accommodate the eclectic product types that are manufactured while maintaining product separation and minimize cross-contamination risks, the approximately 10,000 square feet of classified space is divided into three separate manufacturing “zones” for Cellular Therapeutics, Viral Vectors and Protein production. There are a total of twelve separate production rooms plus various ancillary support spaces (equipment rooms, quarantine and released materials rooms, glass wash area, etc.).In addition to fully validated glass wash, autoclave, and depyrogenation equipment, the CBG facility has a 3-room aseptic fill suite with 2,000 vial lyophilization and semi-automated fill capacity.


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Figure 6: Layout of the CBG 2nd floor

Electronic card access systems, highly segregated air handling systems and strict control over personnel and materials flow are combined to ensure that the potential for cross contamination of products is minimized. Access to and within the facility is controlled by this programmable electronic card access system. There are no exterior windows or doors opening directly into the pilot facility. In all cases there is an intervening space into which exterior doors or windows open to provide continuous and complete air lock around the manufacturing core at all times. However; possible utilities and systems serving the pilot facility are not shared with other unregulated areas of the building. Critical equipment such as the reverse osmosis/ deionization (RO/DI) water system, pure steam generator, vacuum pumps and process gas tanks are housed on the first floor of the building and piped to the manufacturing facility on the second floor.

The design of the facility allows for distinguishable processes to be performed simultaneously in functionally isolated areas of the building. Particulate counts inside the manufacturing facility are maintained at very low levels and air quality within the majority of the pilot facility is classified to a minimum level of International Organization for Standardization (ISO) 8. Large parts of the production areas are classified to meet or exceed the requirements of ISO 7. In addition, the sterile filling suite includes areas of ISO 6 and ISO 5 air quality.

2.3.3.2 Services COH production experience includes full manufacturing and banking/vialing support for:

• Neural stem cells

• Bacterial products

• Monoclonal antibodies

• Pluripotent stem cells

• Lentivirus


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• Plasmid DNA

• Islet cells

• Adenovirus

• Baculovirus proteins

• Transduced HPC

• Vaccinia virus

• Transduced T cells

• Oncolytic VSV

Quality control release testing of materials manufactured at the CBG is either performed in the CBG Quality Control laboratory or contracted out to third party vendors. The QC lab occupies approximately 1,300 sq. ft. and is comprised of a primary laboratory, 3 Biosafety Level 2 cell culture rooms and an equipment room. The main QC lab is set up to accommodate analytical procedures. Access to the QC lab is controlled by an electronic card access system and is restricted to CBG personnel.

2.3.3.3 Accreditations and Master Files The CBG is licensed by the California Department of Public Health, Food and Drug Branch for Drug Manufacturing (License #42078). The CBG facility’s Drug Master File (DMF) was originally submitted to FDA on July 11, 2006. See Table 2 for a list of CBG Master Files (MF).

Table 2: CBG Master Files

Master File # Title

BB-MF 13830 Manufacture of Lentiviral Vectors BB-MF 9778 Plasmid DNA Production & Purification BB-MF 13815 Manufacture of Adenoviral Vectors BB-MF 12494 TM-LCL MCB & WCB Production and Testing BB-MF 11783 293 and 293T Master Cell Bank Production and Testing BB-MF 13081 Biologics Manufacturing Facility BB-MF 16296 Production and Release Testing of ESC and IPSC Banks in Suspension Culture BB-MF 9986 Allogeneic Human Pancreatic Islet Cells

2.3.4 University of Minnesota, Molecular and Cellular Therapeutics

The Molecular and Cellular Therapeutics (MCT) Facility is a free-standing, GMP facility located on the University of Minnesota St. Paul campus at the University of Minnesota (Figure 7). Constructed in 1992, this 33,000 square foot facility supports production of materials for use in clinical trials at the Medical Center as well as for external clients. MCT operates under the Academic Health Center (AHC) and provides critical support for the development of phase I-III clinical trials of advanced cell-, tissue-, and gene-based therapies by translating research laboratory methodologies into clinical applications.


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Figure 7: Molecular and Cellular Therapeutics

2.3.4.1 Facility Description MCT’s overall design, architectural systems and finishes meet regulatory requirements and are consistent with the ability to integrate process equipment and process utilities (Figure 8 and Figure 9). A total of 11,000 square feet of dedicated ISO Class 7 and ISO Class 5 Controlled Environment Areas are available for the development and production of advanced cell-, tissue-, and gene-based therapies. There are 19 clean rooms, with the space divided into five production areas, several with negative pressure, and Biosafety Level 2 capabilities. The flexible, compliant design of the facility accommodates investigator-specific needs regarding bio-safety levels, bio-containment requirements, and project-specific gowning areas.

Figure 8: MCT Lower Level


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Figure 9: MCT Upper Level

An independent Quality Assurance department oversees all production. With production at various stages of developmental maturity and complexity, MCT is supported by a complete set of administrative services and technical team skilled in most advanced and biotechnology methods. MCT’s core competencies include the following:

• Quality and Compliance

• Operations/Materials Management

• Control of Critical Systems

• Program Budgets/Forecasts/Cost Accounting

• Business Plan Development/Project Management

• Equipment Management

• Document Change Control

• Process Development, Qualification, Validation

2.3.4.2 PACT The University of Minnesota PACT group consists of academic faculty and professional staff members employed by the University and highly skilled medical laboratory scientists of the University of Minnesota Medical Center with substantial expertise in the area of cellular


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therapeutics who work in both the Cancer Center/Regenerative Medicine Translational Laboratory and the Clinical Cell Therapy Laboratory.

Clinical Cellular Therapy and Cancer Center/Regenerative Medicine Translational Laboratory Programs

The Clinical Cellular Therapy and Cancer Center/Regenerative Medicine Translational Laboratory programs are managed by the University of Minnesota Medical Center (UMMC) under the direction of David H. McKenna, Jr., M.D. The UMMC Clinical Cell Therapy Laboratory provides cGMP clinical-scale production for the University of Minnesota. All cell/tissue-based products intended for human use are manufactured in the MCT by UMMC Clinical Cell Therapy Laboratory staff. The UMMC Clinical Cell Therapy Laboratory processes over 1,000 cellular products per year. The laboratory currently supports over 80 Bone Marrow Transplant (BMT) program clinical protocols, approximately half of which involve advanced cell engineering, and many of which are performed under IND or Investigational Device Exemption (IDE).

The UMMC Clinical Cell Therapy Laboratory operates 24 hours a day and the main processing space occupies 3,600 square feet within the MCT building. The laboratory is comprised of three main cell processing rooms, four individual pass-through rooms, a supply and material storage room, a liquid nitrogen cell storage tank room and a dedicated loading dock.

The Cancer Center/Regenerative Medicine Translational Laboratory provides translational and product development for the development of novel therapies such as Natural Killer cells, induced/natural T Regulatory cells, CD34 cell expansion, dendritic cells, tumor vaccines, CD34 selection and mesenchymal stromal cells.

2.3.4.3 Facility Accreditations The MCT facility’s DMF #12975 was originally submitted to the FDA on September 7, 2004. The DMF provides confidential detailed information about the MCT facility, processes, and articles used in the manufacturing, processing, packaging, and storing of biotherapeutics and drugs. While the submission of a DMF is not required by law or FDA regulation, it is submitted solely at the discretion of the holder in support of an IND or New Drug Application (NDA).

The UMMC Clinical Cell Therapy Laboratory is CLIA approved and accredited by FACT, CAP, and AABB. MCT and UMMC Cell Therapy Laboratory both maintain current FDA establishment registration certificates.

2.3.5 Interdisciplinary Stem Cell Institute, University of Miami, Miller School of Medicine

The Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami, Miller School of Medicine (UM) houses a Preclinical Program (PCP), Cell Manufacturing Program (CMP), and Clinical Program (CP). The programs operate under GLP, cGMP, and GCP standards. The PCP provides large and small animal and translational research studies with unique access to expertise


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in all major medical and scientific disciplines including surgery, biomedical engineering, advanced imaging, pathology, radiography, interventional cardiology, neurology, animal behavior, chemistry, and engineering.

2.3.5.1 Translational Research The approach at ISCI involves a comprehensive translational research strategy complies with applicable Code of Federal Regulations, state laws and industry accreditation standards, such as FACT and AABB. Led by skilled and experienced staff, the program adheres to established and documented processes to produce top quality cellular products and services. The PCP, CMP, and CP also adhere to GLP, cGMP, GCP, and International Council of Harmonisation (ICH) guidelines, highly defined, and structured approach where everyone in the organization knows their role and responsibilities immediately after the project kick-off meeting (Figure 10). Extensive planning is key to ISCI’s success. As part of planning, the ISCI ensures that project resources are identified, budget is available, comprehensive communication management, risk management, quality assurance, and other operational aspects of the project are continuously reviewed during regularly scheduled progress meetings and communicated to all stakeholders. With unique resources and collaboration within the University of Miami Veterinary Medicine and Biomedical Sciences, Preclinical Program facilitates the inclusion of animals with naturally occurring disease as viable research models. Preclinical Program provides unique opportunities to develop new therapeutics in the fields of, cardiology, pulmonology, immunology, endocrinology, and hematology.

Mission and Vision of ISCI

The PCP at ISCI fosters multi-disciplinary service, research, and education. The primary focus of PCP is to develop research activities and provide core services in the areas of drug, biologics and device development, preclinical studies under GLP, and biomedical imaging.

The vision of ISCI is to become the leader in translational research and provide comprehensive preclinical research services using an interdisciplinary approach to improve the effectiveness and efficacy of drug and device development from early stage and into clinical trials by:

• Seamlessly integrating all aspects of device and drug development from basic research/design to imaging and preclinical testing through human clinical trials;

• Facilitating the use of animals with naturally occurring disease as a viable research model;

• Using unique resources to develop new tools for molecular and translational imaging.


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Figure 10: Operational Structure of Cell Processing Facility at ISCI.

Dr. Joshua Hare, MD, Professor and Director, ISCI, is responsible for oversight of the CMP operations and provides the leadership on strategic planning for facility services. Reporting directly to Dr. Hare is Aisha Khan, Executive Director of Laboratory Operations of the ISCI Cell Processing Facility. Ms. Khan manages all projects of the cell processing facility. Antonio Izquierdo is the Sr. Center Administrator and Business Manager for the processing facility of ISCI. Clinical protocols and INDs are overseen by Dr. Ivonne Schulman. Preclinical research studies are overseen by Dr. Wayne Balkan. Dr. Konstantinos Chatzistergos oversees preclinical methods and processes development and is the subject matter expert of Induced Pluripotent Stem cells (IPS) and Dr. Malik as project manager who oversees all the activities.

Lab Services

The Preclinical Program has 8,000 sq ft of laboratory space located on the 8th and 9th (Figure 11 and Figure 12) floors of the Biomedical Research Building at ISCI. This fully-equipped laboratory includes separate tissue culture, animal cardiac physiology, and microscopy (Leica DMI 6000 inverted microscope imaging system) rooms, a cold room and darkroom, and common equipment rooms, including a multifunctional microplate reader system (SpectraMax M5, Molecular Devices), real-time PCR system (iQ5, Bio-Rad), Berthold Centro XS3 luminometer, and a Beckman LS 6500 scintillation counter. The Imaging Core Lab is designed to have the latest imaging equipment for the imaging of large and small animals. The 1st and the 2nd floors of the building house swine and rodents used by ISCI investigators. These services include a devoted 3T MRI Siemens Trio, Acuson X300PE ultrasound, and a state of the art Artis zee biplane system. The support provided by the ISCI is based on proven standards; experience, skills, and attention to quality of work.


