Requirements for clinical islet laboratories

C H A P T E R

3 Requirements for clinical islet laboratories L. Rodriguez Rilo⁎,†, Renee Cercone†, Jonathan R.T. Lakey‡,§ ⁎

Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States, †Department of Surgery, Northwell Health, New Hyde Park, NY, United States, ‡Department of Surgery, University of California Irvine, Irvine, CA, United States, §Department of Biomedical Engineering, University of California Irvine, Irvine, CA, United States O U T L I N E Introduction

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Allogeneic vs autologous islet

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Registration with the FDA

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Registration with other regulatory agencies

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General requirements for a clinical auto islet lab Establishment and maintenance of a quality program

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Facilities and environmental control The vulnerability of islet cells to contamination Use of a clean room to manufacture islet cells Clean room entry and exit Training Clean room cost Environment control

56 56 57 58 58 58 58

Equipment Specific equipment needs for an auto islet lab

59 60

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Introduction Clinical islet transplantation for type 1 diabetes and chronic pancreatitis (CP) has been performed for close to four decades by a handful of institutions in the United States and around the world. Few formal regulations on cell recovery, processing, transport