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In addition to the primary CPF, ISCI has access to other UM facilities that are adjacent to ISCI. The Confocal Microscope Facility provides investigators with light, fluorescent, electron microscopy and electronic imaging. The Histology Research Core Facility blocks tissue sectioning for routine hematoxylin-eosin and trichrome stains, tissue sectioning for immunohistochemistry, and professional assistance in gross or microscopic pathology. The Oncogenomics Core Facility provides access to the latest in technology, chemistries, and expertise for the detection, quantification, and characterization of genes and gene products. The Biostatistics and Bioinformatics Core facility provides investigators with sophisticated and state of the art biostatistics and computational expertise and infrastructure. The following is a list of services available through the Translation Research Laboratories (not all products/services available through PACT):

• Tissue culture of primary human cells and cell lines

• Optimization of media and culture conditions

• Development of methods for cellular activation

• Evaluation of biological response modifiers

• Use of bioreactor systems

• Cell separation technologies

• Scale-up of culture techniques

• Design and production of plasmids and vectors

• Evaluation of gene transfer strategies

• Transduction and transfection of cells

• Medical Device Evaluation

• Optimization of methods for cryopreservation and thawing

• Hematopoietic Stem Cell Selection -Peripheral Blood Hematopoietic Stem Cells

• Selection of CD34+ cells

• Culture and Expansion of Human Marrow-Derived Mesenchymal Stem Cells

• Bone Marrow Mononuclear Cell Isolation by Density Gradient

• Cryopreservation

• Cord Blood Processing, Culture, Expansion and Cryopreservation

• Schwann Cell Culture, Expansion and Cryopreservation

• Dendritic Cell Vaccine Production

• Development of animal models for cell-based therapies

• Use of imaging to track therapeutic cells


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• Ex vivo monitoring of immune responses

• Monitoring of immune reconstitution

• Assessment of in vivo persistence of therapeutic cells

• Preclinical Bioanalytical Analysis

• Clinical Bioanalytical Analysis for Biologics

• Ligand Binding Assays

• Nonclinical Dose Formulation and Analysis

• Surgical Services and Medical Device Evaluation

• Process Validation

• SOP Development

• Product Characterization assays

• Development of methods for shipping cells

• Development of product quality control testing for lot release

• Stability and storage studies

• GLP/cGMP/cGTP training

• Pre-IND package formulation

• IND CMC writing

• IND CMC amendments submissions

2.3.5.2 Facility Overview ISCI was formed in response to a desire and a medical need for developing a state-of-the-art multidisciplinary research group whose primary goal is to support and develop basic and translational research to further understand the utilization of stem cells and cellular regenerative pathways. ISCI was founded in 2007 to spearhead the development of new regenerative therapies coupling fundamentals of stem cell biology research with the performance of rigorously conducted clinical trials. Since then, ISCI has grown to 62 full-time faculty members with areas of research including Cardiology, Pulmonology, Dermatology, Diabetes, Hematology, Neurology, Orthopedics, and Oncology. ISCI is housed in the Biomedical Research Building comprising of 26,000 sq. feet that includes laboratory space, tissue culture rooms, general equipment rooms, imaging, cell production, core facilities, and administrative and faculty offices. A GMP laboratory for the preparation of cells for preclinical and human clinical trials is an important ISCI strength. The facility has restricted access (card key controlled) and all essential equipment is continuously monitored through automated alarm system. The Regulatory/ QA team maintains a quality management system, which oversees and monitors the entire laboratory operations and routinely evaluates production outcomes, as well as, providing


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summary reports to the investigators. The comprehensive quality management system includes, but is not limited to, both internal and external audits, assuring compliance with the current federal (FDA) requirements (21 CFR Part 1271 & 21 CFR Part 210 & 211) and other applicable standards such as, AABB and FACT. ISCI is CLIA certified and holds a State of Florida Clinical Laboratory License as well as a State of Maryland Tissue Bank Permit. The quality system is organized to monitor day-to-day operational and manufacturing activities to prevent, detect, and correct deficiencies that could affect donor and patient safety, and the safety, purity, potency, or efficacy of manufactured products. The facility consists of four separate production suites equipped with biosafety cabinets, incubators, bench top centrifuges, and microscopes. The laboratory is HEPA filtered, under appropriate air handling (positive pressure) and meets class 10,000 specifications in the manufacturing suites (1-4) and class 100,000 in the general laboratory, liquid nitrogen freezer room, storage room, and gown in/out areas. Laboratory equipment is cleaned and maintained according to the established quality control schedule. Open manipulations are performed in class 100 Bio Safety Cabinets. As a large research institution, the University of Miami, Miller School of Medicine has the expected full range of research support services, including telecommunications and information technology, environmental health and safety, radiation control, animal care, and libraries. The ISCI has access to all core resources and facilities, including those for flow cytometry, microarray analysis, and transgene and gene knockout mouse production, among others.

Quality Program

The ISCI CMP Quality Programs have a well-established pre-clinical compliance program as well as cGMP program to ensure high quality of products and integrity of scientific data. Quality Programs are overseen and administered by the Regulatory/Quality Assurance unit. The programs are designed to assess the operations through monitoring of the entire operations, processes and practices through the established quality indicators. The system is in place for audit and/or tracking and trending of deviations, effectiveness of review of the production process, effectiveness of quality control, personnel training and competency assessments and other relevant operational performance. Also included in the programs are SOP management; products, materials and supply qualifications and approval; performing audits; monitoring of product manufacturing record; and data quality indicator monitoring.

Quality approach is applied at the earliest stages of processing from pre-clinical operations and carries through clinical productions. All manufacturing processes are monitored to assure the quality, safety, and effectiveness of the product. The system is intended to remain dynamic through continuous feedback, monitoring by system audits, management review, and corrective/preventive actions.


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Figure 11, Figure 12, and Figure 13 show the physical layout of the ISCI research and cell manufacturing facilities.

Figure 11: 8th Floor of the Biomedical Research Building (BRB). (12,895.47 sq. ft., 75 rooms) Floor

Plan of the ISCI Cell Manufacturing Facility. Shaded area indicates areas occupied by ISCI.

Figure 12: 9th Floor of BRB (12,931.28 sq. ft., 85 rooms). Floor Plan of the ISCI Cell Manufacturing

Facility. Red square indicates location of the ISCI Cell Manufacturing Facility.


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9

9

9

9

9

9

9

9

9

9

9

9

9

9

9

Figure 13: Floor plan of the clinical research cell manufacturing (Clean Room) facility

where clinical grade products are manufactured and processed.

2.3.6 Moffitt Cancer Center

Moffitt Cancer Center (MCC) opened in 1986 on the campus of the University of South Florida in Tampa, Florida. MCC achieved its initial National Cancer Institute (NCI) designation in 1998 and its NCI Comprehensive Cancer Center designation in 2001, which continues to date. MCC is ranked # 6 on 2016 U.S. News & World Report’s Best Hospitals for cancer treatment, making MCC the top ranked cancer hospital in the Southeast and in the state of Florida.

2.3.6.1 Moffitt Cell Therapy Facility Description The Cell Therapy Facility (CTF) occupies 10,000 square feet in the M2Gen building on Moffitt’s McKinley Campus. The facility comprises ten class 10,000 clean rooms, each with gown-in and gown-out anterooms. Ancillary, non-classified, space for the facility includes dedicated QC and process development laboratories, raw materials and liquid nitrogen storage suites (Figure 14 and Figure 15).

Figure 14: Moffitt Cell Therapy Facility located on the 4th floor in the M2Gen building

on MCC’s McKinley Campus


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CLEAN ROOMS – GOWN IN/OUT

SUPPORT AREA

PREP, SUPPLY, LABS

CLEAN ENTRY/EXIT COORIDORS, AIR LOCK

Figure 15: MCC CTF Processing Laboratories

The Cell Therapy Facility (CTF) enables research, development and manufacturing of human cells for use in subjects undergoing hematopoietic cell transplantation (HCT) for malignant and non-malignant blood disorders and immunotherapy for cancer treatment. MCC CTF manufactures cellular products in support of novel, investigator-initiated clinical trials, while maintaining compliance with standards set by the U.S. FDA and other accrediting bodies. To accomplish this goal, MCC CTF’s Specific Aims are to: i) develop new technologies for translation of cellular therapies; ii) provide regulatory assistance in support of cellular therapies, iii) educate and train scientists and clinicians committed to careers in cellular therapies, and iv) produce the highest quality cellular products for IND-enabling studies and clinical trials.

MCC CTF has supported dozens of FDA-approved investigator-initiated cell therapy clinical trials by providing dendritic (DC) and tumor cell vaccines, gene-modified stem and progenitor cells, T regulatory (Treg) and Natural Killer (NK) cells, Tumor-infiltrating Lymphocytes (TIL) and Chimeric Antigen Receptor (CAR) T cells. The expertise of MCC CTF is consistent with the contemporary mission to direct efforts toward trials evaluating ex vivo selection and expansion of cells, transgene expression, stem cell engineering, and genetic strategies to enhance immunity or cure blood diseases.

MCC CTF works with investigators through all stages of pre-clinical development and clinical trial implementation to facilitate: i) new product development, wherein new cell therapy products undergo pre-clinical scale-up, testing, and validation, ii) cell collection and cryostorage to obtain mononuclear cells, lymphocytes, and antigen presenting cells for production of cell therapy


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products and immune monitoring studies, iii) cell therapy product manufacturing and iv) analytic laboratory testing for product quality control and post-treatment immune monitoring.

2.3.6.2 Moffitt CTF Organizational Chart MCC CTF leadership is provided by the Laboratory Technical Director, Linda L. Kelley, PhD, Medical Director, Marco Davila, MD, PhD, and Scientific Director, James Mulé, PhD. Quality Management reports directly to the Moffitt Quality and Safety Department. Separate Laboratory Managers oversee activities associated with the Blood and Marrow Transplant Program, Experimental Cell Therapies and Facility Operations (Figure 16).

Marco Davila, MD, PhD Linda L. Kelley, PhD James Mulé, PhD Medical Director Technical Director Scientific Director

Medical Director

Scientific Director

Quality Management

Director

Laboratory Director

Business Analyst

IMS Analyst

Training Specialist

Assistant Laboratory

Director

Quality Management

Specialists

Manager, BMT & Quality Control

Manager,

Experimental Cell Therapies

Manager, Facilities

Operations

Cell TherapySpecialists

Cell Therapy Specialists

Operations Specialists

Quality & Safety

Director

Basic Science

Program Administrator

Figure 16: CTF Organizational Chart


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2.3.6.3 Moffitt CTF Project Management MCC CTF approaches project management as a discipline of initiating, planning, executing, controlling, and closing the work of the team to achieve specific goals and meet specific success criteria. Effective project management requires the development of distinct technical skills and management strategies with a primary challenge to achieve all of the project goals within the given constraints. The primary constraints include scope, time, quality and budget. The secondary, more ambitious, challenge is to optimize the allocation of necessary inputs and integrate them to meet pre-defined objectives. MCC CTF project management teams include technical development, quality and operations specialists (Figure 17).

Figure 17: MCC CTF Project Management Schema


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2.3.6.4 Moffitt CTF Services Table 3 lists the services available at Moffitt CTF.

Table 3: CTF Services: Cell Types; Cell Processing Techniques; QC Testing Assays

Cell Types Cell Processing Techniques QC Testing Assays

Tumor Infiltrating Lymphocytes (TIL)

Tumor Digestion 8-color flow cytometry assay development

Monocyte-derived Dendritic Cells

Monocyte Enrichment Endosafe®-PTS™ Endotoxin Testing

Regulatory T cells Cell Purification and Isolation Viability testing- AO/PI Cellometer® Vision

Gene-modified Stem and Progenitor Cells

Vector Transduction and Transfection

ELISA

Dendritic Cell Vaccines Dendritic Cell Maturation and Differentiation

Gram stain

Tumor Cell Vaccines Tissue Culture (primary human cells and cell lines)

BacT/ALERT® Aerobic and Anaerobic System sterility cultures

Artificial Antigen-presenting Cells

Closed-system GRex Cell Culture IntelliCyt iQUE cell screening

HPC, marrow Controlled-rate cryopreservation Viability testing – Trypan blue; 7-AAD

HPC, apheresis Master and Working Cell Bank Generation

MycoAlert™ Mycoplasma Detection

HPC, cord blood Cell washing and volume reduction VenorTMGeM Mycoplasma Detection Kit

Chimeric Antigen Receptor (CAR) Natural Killer (NK) Cells

Cell elutriation, Ficoll separation and buffy coat preparation

Methylcellulose Colony-forming Units (CFU) Assay

Chimeric Antigen Receptor - T (CAR-T) Lymphocytes

Cell irradiation QuickTiter™ Viral Titer

Feeder cells Cytotoxicity assays

2.3.6.5 Moffitt CTF Training Program CTF has a comprehensive training program for technologists, laboratory assistants, graduate students and physician scientists. Training is accomplished through oversight and management by a dedicated Cell Therapy Training Specialist and augmented with Subject Matter Experts (SME). The training program utilizes a diverse set of learning tools including didactic lectures, web-based exercises, direct observation, hands-on participation, checklists and examinations.


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2.3.6.6 Moffitt CTF Quality Management The primary goal of MCC CTF is to manufacture cell products that meet high quality standards for administration to patients with therapeutic intent. Oversight of all quality and regulatory aspects of manufacturing is accomplished through an independent Quality Program, under the leadership of the Quality Management Director. The Quality Program works with the support of an experienced group of individuals including a Supervisor and Quality Assurance Specialists.

The CTF Quality Program develops and oversees the following systems and activities:

• Document Control

• Process Control

• Change Control

• Training and competency

• Process Validation

• Equipment Qualification

• Supplier/Vendor Qualification

• Facility Control

• Record Review

• Deviation Management

• Audit Program

• Corrective and Preventive Action (CAPA)

• Outcomes Analysis

• Key Quality Indicators monitoring

• Regulatory and Accreditation Compliance

2.3.6.7 Moffitt CTF Accreditation The CTF abides by cGTP and cGMP regulations applicable to the early phases of clinical trials. The CTF is CLIA approved and accredited by The Joint Commission, FACT, and CAP.

The MCC CTF filed a Type V Master File (BB-MF 13743) with the FDA in 2008. The facility is registered with the FDA for Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (FEI: 0001038768) to package, process, store, label, and distribute peripheral blood stem cells and somatic cell therapy products. Moffitt CTF is also registered to process, store, label, and distribute umbilical cord bloods.


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2.3.6.8 Moffitt CTF FDA Approval Process Program Leader Protocol Approval

Scientific Review Committee (SRC)

Recombinant DNA Advisory Council (RAC)/Office Biotechnology Activities (OBA)

Institutional Biosafety Committee (IBC)

FDA IND Application

Institutional Review Board (IRB)

2.4 PACT Coordinating Center (CC)

The Emmes Corporation is a small business organization located in Rockville, Maryland. For over 37 years, Emmes has devoted its efforts exclusively to providing biostatistical, epidemiological, data management, computer systems development and maintenance, and organizational and logistical support for clinical and laboratory research programs. Emmes' organization, staff, facilities, and work methods have been developed solely for the purpose of supporting clinical and laboratory research programs.

The Emmes Corporation's staff are organized into functional groups and service groups, with the goal of providing projects with staffing selected from each appropriate group. The –PACT Coordinating Center includes staffing from the following functional groups: statistical, data management, and administrative support and the following service groups: information technology, and regulatory services.

CC OrganizationRobert Lindblad, MDPrincipal Investigator

Debbie WoodProject Director

Regulatory Affairs

Data Manager

IT

Web Development

Administrative Coordinator

Laarni IbenanaProject Manager

Statistician


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The functions of the CC include (see also MOP Section 7 Policies and Procedures for Coordinating Center):

• Coordinate the development, updates to, and distribution of the MOP

• Develop, print, and distribute PACT program materials

• Develop and maintain the PACT website

• Develop and maintain data management system for Request for Services Applications (RSA)

• Facilitate management and coordination of PACT activities including: consistent standards and procedures across CPF, oversight of RSA submission and review/approval processes, liaison with relevant National Institutes of Health (NIH) program and external government staff and cellular therapy organizations

• Develop and implement procedures for product or service requests in collaboration with CPF including development of QC/QA plans, monitoring plans for product manufacturing, and regulatory support

• Facilitate and promote communications among the PACT group through website development and maintenance, the private website portal, rosters, calendars, and assistance with issues resolution

• Organize and facilitate meetings and teleconferences including SC, EEP, Scientific Review Board (SRB), Working Group (WG) and other subcommittees

• Participate as member of SC and subcommittees

• Provide statistical support for product-related activities including data analysis and statistical support for manuscripts and reports, and customer questionnaires

• Provide coordination for PACT training and educational activities

• Monitor and assess, and provide reports on the PACT CPFs’ program status

• Participation in CPF site visits for review and/or QC of data

2.5 National Heart, Lung, and Blood Institute (NHLBI)

The NHLBI is responsible for organizing and providing funding support for this program. The NHLBI Program Team consists of NHLBI staff from the Division of Blood Diseases and Resources.


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The NHLBI COR are active and fully participating members of the Steering Committee.

Contracting Officer Representative Alternate Contracting Officer Representative

Lisbeth Welniak, PhD Contracting Officer Representative Program Director NHLBI Translational Blood Science and Resources Branch Division of Blood Diseases and Resources Two Rockledge Center, Room 9168 6701 Rockledge Drive, MSC 7950 Bethesda, MD 20892-7950 Phone: (310) 827-8297 (direct line) Phone: (301) 435-0065 (main line) Fax: (301) 480-0868 Email: [email protected]

Traci Heath Mondoro, PhD Alternate Contracting Officer Representative Branch Chief NHLBI Translational Blood Science and Resources Branch Division of Blood Diseases and Resources Two Rockledge Center, Room 9174 6701 Rockledge Drive, MSC 7950 Bethesda, MD 20892-7950 Phone: (301) 827-8283 (direct line) Phone: (301) 435-0065 (main line) Fax: (301) 480-0867 Email: [email protected]

2.6 Expert Evaluation Panel (EEP)

Individuals are appointed to the EEP. The EEP will evaluate the goals and progress of the PACT program and will act in an advisory capacity to the NHLBI. The EEP will consist of five members and consultants as necessary.

2.6.1 Purpose

The overall objective of the EEP will be to determine if the PACT program is meeting the needs of the scientific community. This includes an assessment of PACT’s contribution to and impact in the cell therapy community, the types and scope of projects accepted by PACT, progress in providing cell products for IND-enabling studies, educational initiatives conducted by PACT, and the overall leadership that PACT provides to the cell therapy community.

2.6.2 Membership

Individuals are invited to serve on the EEP by the NHLBI COR. A Chair will be appointed. Members are required to complete a Conflict of Interest (COI) and Confidentiality Certification for review and acceptance by the NHLBI prior to serving on the Panel.

2.6.3 Meetings

The EEP will hold face-to-face meetings at least yearly, starting in year two of the program. Meeting attendees include EEP members, NHLBI COR, CC Representatives, SC Chair, and, ad hoc consultants or other representatives invited to the meeting as needed.




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2.6.4 Reports

The CC will prepare and deliver reports on PACT activities to the EEP members prior to the face-to-face meetings. The EEP reports will include general progress reports and summary product information. Typically, the reports will include information on project status and issues. The reports provide a summary of the year’s activities for review by the EEP.

2.7 PACT Working Group and Other Subcommittees

2.7.1 Purpose

The PACT program will establish a Working Group and other subcommittees at appropriate times throughout the duration of the program to accomplish focused program tasks. The Working Group is a subgroup of the Steering Committee and is initially tasked with MOP development and collaboration with the CC on the RSA submission and review process. A subcommittee will be formed to address the program’s education initiative. PACT’s education mission is to promote interest in cellular therapy/engineering among physicians- and scientists-in-training and to prepare interested individuals for academic careers in cellular therapy/engineering.

The Working Group or other subcommittees’ tasks will be specific to the group but overall functions will include:

• Reviewing and/or drafting program materials as appropriate • Providing requested materials to the CC • Serving as a liaison to other PACT CPF team members to move action items forward at

each CPF

2.7.2 CPF Membership

The PACT Working Group or other subcommittees will be comprised of elected members of the NHLBI, CPF, and the PACT CC with roles that are relevant to and will enable completion of tasks undertaken by that Working Group/subcommittee. NHLBI, PACT CC, and CPF team members may participate in more than one subcommittee at any given time throughout the program.

2.7.3 Teleconferences

The Working Group/subcommittee conference calls will occur on a monthly basis or more frequently if needed. Additional participants from the CPF may join the calls, but programmatic decisions/approvals will be limited to the elected committee members or an NHLBI approved designee if the elected committee member is unavailable for a call or meeting. The CC staff schedules the conference calls, distributes call agenda items solicited from the committee, provides details to access the calls, sends reminders regarding scheduling, and drafts and distributes the call minute summaries. The CC takes responsibility for tracking and follow-up for actions items identified during these conference calls.


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3.0 POLICIES AND PROCEDURES FOR FACILITIES OPERATIONS

Production Assistance for Cellular Therapies (PACT) Cell Processing Facilities (CPF) maintain fully developed written standard operating procedures (SOP) describing all aspects of the production environment and product manufacture. Fully traceable lot or batch production records (BPRs) are also maintained, including identification of raw materials, donor tissues, cell lines and vector components, solvents, reagents, inactive ingredients, and equipment and containers coming in contact with the product during its preparation, storage or shipment, and in process and post-production test results. Due to differences in local regulations and practices, SOPs, even those with a common purpose, are not expected to be identical in content or format between facilities. However, to improve efficiency and further the project goals, CPF will offer to share techniques and documentation with the other program facilities. The following sections outline key operational elements that CPF utilize in meeting its regulatory and voluntary standards.

3.1 Process Control

PACT CPF control all processes within their facilities that affect the quality of products and services. These processes include the processing, testing, storage, distribution, and administration of products and services. The CPF ensure that these processes will be carried out under controlled conditions by establishing procedures that define:

• Use of standardized procedures for the collection, processing, testing, storage, distribution and administration of products and related services

• Compliance with procedures and standards, including regulatory requirements

• Use of suitable equipment and working conditions

• Control of all equipment used in the collection, processing, testing, storage and distribution of its products

• Monitoring and control of process parameters and product characteristics

• Approval of procedures, supplies, equipment, and product release

• Criteria for acceptable results

The CPF will identify, design, and validate the policies, processes, and procedures that affect the quality of cellular therapy products and services. The CPF will ensure that these policies, processes, and procedures are carried out under controlled conditions designed to prevent contamination of cellular therapy products, maintain the cellular therapy products function and integrity, and prevent the transmission of infectious disease.


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3.1.1 Specific Elements of Process Control Policy

• Materials used during the collection, processing, testing, storage, and distribution of products are sterile and without excess toxicity and whenever possible, are approved for human use by the Food and Drug Administration (FDA).

• PACT CPF participate in proficiency testing programs and have systems in place to monitor the accuracy and reliability of test results. Records will be maintained according to established procedures.

• Quality control procedures are established to ensure that all equipment and reagents used in the collection, processing, testing, storage, and distribution of products function as required.

• Laboratory procedures are established to ensure that aseptic methods are used to provide maximal assurance of sterile processes.

• Procedures used in the processing, testing, storage, distribution, and administration of products will be validated before use. Records of the validation process will be maintained according to established procedures.

3.1.2 Process Validation

Process validation, as defined by FDA, is establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics. Each manufacturing process must be validated to ensure that product specifications can be met reliably and reproducibly. Validations must be based on written procedures, and should be thoroughly exercised to establish that the procedure can be performed as specified. The written method and results of each validation exercise must be maintained and be traceable to each process, product batch, or lot.

In addition to the manufacturing process steps, each equipment unit and in-process assay or post-production assay method must also be validated. Each validation procedure should specify prospectively the steps involved in the procedure, any assessments that are made and the requirements and means for adjustments to the process. Measurement equipment must be properly qualified and demonstrated to react reliably when the process is changed and the measured parameter is affected. Equipment validations must be exercised under the conditions expected during actual use in the manufacturing process, including “worst case” conditions for the process. A systematic recording of information about the process should be identified for each procedure, including a recording form or log when appropriate.

PACT CPF are responsible for documenting their own validation procedures and quality program effort. Computerized systems that control production or testing apparatus must also be validated, as must automated data recording and documentation systems.


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3.1.3 Assay Design and Validation

Assay development and validation may be required for in-process testing, and product release. When assays have been established on a research scale, they may need to be re-validated for scale-up and current Good Manufacturing Practice (cGMP) (i.e., production) use at the CPF. Product release assays must be developed based on product-specific requirements. Product release requirements should satisfy all the quality criteria relevant for safe use of the product as intended.

These would routinely include:

• Sterility

• Identity

• Purity

• Potency (initiated in Phase I and fully developed in Phase III)

• Stability

3.2 Document Control

PACT CPF must establish procedures to control and maintain all documents that relate to the processing, testing, storage, distribution, and administration of products. The facilities’ quality assurance (QA) unit must maintain control and documentation for the creation, approval, release, modification, periodic review, and retirement of SOPs and related recording forms or logs used at each facility. The document control procedures will ensure that:

• Appropriate documents are available at all locations where operations covered by these documents are performed

• Only properly issued, current revision documents are used

• SOPs, forms and worksheets, i.e., production records are written with a standard format

• Obsolete documents are suitably identified and controlled. Obsolete SOPs, production records and forms are archived and retained

• Changes or revisions to documents are reviewed and approved before implementation

• Individuals authorized to review and approve changes have all the background information necessary to conduct the review and approval

• Distribution is controlled

A master list of all controlled documents is maintained.


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3.2.1 Standard Operating Procedures

PACT CPF are responsible for ensuring that written procedures and policies addressing all appropriate aspects of operation established at the CPF are in line with current Good Manufacturing and Laboratory practices where appropriate.

3.2.2 Deviations from Standard Operating Procedures

Procedures must be in place to ensure the detection, reporting, assessment, investigation, and monitoring of events that deviate from acceptable procedures (cGMP or current Good Laboratory Practices (cGLP) requirements, as applicable), standards or applicable laws and regulations. Deviations must be reported in accordance with specified requirements. These procedures are employed not only as a means of tracking errors but also as a tool for improving quality.

3.3 Audits

Records of all internal and external (customer and/or FDA) inspections will be maintained by the CPF. These records indicate whether the facility passed or failed the inspection and detail any recommended or required corrective actions. The CPF may ask the Coordinating Center (CC) to assist in audits. A checklist will be developed by both the CPF and the CC, which will specifically outline which aspects of the audit the CPF would like the CC to perform.

3.4 Equipment

PACT CPF will establish and maintain written procedures to control, calibrate and maintain critical equipment used in the measurement, processing, testing, storage and distribution of the products they manufacture. Dedicated equipment will be used for the storage of specimens, products, and reagents. Measurement equipment must be used in a manner that ensures that the measurement limitations are known and are consistent with the measurement capability that is required. Critical equipment items are those involved in a process or measurement where an equipment failure or erroneous output would have a direct, detrimental impact on product quality or safety. All equipment is assessed to determine if it qualifies as critical equipment for the intended production or other use.

A written equipment maintenance program will be in place to ensure that all pieces of equipment are on a regular cleaning, maintenance, and calibration schedule. The program must be specific and appropriate for each type of equipment, relative to its useful life, criticality, performance and environmental requirements, durability, and stability. Each individual durable unit of equipment, where practical, should have a unique identification mark to facilitate tracking of its use and maintenance. Calibration, cleaning and maintenance records for all equipment units must be maintained according to written SOPs and be available for inspection at all times. The records of the most recent maintenance activities for each equipment unit should be located near the unit to facilitate easy reference and recording of new information. Only qualified personnel may


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perform cleaning, maintenance, or calibration procedures on critical equipment units or for any equipment as specified by the relevant SOPs.

Records of equipment malfunctions and any associated corrective actions must be maintained.

Measurement equipment must be calibrated using certified standards or calibrating equipment traceable to recognized or reproducible standards. The environment in which equipment is used must be comparable with the conditions used during the calibration, inspection, measurement, and testing of that unit.

Facility maintenance operations including heating, ventilation, air conditioning (HVAC), and water systems must be performed by qualified personnel or contractors on a regular basis according to the recommendations of the manufacturer or as specified by facility SOPs. Formal service reports provided by contract personnel or testing laboratories must be obtained and filed in the facility records.

All critical equipment should have emergency back-up power available to maintain operation during interruption of electrical service. Where appropriate, sensitive electronic components should have Uninterruptible Power Supplies (UPS) with adequate surge suppression function to maintain continuous operation during storms, blackouts, or brownouts. Temperature-controlled (or other controlled environmental conditions like liquid nitrogen level, humidity, CO2 or O2 concentration) storage or incubation equipment must be connected to an alarm system to alert facility staff when internal environmental conditions do not meet the required specifications. Plans should be made in advance for the transfer of stored materials to a back up location should a controlled storage or incubation unit fail. Continuous recording systems (with data collected at intervals relevant to the controlled condition) for controlled environment units should be installed and the records reviewed regularly and archived according to facility SOPs.

Major critical equipment units must be qualified at the time of installation, and validated for use after installation and following relocation or major servicing activities. Each unit should have documentation of its installation, operation, and performance qualification (IQ, OQ, PQ) according to either the manufacturer’s recommendations or facility SOPs.

3.5 Reagents and Supplies

The CPF will establish and maintain policies, processes, and procedures to ensure that purchased, donated, or otherwise acquired materials or services conform to specified requirements.


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Policies and procedures will be in place for the control of supplies and reagents used in the processing or preservation of cellular therapeutics to ensure that:

• Written policies exist for reagent selection, ordering, evaluation, and acceptance

• Reagents will be of appropriate grade for the intended use and will be sterile

• Procedures for production of in-house reagents will be validated

• Visual inspection of supplies and reagents used in the processing or infusion of products will be performed at the time of receipt

• Supplies and reagents received but not yet qualified or verified as acceptable for use must be quarantined to avoid inadvertent use prior to documented acceptance

• Qualification studies of supplies and reagents will be performed as determined by the facility

• Supplies and reagents will be stored in a safe, sanitary, and orderly manner

• Supplies and reagents will be used in a manner consistent with instructions provided by manufacturer or according to established procedures at the facility

• Lot numbers and expiration dates of reagents and disposables will be recorded

• A certificate of analysis (C of A) from the supplier for material that comes into contact with the cell therapy products will be obtained

• Records of materials obtained will be maintained in conformance with AABB and/or Foundation for the Accreditation of Cellular Therapy (FACT) standards, as applicable

• For materials, supplies, services and reagents used in the manufacture of cellular therapy products, the CPF will:

o Evaluate and select any supplier of a material or service that is intended for incorporation into the final cellular therapy product or service, or that affects the quality of the final cellular therapy product or service, on the basis of the supplier’s ability to meet specified requirements

o Define the type and extent of control required over the supplier. The type and extent of control will depend upon the type of material or service, the impact of the material or service on the quality of the final cellular therapy product or final service, and the previous performance of the supplier

o Maintain records of acceptable suppliers

o Report to management with contracting authority of a supplier’s failures to meet specified requirements


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3.6 Inspection and Testing of Incoming Materials

CPF will have procedures for the inspection of incoming materials that are used in the collection, processing, testing, storage, and distribution of its products. This inspection verifies that the materials conform to facility requirements. When appropriate, quarantine of materials (including reagents and equipment) must occur until they have passed any necessary testing or adequate documentation is obtained regarding their suitability for use in further processing. All incoming materials should undergo verification procedures prior to their release for use.

CPF must have a procedure to follow for occasions in which a material is used on emergency basis, prior to verification and release. The material is identified and recorded in a manner to permit immediate recall and replacement in the event that it is later determined not to conform to established requirements.

3.7 Product and Sample Identification and Traceability

Procedures are established and maintained to make it possible to identify and trace in a confidential manner each product from its donor source, through processing and testing, to final disposition.

The original facility donor study identifier must remain constant throughout processing (see Log-in and Sample Processing below). Any additional or supplementary unique identifier may be used, but will not obscure the original identifier.

Each product will be labeled in accordance with the AABB and/or FACT standards, as applicable. Abbreviated labels for the final products may be used.

3.8 Log-In and Sample Processing

Log-in and sample processing must occur at all CPF and proceed according to the established SOPs for various types of specimens. Records must be maintained to identify the individual collecting the cell or tissue product at the originating location, unless a registry provides the product to the facility. Established procedures must exist to identify individuals performing each critical step from receipt of the sample through administration to a recipient or other disposition. The specimens are examined for the integrity of the external container and, after unpacking, for the temperature of the recording device when such a device is included in the shipping kit. The laboratory personnel also confirm that a signed consent form is available for every received specimen.

The log-in SOP should include direction for the recording of all essential information appearing on the requisition form accompanying the product/specimen and the condition of the product upon receipt. At a minimum, this includes the study number and a unique identification number of the donor, protocol name or number, date, time and location of procurement and the date/time of arrival in the laboratory. Each received product/specimen is assigned a unique laboratory


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accession number that will identify it throughout its tenure in the laboratory and at delivery of a facility product. The unique accession number and the recipient subject’s study identification number are used to link together all of the specimens (tissues, blood, and fluids) derived from an individual patient. The study number links specimens collected at baseline to those obtained at follow-up visits. Thus, specimens collected longitudinally can be easily identified.

After log-in is completed, each product is appropriately identified and then directed to the specified location for processing, which proceeds according to established SOPs.

3.9 Inspection of Products During Processing, Prior to Distribution, and Before Administration

At specific points during processing, products will be tested and inspected, as defined in facility procedures. Products will be labeled and stored in quarantine until all testing has been completed and the results reviewed and the product has been found to be suitable for the intended investigational use.

Product release criteria must be established to ensure that products are deemed suitable for administration and are appropriate and safe for the intended recipient. If the product does not meet all standard release criteria, the Medical/Laboratory Director must give specific authorization for release (considerations include viability, phenotype, endotoxin and gram stain results) to the requesting investigator. Before release of a product unit from long-term storage, a final inspection by QA staff must be completed. The inspection will ensure that the labeling and testing of the product has been in accordance with the facility procedures and standards and will include the requirements for materials and quality control functions.

3.10 Requirements for Testing and Controls

Testing and controls are required to ensure that all products generated in the facility are aseptically manufactured and tested for sterility, and have the expected quality, viability, functional potency and purity. Laboratory tests required by regulatory and/or accrediting agencies will be performed by a laboratory accredited or licensed in accordance with applicable governmental laws and regulations, using one or more tests approved by the FDA or non-U.S.-equivalent. Documentation of accreditation, certification or licensure will be maintained where required.

To define a measure of potency, as appropriate for the cell population tested, it is necessary to measure its expected function. The appropriate assays for evaluating the functional potency of cultured cells will be selected based on the known functional characteristics of a control population.


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3.11 Product Release Requirements

A critical component of the manufacture of all cell therapy products is the development of testing methods and release criteria to provide the benchmarks for evaluating the products. Several of these are self-evident, e.g., sterility, purity, etc. and are prescribed by the Federal regulations and voluntary standards. Others, such as functionality, may be unique to the specific product and may require development and/or validation or out-sourcing if available commercially.

For an investigational product, all of the original QC test reports, together with the batch record worksheets, must be reviewed by the QA staff. The CPF will establish the appropriate release criteria.

Release criteria based on the purity or functional characteristics of the generated product may be difficult to establish for a variety of reasons, including variability of products (different sources or different donors) and incomplete knowledge of which characteristics are most important and relevant in defining therapeutic efficacy. Nevertheless, the CPF will establish release criteria for products, for example, as >95% viability and at least 70% purity based on the phenotype, activity or other applicable criteria. Other criteria may include number of cells, sterility by culture and Gram stain, absence of mycoplasma contamination, and endotoxin levels below acceptable limits. Other cellular functions may be measured and reported but may not be considered as release criteria.

The CPF will carry out all final inspection and testing for final cellular therapy products in accordance with written policies, processes, and procedures. These policies, processes, and procedures will (a) specify the criteria that will be used to assess each final cellular therapy product’s acceptability for release (as applicable), and (b) require that all specified inspections and tests have been carried out and that the results meet specified requirements. The inspection and testing used to ensure that criteria for acceptability for release are met apply to both materials and cellular therapy products. No final cellular therapy product will be released until the activities specified in processes or procedures and the associated records have been completed. If a final cellular therapy product or product lot fails to pass an inspection or test, the product will be considered a nonconforming product and handled as such. Policies will be in place for authorizing the use of products that do not meet all of the release criteria.

3.12 Requirements for Packaging, Labeling, and Shipping Procedures

Procedures will be established for the storage, distribution, and transport of materials, and in-process and final products. These procedures will be expected to prevent deterioration or damage to the materials and products.


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3.12.1 Labeling and Labeling Controls

The CPF will have policies, processes, and procedures for labeling products and samples. At a minimum, they will include:

• A defined, written procedure for the acquisition and creation of label templates

• Adequate controls in place to ensure proper product identification

• A system for discarding of obsolete labels

Labels will meet specified criteria prior to release for use. All containers of source material, in-process products, and final products will be labeled according to established standards and regulations. Biohazard labels will be affixed to products or samples in accordance with established standards and regulations. Labels must be designed and tested to assure that they adhere to the containers and remain legible under the recommended storage conditions of the product.

3.12.2 Storage and Preservation

The CPF will establish and maintain policies, processes, and procedures for storage of materials and products in order to limit deterioration and prevent damage. This will include the use of designated, secure storage areas, with controlled access and removal of product.

3.12.3 Storage Conditions

Products should be stored in designated quarantine and release areas at a controlled temperature and for periods of time that are designed to preserve the viability, recovery, sterility, and potency of the product. In order to detect deterioration, the conditions of the stored units will be monitored at designated intervals. Appropriate action will be taken before products reach undesirable temperatures. Products, reagents and/or supplies will be stored in a manner to prevent contamination, commingling, damage or improper release.

3.12.4 Storage Devices

Laboratory storage devices will be located in properly secured areas. An inventory control system must be established to identify the location of each product and associated sample aliquots. Products will be segregated and stored in a manner to prevent cross-contamination of untested, bio-hazardous, and approved-for-release products.

3.12.5 Distribution and Transportation

Prior to shipment of a product, the CPF will review and confirm shipping details with the intended recipient and schedule the shipment.

Products will be removed from inventory under double signature to confirm their identity. Packaging and shipping procedures will be established to limit deterioration and prevent damage


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to products during distribution and transport. These procedures must outline the method of packing to ensure conformance with specific requirements. Cellular products will either be shipped in a validated liquid nitrogen dry shipper, or on dry ice; or at ambient temperature as the product may require, in a validated, insulated container accompanied by a continuous temperature logger. Temperatures will be monitored during shipment to ensure that they remain within an appropriate range during transit. Shipping containers will be validated for temperature maintenance and product integrity. Depending on the product, shipment will be made via commercial express shipment companies or through a courier service. The shipment will contain a copy of the product C of A, a batch record summary, and a confirmation of receipt form that must be completed and returned to the manufacturing facility.

Records relating to the storage and transportation of products will be maintained according to established procedures that are compliant with FDA regulations, FACT and/or AABB guidelines, as applicable.

The facility must ensure that the transportation and labeling of its products complies with applicable legal requirements.

3.12.6 Product Shipping Receipt Confirmation Form

The CPF are required to document information regarding the shipping and receipt conditions. The CPF may use their pre-established internal product shipping receipt confirmation form. The form is to accompany all PACT-manufactured cell products upon their shipment. Both the product manufacturing facility and the product requestor are required to fill out designated sections of the form where applicable. The product requestor is required to return the form once completed to the product manufacturing facility.

3.13 Sample Repository

The CPF may maintain inventories of products produced by the CPF, if quantities permit, and as negotiated in the contract agreement between the investigator and the CPF. If samples are to be retained by the CPF, safe, reliable, and controlled storage will be provided. Sample data will be entered into an inventory system recording all pertinent information for each sample. Aliquoting and labeling of designated samples will be provided according to SOPs and product specific requirements. The system will allow retrieval of designated samples for shipment. Samples will be shipped at proper designated temperatures. Shipments will include the list of samples in that shipment, acknowledgement and tracking of shipment receipt, and reconciliation of any problems with shipment.

The CPF may prepare archival samples from each lot of product manufactured. Properly labeled samples may be archived at a designated National Heart, Lung, and Blood Institute (NHLBI) repository according to standard procedures, depending on availability of material. A schedule for timing and batching of shipments will be established for each product.


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4.0 REGULATORY REQUIREMENTS

4.1 Master Files for Facilities’ Information

A regulatory document that each of the Production Assistance for Cell Therapies (PACT) Cell Processing Facilities (CPF) is recommended to develop and maintain is a Type V Drug Master File (DMF). A DMF is a submission of information to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of human drugs and biological products. The FDA accepts DMFs in support of applications and supplements, such as investigational new drug applications (IND), biologics license applications (BLA), and new drug applications (NDA). DMFs are generally used to allow a sponsor or applicant to reference the material in the DMF without disclosing the contents of the DMF to the sponsor or applicant. FDA reviews information in a DMF only when a sponsor or applicant incorporates material in the DMF by reference.

Type V DMFs are accepted for facilities for production of gene- or cell- based therapies for Phase I and II clinical trials. Information on these facilities is important so the FDA can assess the safety of the products used in clinical trials of gene- or cell- based therapies. Information that may be submitted in a DMF includes:

• Floor diagrams that depict the manufacturing areas

• A list of products to be manufactured and whether equipment and areas are dedicated or shared

• Overview of production steps for all products manufactured in the facility

• Description of the containment features and contamination precautions, such as specialized equipment, air quality classification, description of the air handling units, and pressure differentials in production areas

• Screening and acceptance procedures for cell lines brought into the facility

A Type V DMF will eliminate the need for PACT CPF to submit the same information numerous times and will facilitate IND reviews. Should an approved investigator file an IND for a product to be manufactured at one of the CPF, a cross-reference letter to the DMF should be prepared by the applicable PACT facility. This will reduce the burden on the investigator to fully describe the PACT facility and production methods in their application, and maintain the facility’s confidential information from being revealed to the IND holder. The DMF should be updated regularly as improvements are made or new products and procedures are introduced to the PACT facility.


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4.2 IND/IDE Applications

The Coordinating Center (CC) or assigned CPF regulatory staff will provide technical and administrative services to requesting investigators with planned IND applications and submissions. The PACT program will be able to take on requests for regulatory services, including assistance with items listed below.

4.2.1 CMC Section Development

The CC and PACT CPF are experienced in preparing the Chemistry, Manufacturing and Controls (CMC) section of an IND in compliance with the Code of Federal Regulations (Title 21 CFR 312). An assigned regulatory specialist may assist in preparing and compiling the CMC section. A standard process will be followed to ensure that the CMC section follows the format and content requirements for submission to FDA with regard to the stage of the proposed investigation(s).

4.2.2 FDA IND Meetings

Periodic communications/meetings between a sponsor and the FDA are conducted to resolve questions and issues prior to filing an IND, and occasionally throughout the course of a clinical investigation and product development as warranted by issues and events. Product characterization and manufacturing can be addressed by PACT facility representatives and forwarded to the assigned regulatory staff for incorporation in pre-IND packages and IND submissions.

4.3 Quality Monitoring Program

The Quality Plan at each PACT facility describes objectives for quality cell processing, the means of achieving those objectives and the process for continually improving upon quality. Executive management at each facility has made a commitment to ensure that the Quality Plan is understood, implemented, and maintained at all levels of its organization. Implementation of the Quality Plan provides structure to the quality program.

The Quality Plan provides a strategic description of the quality management system that has been developed in accordance with the Foundation for the Accreditation of Cellular Therapy (FACT) guidelines, AABB guidelines, and when required, the U.S. FDA’s current Good Manufacturing Practices (cGMP) and current Good Tissue Practices (cGTP) regulations. The Quality Plan employs an organized systems approach that emphasizes thoughtful prospective planning and design to maximize the likelihood that quality standards will be achieved. Widespread monitoring is used to assess and improve performance and to prevent or minimize errors that could compromise product safety or patient outcome. The Quality Plan uses assessment elements to monitor quality standards, minimize errors, evaluate quality performance, and to determine where areas of less-than-optimal performance exist. The assessment elements of the Quality Plan


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are used to determine whether the facility is achieving quality standards, and if these standards are adequate.

PACT CPF will operate in accordance with cGMP and cGTP where applicable. Periodic surveillance inspections will assess facilities compliance with cGMP regulations. PACT CPF representatives and regulatory specialists will participate in the development of plans for implementation and maintenance of quality control and quality assurance procedures for the facilities and for the manufacturing processes for each product.

4.3.1 QA Monitoring Policy

The Quality Assurance (QA) Program is designed to ensure that manufacturing is consistently performed in a manner that yields products of consistent quality and generates records that are complete and traceable. QA is the sum of activities planned and performed to provide confidence that all systems that influence product quality are functioning as expected and can be relied upon. The QA Program is composed of the following elements: documentation control, standard operating procedure review, product release review, process validation, training, deviation reporting, records retention, quality auditing, materials management, equipment validation and calibration, and facility maintenance and monitoring. Each of these functions is summarized in standard operating procedures (SOP) at the PACT CPF.

Quality Assurance provides programs resident at the facilities with independent oversight to ensure program compliance with FDA cGMP and other regulatory and industry standards applicable to each program. Programs at the PACT CPF will also have certain QA/QC functions built into their procedures. These include, but are not limited to, routine monitoring of manufacturing processes, product testing, and verification of manufacturing documentation. Functions may be assigned to specified program QA/QC staff, or may be shared by all staff; functions will be written so that an individual will never have final oversight over his or her own work. A quality plan, manual, or SOP describing QA/QC functions and responsibilities will be prepared by each program, and will be consistent with the policy of the QA program described in this document.

PACT CPF will designate an individual responsible for QA/QC activities who will also be responsible for coordinating the review and reporting of project-related activities to the CC staff. Data from PACT CPF will be monitored and subjected to standard reviews and reports on data quality. Batch production records will be reviewed to evaluate compliance with manufacturing parameters should these materials be required as part of established IND materials provided to the FDA for each product. In-process and final product test results will be reviewed to evaluate safety, identity, purity, and potency of products as well as lot-to-lot reproducibility. Specific parameters will be developed and monitored relevant to adequate characterization of each new product. The CPF QA monitoring program will address product quality and consistent results within each CPF.


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4.3.2 Quality Monitoring Plan

PACT CPF will have a quality monitoring plan, which will include evaluation and documentation tailored to their facility of the following parameters:

• Organization

• Quality program

• Procedures

• Facilities

• Environmental control and monitoring

• Equipment

• Supplies and reagents/materials management

• Process controls

• Process changes/deviation management

• Process validation (aseptic processing; bio-burden; steps to be validated)

• Receipt and distribution

• Records (batch, production and control)

• Tracking

• Complaint files

• Storage

• Label control

4.3.3 CPF QA Monitoring

Quality improvement is a high priority for the PACT CPF. Each of the CPF has a list of quality indicators including product contamination, accidents, variances, and failure to meet release criteria etc., which are reported at periodic quality assurance meetings. Meetings are held periodically to review conditions and problems within the facilities and to try to institute system wide improvements. Summary records of these meetings are prepared and archived. PACT CPF would be expected to undertake quality improvement projects where indicated.

Procedures should be established at the PACT CPF for performing quality assessments to verify whether the quality system and the processing, storage, distribution, and administration of its products and the provision of related services comply with quality requirements, and to determine the effectiveness of the quality system.

Internal assessments at the PACT CPF should be implemented based on the importance of the activity to the quality of the product or service. These internal assessments must be conducted by


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an individual who does not have direct responsibility for the activity being assessed. In addition, the CPF are expected to participate in external quality assessments by CC and/or National Heart, Lung, and Blood Institute (NHLBI) representatives. The executive management at the PACT CPF and the NHLBI reviews the results of external assessments. Corrective and/or preventative action must be initiated and monitored as appropriate. Results of internal and external assessments are recorded. These records are maintained according to established procedures at the CPF. The CPF may be requested by the NHLBI and/or CC to provide a copy of assessments performed on PACT-supported products and any copies collected will be maintained on file at the CC.

4.3.3.1 Audits PACT CPF audits on procedures, processes, and documentation should be performed at scheduled intervals. These are usually carried out by local QA/QC staff, but may be supplemented by external auditors including the CC and/or NHLBI representatives. Items for audit are chosen based upon issues raised at QA meetings, randomly selected by the facility QA Director, or may be based on concerns or random selection of items specified by the CC or NHLBI staff. The results are documented and follow-up is performed to ensure that any identified deficiencies have been addressed and corrected. The PACT CPF should also expect and facilitate external audits by the FDA, and by customer representatives. In case of any announced or unannounced inspection by an FDA official, the PACT CPF must contact their assigned regulatory specialist and follow their facility-approved guidance for FDA inspections. If applicable the CPF may ask the CC to send a CC regulatory specialist to observe, advise, and support CPF during an FDA inspection. In addition, the PACT CPF may be examined by the State authorities from Departments of Health under the Clinical Laboratory Improvement Amendments (CLIA).

4.3.4 Corrective and Preventative Action Plans

Procedures will be established at the PACT CPF for implementing corrective and preventative action plans. Corrective and preventative action plans will be developed and implemented in response to any unsatisfactory findings during monitoring of cell processing facilities. The CC Program Director and Regulatory Specialist will work with the CPF and other resources in resolution of operational problems. The facility’s management personnel review and approve all relevant information on corrective or preventative actions taken.

Any corrective or preventative actions taken to eliminate the cause of actual or potential non-conformances are proportional to the magnitude of the problem and risks encountered. If necessary, changes to the procedures will be implemented as part of the corrective or preventative action plan.


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The procedures for corrective action include:

• Effective handling of deviation reports

• Investigation of the root cause of the deviation

• Investigation of customer complaints

• Determination of the correction action needed to eliminate the cause of the nonconformance

• Ensuring the corrective action is taken and that it is effective

The procedures for preventative action includes:

• Use of appropriate sources of information, such as quality control results, testing results, and/or customer complaints, to detect, analyze, and eliminate potential causes of nonconformance

• Determination of steps needed to deal with any problems requiring preventative action

• Initiation of preventative actions and application of controls

• Evaluation of preventative action outcomes to ensure their effectiveness


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5.0 POLICIES AND PROCEDURES FOR REQUEST FOR SERVICES APPLICATIONS (RSA)

The Coordinating Center (CC) maintains on the Production Assistance for Cellular Therapies (PACT) public website the resources needed to apply for manufacturing assistance, including general information and timelines regarding the application and approval process, a list of product manufacturing experience at the PACT Cell Processing Facilities (CPF), and Request for Services Application (RSA) evaluation criteria. The on-line application along with instructions and timelines for submission can be found on the PACT website at www.pactgroup.net under the Apply to PACT tab. The CC will maintain a database to track the life cycle of an RSA through to project completion. A new component in this iteration of PACT is the indefinite delivery/indefinite quantity (ID/IQ) Task Order Award process when approving RSAs as described in MOP Section 5.6.

5.1 Cell Processing Facilities Product Experience

The following table lists the major cell product manufacturing capabilities at the PACT CPF*:

Table 4: Cell Processing Facilities Products and Capabilities

PACT Products / Capabilities*

Progenitor Cells • c-kit+ cells (cardiac/renal) • Endothelial cells • Hematopoietic stem cells (HSC) o Aldehyde dehydrogenase-bright cells o Bone Marrow (BM) o Peripheral Blood (PB) o Umbilical placental/cord blood (UCB)

• Hepatic stem cells • Human embryonic stem cells (hESC, NIH-approved cell lines) • Induced pluripotent stem cells (iPSC) • Mesenchymal stem cells (MSC) (BM, Umbilical cord

blood/tissue) • Neural stem cells • Skeletal myoblasts • T cells - UCB-derived


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Antigen Presenting Cells/ Dendritic Cells/ Tumor Vaccines • Antigen-presenting cells o Dendritic cells/Monocytes o K562-genetically modified o Pepmix-pulsed activated T cells

• Dendritic cells o Adenovirally transduced o Apoptotic tumor cell pulsed o Transfected o Tumor lysate pulsed o Tumor-dendritic cell hybrids

• Large multivalent immunogen (LMI) vaccine (allogeneic) o Breast adenocarcinoma o Melanoma

Lymphocytes • EBV-transformed B cell lines (LCLs) • Marrow-infiltrating lymphocytes • PB-derived o Activated NK cells o CD4+/CD25+ T regulatory cells o TGFβ-induced T regulatory cells

• T cells - virus specific o Adenovirus o BK virus o Cytomegalovirus o EBV o EBV-LMP-directed o HIV o HHV-6 o Vaccinia o Varicella zoster (VZV)

• Thymidine kinase (suicide gene)-transduced T cells • Tumor-infiltrating lymphocytes (TILs) • UCB-derived CD4+/CD25+ T regulatory cells Genetically Modified Cells • Activated T cells • CAR-T cells / CAR-VSTs • Cytotoxic T Lymphocytes (TGFβ, CAR) • Dendritic cells • Fibroblasts • HSC • Neural stem cells • Tumor cells/vaccines Master/ Working Cell Banks • B95-8 EBV • Fibroblasts • hESC (NIH-approved cell lines) • iPSC • MSC • Neural stem cells • NK cell lines


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Services • Alloreactive T cell depleted (immunotoxin) • Aseptic filling • Biochemical, ELISA, Western blot analysis • Cell culture isolation, expansion, and cryopreservation

technologies • Cell Depletion/Cell Enrichment (BM/PB/UCB) o CD3/CD19 depletion o CD14 selection o CD34 selection o CD56 selection o TCR-alpha/beta depletion

• Cell manufacturing for large animal models • Counterflow elutriation • Cytokine capture technology • Estimation of product telomere length and activities • Extraction of biomarkers and gene expression • Immune monitoring • Immuno histofluorescence • Pancreatic islet cell production • Plasmid production • Potency assay development • Tumor digestion *List is not inclusive 11/2016

5.2 Scope of Product or Service Request

The types of requests to be solicited and accepted should demonstrate relevance to the scope of the National Heart, Lung, and Blood Institute (NHLBI). The application process will identify the cell therapy proposed product or service. More information regarding the evaluation criteria used for supporting translational service requests can be found on the PACT website at www.pactgroup.net under the Apply to PACT tab. RSAs possessing procedural advancements to further foster and standardize cellular therapies will be accepted and evaluated.

The following table lists some broad areas of NHLBI programmatic interest.

Table 5: NHBLI Program Areas of Interest Heart Development, Function and Disease Sleep Disorders Sickle Cell Disease

Vascular and Lymphatic Biology Cystic Fibrosis Developmental Biology and Pediatric Lung Disease

Rare and Pediatric Cardiovascular Disease Red Blood Cell Disorders Hematopoiesis and Stem Cell Biology

Peripheral Arterial Disease, Critical Limb Ischemia and Therapeutic Angiogenesis

Lung Cell and Vascular Biology Innate and Adaptive Immunology related to Heart, Lung, Blood, Sleep Diseases and Disorders

Acquired Immunodeficiency Syndrome and Tuberculosis Pulmonary Immunology and Fibrosis Molecular Genetics related to Heart, Lung,

Blood, Sleep Diseases and Disorders

Congenital Heart Defects Thrombotic Disorders Heart, Lung and Hematopoietic Transplantation

Critical Care, Trauma and Acute Lung Injury Hemorrhagic Disorders Asthma, and Chronic Obstructive

Pulmonary Disease


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5.2.1 Areas of Shared Interest

NHLBI shares many areas of interest with other National Institutes of Health (NIH) Institutes. NHLBI’s interests lie with the development, structure and function of heart, lung and blood organ systems in normal and diseased states, as well as any disease or dysfunction of other closely related organs and systems where the problem is primarily cardiac, vascular, pulmonary or blood related.

The following information identifies certain aspects of shared research interest that NHLBI will consider supporting through the PACT program. Please note that the information below is not inclusive and not all NIH Institutes and shared interests are represented. Each RSA submitted to PACT will be considered on an individual basis.

National Cancer Institute (NCI)

• Studies of effects of primary tumors of the heart on cardiac function and in non-tumor dependent angiogenesis.

• Studies of the circulatory system and lungs, tumors affecting cardiovascular or pulmonary regulation.

• Studies on hematopoietic transplant or novel cellular therapies for repair and regeneration of heart, lung, and blood diseases.

• Autologous and allogeneic transplant or cellular therapies for hematologic disorders.

National Institute of Allergy and Infectious Diseases (NIAID)

• Studies involving infectious agents including HIV, or immunologic responses where the cardiovascular, pulmonary or hematologic systems are the major targets of investigation.

• Studies of the immunology of transplantation of the heart or lung, including but not limited to studies of acute or chronic rejection, immune tolerance in the setting of heart or lung transplantation and transplantation of genetically engineered hearts or lungs.

• Studies of hematopoietic cell or progenitor cell transplantation and its complications.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

• Studies dealing with the etiology and pathogenesis of hypertension, diabetic vascular or kidney disease and their effects of hypertension; endocrine regulation of the cardiovascular system; diabetes-related cardiovascular complications; treatment and prevention of cardiovascular disease; target organ damage (e.g. kidney, heart, generalized vascular abnormalities, and cerebrovascular disease) as a function of chronic high blood pressure.

• Research that pertains to growth factors important in megakararyocytopoiesis and platelet production.


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• Research focused on the genetics, etiology, pathogenesis, treatment, and psychosocial needs of the pulmonary manifestations of cystic fibrosis.

National Institute of Neurological Disorders and Stroke (NINDS)

• Applications dealing with cerebrovascular biology and its diseases or blood disorders involving the cardiovascular system.

• Applications that involve cerebrovascular disease, abnormal blood flow, and disturbances in vascular biology.

5.3 Request for Services Application (RSA)

The RSA is submitted using the on-line application system maintained by the CC. The application system is accessed via the PACT website once the applicant has completed the registration process. The application system allows the applicant to move between the sections of the RSA and save any data entered. Applicants can access the application system at any time. The applicant will be able to view, complete and/or submit their RSA as appropriate. The CC is available during business hours to assist applicants with questions pertaining to the application or troubleshooting issues with the application system. The RSA includes requests for information in the following broad categories:

• Investigator information (Biosketch, CV, etc.)

• Study overview

• NHLBI programmatic scope

• Product information

• Current funding

• Manufacturing information

• Production methodology

• Product development

• Regulatory information

• Timeline

• Budget

• Institutional/Organizational contact information

Detailed manufacturing/procedure information and product specifications should be provided when requested and as applicable.


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5.4 NHLBI Initial Scope Review

The on-line application system allows initial scope review to be conducted using information provided by the applicant in the first section of the RSA. The applicant is strongly encouraged to complete and submit this section of the RSA in a timely manner to initiate the scope review process (refer to scope review criteria document posted on the PACT website under the Apply to PACT tab). NHLBI will review and determine whether the applicant should proceed with completing the RSA. The NHLBI may request additional information be provided by the applicant to complete their initial scope review. The CC will forward these requests to the applicant via email. Applicants are strongly encouraged to provide the requested information to the CC in a timely manner to prevent any potential delays in the review process. RSAs that do not meet the initial PACT program and NHLBI scope criteria will be rejected. The applicant may elect to complete the RSA in parallel with or wait until the NHLBI scope review is completed. If the RSA is determined to be in scope, the applicant is invited to submit the full RSA. The full RSA will undergo a quality check by the CC to ensure the requested information has been provided, followed by a scheduled full review by the Scientific Review Board.

5.5 Scientific Review Board Review

The Scientific Review Board (SRB) is an independent peer review panel with members selected by the CC from a list of individuals recommended by the NHLBI and CPF who possess scientific and pre-clinical expertise relevant to the proposed product. The potential SRB members will be reviewed by NHLBI for apparent conflicts of interest with CPF institutions and key personnel prior to the finalization of the SRB member roster. The identity of selected reviewers from the SRB will remain anonymous to NHLBI program staff. The SRB will evaluate each submitted RSA on a monthly basis, as directed by the CC. The SRB will use the NHLBI-approved SRB review questionnaire and provide a written critique for each submitted RSA. The comprehensive list of criteria for evaluation of product and service requests is posted on the PACT website under the Apply to PACT tab. The CC informs the SRB of RSA submissions requiring SRB review as soon as possible so the SRB members can begin reviewing RSAs in preparation for discussion during the scheduled monthly review calls. The SRB may request additional information be provided by the applicant to complete their review prior to the scheduled SRB call. The CC will forward these requests to the applicant via email. Applicants are strongly encouraged to provide the requested information to the CC in a timely manner to prevent any potential delays in the SRB review process. The SRB members will submit their review and provide a written critique to the CC within two weeks of the scheduled SRB review call.

5.6 NHLBI Final Review

The CC will notify NHLBI that SRB reviews and critiques have been completed and are available for NHLBI to incorporate in its overall assessment.


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Once the review is complete, NHLBI will access the online application system to record its final vote to approve or reject the RSA. The CC will notify the applicant of the outcome of NHLBI review, and if approved, will provide pertinent details regarding the CPF designation process.

5.6.1 Task Order Request for Proposal

When a RSA is approved, the NHLBI will solicit proposals via a Task Order Request for Proposal (TORFP) from the PACT CPFs. The CPFs will competitively bid to perform the work by submitting a task order (TO) proposal to NHLBI.

5.6.2 Task Order Award

NHLBI will evaluate proposals against the requirements of the TORFP and the award will be issued to one CPF in accordance with the requirements stated in the TORFP.

The awarded CPF will assist the approved investigator with the planning and initial work, which may include:

• Production requirements

• Development of product specific manufacturing and testing procedures

• Preparation of batch records

• Timelines for production

The investigator will communicate directly with the awarded CPF to finalize the services and production timeline prior to the start of any activities within the designated facility. The next steps will be dedicated to product and process validations that need to be developed specific to the product. Appropriate documentation will be provided to demonstrate satisfactory completion of each step in development and preparation for production in compliance with regulatory requirements (See MOP Section 4 - Regulatory Requirements). The designated facility will be responsible for providing assistance in generation of data to support an Investigational New Drug (IND) application, if needed, and to manufacture the product under current Good Manufacturing Practice (cGMP) and current Good Tissue Practice (cGTP) conditions.

After the TO is awarded, project implementation is expected to commence within two to six months at the assigned CPF depending on the technology transfer and service agreement process. The awarded CPF will negotiate an agreement with the approved investigator and any associated organization or institution. The agreement will define the product or service to be provided based on the approved application. The agreement is between the CPF and the designated individual or organization. The term of the agreement should not exceed the duration of the PACT program. The assigned CPF will work with the requesting investigator to further develop the production timeline and milestones.


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The PACT group expects that an agreement will be negotiated within 60 days following TO award. To expedite this effort, the CPF have worked with their legal representatives to prepare a template of the agreement that will serve as a starting place for negotiations. The terms of the agreement should be reviewed by the requesting investigator’s contract office to assess the likelihood that this approach will be acceptable to the requesting investigator and a commitment can be made by the requesting investigator to meet the 60-day requirement. Contact information for the requesting investigator’s contract representative is solicited in the RSA.

The agreement should include a budget for the funds to be expended by PACT for the product or services to be provided to the investigator. The investigator is not required to pay these funds. The budget is used for the PACT SC to monitor activities in the PACT program. Refer to Figure 18 for a schematic of the RSA process.

Figure 18: Schematic of RSA Submission and Implementation Process


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5.7 Project Progress Reports

The assigned CPF are required to generate progress reports for each approved TO that has been awarded to the CPF. The information derived from these reports is used to keep all members of the PACT program including the Expert Evaluation Panel (EEP) apprised of the status of the individual projects and to verify compliance with appropriate regulatory requirements. Information in the progress reports should include the budget, work plan, and timelines. CPFs are to provide the progress reports to the CC for review and discussion during the SC meetings. The EEP will receive a brief summary report. The list below includes, but is not limited to, the required progress report information:

• Application ID

• Principal Investigator

• Project Approval Date

• Agreement Status

• SOP Development

• Product Testing

• QA/QC Status

• Translational

o Pre-clinical studies

o Validation runs

o Practice runs

o Assay development

o Manufacturing/production status

o IND status

• Timeline

• Budget – Projected and Actual

• Publications


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6.0 CONFIDENTIALITY

The Production Assistance for Cellular Therapies (PACT) group will provide manufacturing and testing services to varying types of customers, with potential products at different stages of development where related information may be considered confidential. In addition, the PACT Cell Processing Facilities (CPF) have confidential information regarding their organization, processes, products, and services that may require review by potential customers, regulatory authorities, peer reviewers, or other parties. Certain information regarding the PACT program and CPF may be made available via the PACT website and may be considered public information.

6.1 Confidential Information

Confidential information includes trade secrets, technical data, or business data such as product definition and test data, innovative processes, related materials, or financial information. In the course of the PACT program project, materials may be provided that may contain data which parties do not want disclosed for any purpose other than the specific defined objectives such as evaluation of a product request or manufacture of a product.

All information deemed “Confidential” will be clearly identified by marking as “Confidential.”

6.1.1 Responsibility

The CPF Principal Investigator will be responsible for ensuring that all staff (and contractors, if applicable) involved in handling data (trade, technical, or business information as defined above) be familiar with and adhere to the National Institutes of Health (NIH) policy described below throughout the period of performance. When there are special contractual obligations regarding confidentiality, additional safeguards may be imposed that must be strictly adhered to. Access to or disclosure of information is limited to collaborating researchers, contractors and NIH officials who are involved in the conduct, support, review or evaluation of the research activity. PACT group members will not release, publish, or disclose sensitive information to unauthorized personnel and will protect such information in accordance with applicable laws and regulations.

6.1.2 Records

It is important to determine the information that is confidential within each project, adhere to project confidentiality standards, and comply with any contractual requirements. All confidential documents, whether electronic or hard copy, will be maintained in secure locations.

6.2 NIH Policy

The PACT program will rely on the policy entitled, “Sharing Biomedical Resources: Principles and Guidelines to Recipients of NIH Research Grants and Contracts,” to evaluate and establish


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conditions for balancing the protection of proprietary interests with facilitating product development.

Ownership and patents will be handled by agreements between the requesting Investigator’s institution and the designated CPF according to their policies.

Rights to publish will be protected.

6.3 PACT Steering Committee and Expert Evaluation Panel

Materials for review by the Steering Committee (SC) and Expert Evaluation Panel (EEP) will be prepared by the Coordinating Center (CC). A meeting report summarizing the actions taken at each SC and EEP face-to-face meeting and recommendations to the National Heart, Lung, and Blood Institute (NHLBI) will be prepared by the CC in collaboration with the SC and EEP chairs and circulated to the SC and EEP members for each meeting, respectively. These reports may contain confidential information presented at these meetings. No communication, either written or oral, of the deliberations or recommendations of the SC or EEP will be made outside the SC or EEP members. Outcome results are strictly confidential and must not be divulged to any non-member of the SC or EEP unless a recommendation to release the results has been accepted and implemented.

6.4 Scientific Review Board and Expert Evaluation Panel: Confidentiality and Conflict of Interest

Individuals serving on the Scientific Review Board (SRB) and/or EEP agree that they will keep Confidential Information strictly confidential. Additionally, these individuals will agree to disclose any affiliations, activities, interests and influences that are perceived as a potential conflict with their SRB and EEP member duties. A conflict of interest form will be provided by Emmes to the individual SRB members for signature before and after review of each assigned RSA and will serve as acknowledgment regarding conflict of interest processes of the PACT program. A conflict of interest form will be provided by Emmes to the individual EEP members for signature, as needed, and will serve as acknowledgment regarding conflict of interest processes of the PACT program

Copies of the completed COI forms will be submitted to the NHLBI Contract Office.

6.5 PACT Website

The PACT website is a portal used to provide a well-defined area for project collaborators to find and download program reference information, while maintaining an appropriate level of security for confidential information. The information posted on the website is divided into three groups:

• Public site, requiring no authorization, used to provide the general public with information about the program, including its purpose, status, sponsors, participating sites, contact information, and the ability to register to obtain access to the application system.


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• Private, secure program website component, requiring advanced password authorization and used for distributing non-sensitive project related information, including notices and agendas for meetings, conference calls, meeting minutes, protocol documents, and other non-confidential operational materials. The private portal may include sensitive project information such as progress reports, SC meeting and Working Group (WG) call summaries.

• Secure areas, requiring password authorization, include the web-based application system.


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7.0 POLICIES AND PROCEDURES FOR COORDINATING CENTER

7.1 Introduction

The Coordinating Center (CC) will be the monitor and coordinator for organizational and regulatory aspects of the Production Assistance for Cellular Therapies (PACT) program. The CC for the program will be responsible for facilitating communications with the Cell Processing Facilities (CPF) and the National Heart, Lung, and Blood Institute (NHLBI). Support will be provided for meetings, teleconferences, documentation, as well as regulatory activities. The CC has primary responsibility for coordination of Steering Committee (SC) meetings, subcommittee meetings, Scientific Review Board (SRB) meetings and the annual Expert Evaluation Panel (EEP) meeting. The CC manages the Request for Services Application (RSA) process, outreach activities for the program, and the project website to assist investigators requesting PACT services.

7.2 Communications

7.2.1 Teleconferences

Committees may meet weekly, biweekly, or monthly depending on the nature and timing of the tasks. The CC will provide an agenda, details to access the call, reminders regarding scheduling, and meeting summaries. The CC will take responsibility for tracking and follow-up for actions identified during teleconferences and as advised by the PACT CPF and NHLBI.

Items to be addressed in teleconferences may include the Manual of Procedures (MOP), standard operating procedures (SOPs), inventories, repository requirements, product requests or applications, products, Quality Control/Quality Assurance (QC/QA) plans, Investigational New Drug (IND) and regulatory requirements, customer satisfaction questionnaires, educational web seminars and other outreach initiatives, and special needs.

The program uses a service provider for teleconferences. When participants are notified of the scheduled conference call, they are provided with a telephone number and an access code. This procedure prevents unauthorized individuals from accidentally or intentionally accessing a privileged communication.

Teleconference and videoconference equipment can facilitate the participation of committee members who would otherwise be unable to attend a meeting. Additionally, the program utilizes a vendor for conducting educational web seminars.

7.2.2 Email

Posting of website materials is often accompanied by email notice to the users. To facilitate communications, email addresses and other contact information will be made available to all


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program staff. Standardized email subject lines can be developed to assist program staff in finding relevant information when needed.

7.2.3 Meetings

Scheduled face-to-face meetings identified in the statement of work include:

• SC – twice in the first year, and one per year in years 2-5

• EEP – once a year

The CC will work with the CPF and the NHLBI to make the meetings as productive as possible. Teleconferences will be used to facilitate preparations and to provide maximum focused materials for consideration in advance and at meetings.

7.2.4 Web Communications

A web-based information dissemination system will be used to address communications among the NHLBI, the CC, and the CPF. The design will include areas for group-wide and CPF-specific, or committee-specific activities. The private area of the website will provide a communications portal for the five participating CPF, SRB, EEP and the CC to foster collaboration and work contributions from all program groups. The website will be used to post meeting agendas, minutes, significant calendar events, application information, and other forms of communication that need to be distributed to the CPF, SRB, and EEP members.

7.3 Website

The public area of the PACT website will provide information regarding the scope of the program and activities of the group. Education materials, newsletters, updates, and press releases will be posted. The site will include information on the product manufacturing RSA and review process. There will be announcements and attendee registration information regarding upcoming events such as educational web seminars.

The private area of the website will be a primary resource for secure communications. The user list and access rights will be established in conjunction with the program rosters. The website will centralize document availability for the program. Documents and information areas may include: rosters, PACT MOP, data systems, reports, RSA packages, final documents, drafts in development, calendars, agendas and meeting summaries, training materials, regulatory references, other reference materials, and links. Specific areas for working groups may be established on the website to facilitate communications by making information available in a standard location on a timely and continual basis. Individuals can provide information to the administrator for posting and meetings can be scheduled. The public and private websites will use the same uniform research locator (URL) and a unique login (username/password) will be required for PACT representatives to gain access to the private website. Authorized users can access more sensitive information, such as product specific or confidential information. Product specific areas are added as needed.


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7.4 Roster

To maintain efficient communications with the various participating CPF and NHLBI staff, the CC will develop an on-line roster. This roster will list the name, title, address, e-mail address, and phone and fax numbers of all PACT members. Further, the roster will be specific to each committee page and can be accessed after logging in to the members’ area and clicking on the roster link on the page.

Members with private website access will be responsible for updating their own information as the need arises. Any new members will be added by the CC to the roster when they are given website access. It is important for each PACT member to ensure all information is up-to-date as rosters and distributions lists facilitate the ability to do targeted mailings, e.g., sending materials to all technicians or sending minutes to all participants on a committee.

7.5 Logistical Support for Meetings

The CC will support meetings, ranging from small, short conferences in the Rockville office to large gatherings involving multiple committees requiring comprehensive materials distribution and reporting services. For meetings, CC staff will:

• Prepare a roster listing contact information for meeting participants

• Poll participant availability and determine the optimum schedule for the meeting

• Select a meeting site based on costs and convenience factors

• Provide audio-visual equipment or other necessary supplies

• Provide courtesy information on facilities and attractions in the host city

• Assist committee Chair(s) in preparing the meeting agendas

• Duplicate and distribute any required materials prior to the meeting

• Staff the meeting to provide on-site administrative and technical support

• Take detailed notes, and prepare and distribute minutes of the meetings

• Respond to and follow-up on meeting action items

Collaborative activities rely on transparent and open decision-making processes. In general, the meeting minutes will be recorded by a member of the CC familiar with the important scientific, clinical, and operational issues involved. The minutes summarize important aspects of the discussions and document decisions and action items, and should be comprehensive and concise. These minutes will be available to meeting participants.


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7.6 Documentation Support

The PACT program will require support in the preparation, file maintenance, duplication, and dissemination of a variety of documents, administrative and technical reports, and manuscripts. These documents will include:

• Roster of program participants

• MOP with history of revisions

• User's Guide for Web-based Data Entry System

• Requests for Services Application (RSA) scope/evaluation criteria documents

• CPF Site visit reports

• Calendars and schedules of events

• Program meeting and conference call minutes

• Program reports and deliverables

• Program metric reports

• Bibliographies

• Abstracts

• Manuscripts for publication

• Slides and other presentation materials

• Outreach materials

When preparing these materials, the CC will work closely with the PACT CPFs and NHLBI. Beyond editorial and clerical services, the CC staff routinely assists with:

• Compiling and organizing materials

• Coordinating review and incorporating comments

• Summarizing background materials

• Writing administrative reports

• Ensuring that technical language can be understood by lay readers

• Assuring that presentations are visually effective

7.7 Metrics

The CC will develop and provide metrics to track and monitor program progress. Performance measures will be considered for the timeliness of product reviews and success of the program. Metrics reports will be used to evaluate and consider process improvements. The following areas will be monitored:


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• Applications: The application process will be monitored for time to response in various steps of the RSA submission to delivery of product. The number of applications submitted and task orders approved will be monitored and reported to the SC.

• CPF budgets: Use of PACT funds at the CPF will be monitored by the NHLBI.

• Questionnaires: Questionnaires will be collected for web seminars, and other educational initiatives, outreach activities, and customer feedback related to products and services. Results will be reported to the SC.

• Website traffic: Reports of activity to the PACT website will be developed and monitored.

Another measure of activity will be provided through the list of publications authored by representatives of the PACT program and/or approved applicants provided PACT manufactured cell products or services. A bibliography will be maintained.

7.8 Customer Satisfaction Questionnaires

A Customer Satisfaction Questionnaire form will be developed to assess the quality and the acceptability of the product or service to the requestor. For cell therapy, where product characterization requires novel and specialized approaches to development and testing, there will be extensive interaction with the requestor. Follow-up to these activities will be critically important to the program improvements. Reports of questionnaire results will be prepared and provided to the PACT SC and EEP.

Obtaining performance evaluation information is important to enable the program staff to meet the goals of the program. Since product requests will involve a significant amount of detail in order to define novel cellular therapies, there will be multiple opportunities to collect information from the customer. The CC will develop assessment tools to evaluate customer satisfaction with the staff interactions and responsiveness at the stage of product characterization, in relation to the guidance or performance on IND applications, during or following the support of study design, as well as at the point of product delivery and use. The questionnaire may be adapted based on product requests to include relevant steps in the process for review and assessment by the customer. Quality and acceptability of the product may be measured in relation to predetermined specifications. The questionnaire will be designed to take advantage of these measurement points.

Objectives and designs for the questionnaires will be based on generally available resources and references. Since these resources are not specific to cell therapies, the CC in collaboration with the CPF will appropriately adapt the proposed tools.

Reporting on process and product data to the investigators may be utilized to assess customer satisfaction. In addition, process and product monitoring reports based on manufacturing may provide a baseline performance assessment for comparison with the customer satisfaction questionnaire.


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8.0 PUBLICATION POLICY

8.1 Publication Classification

Publications are classified according to the following categories:

• Peer-reviewed publications of studies utilizing Production Assistance for Cellular Therapies (PACT) product and/or services

• Non-peer reviewed publications – Publications that pertain to the PACT program, the functional aspects of the Cell Processing Facilities (CPFs) and current scientific relevance of PACT to the scientific community

• Investigator or PACT developed slide presentations

• Outreach materials including press releases, and newsletter materials

8.1.1 Peer-reviewed Publications of Studies Utilizing PACT Product

All abstracts and manuscripts that report on studies which had cell product and/or services provided by PACT will acknowledge PACT in the publication. Standard language is required and is available from the PACT Coordinating Center (CC) for investigators to include in their abstracts and manuscripts. These publications will be tracked by the CC with assistance from the CPFs, but will not be reviewed for specific content other than appropriate acknowledgment.

8.1.2 PACT Non-peer Reviewed Publications

For non-peer reviewed publications, authors (i.e., CC or the CPFs) are recommended to submit a draft of the publication, as a courtesy, to the National Heart, Lung, and Blood Institute (NHLBI) for comments.

8.1.3 Investigator or PACT-Developed Slide Presentations

For slide presentations developed by Investigators that report on studies which have product(s) and/or services provided by PACT, standard language is required and is available from the PACT CC for investigators to include in their meeting slide presentations.

Requests for slide presentations that pertain to the PACT program, the functional aspects of the CPFs and current scientific relevance of PACT to the scientific community will be developed by the CC in conjunction with NHLBI and/or CPFs as appropriate. Slide presentations will undergo final review by the NHLBI prior to finalization and distribution.


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8.1.4 Outreach Materials

Outreach materials will be prepared by the CC in conjunction with NHLBI and the CPFs. The outreach materials will undergo final review by the NHLBI and CPFs prior to finalization and public distribution.

8.2 Intellectual Property

PACT is aware of the need to protect the proprietary interests of academic/industrial partners without compromising fundamental academic principles. As such, all collaborative agreements with industry must contain a publications clause that will, upon the request of the industrial partner, delay submission of manuscripts/abstracts for a period not to exceed 30 days to ensure that associated intellectual property rights can be protected. This principle notwithstanding, publication of the relevant data will necessarily follow academic standards and procedures. Furthermore, individual agreements with industry may override these policies in cases deemed appropriate by the NHLBI.

8.3 Archive

All investigators will be requested to provide the CC with final electronic or hard copies of the abstracts, manuscripts, and presentations. The CC will maintain a library of the publications, manuscripts and presentations titles, and electronic or hard copies.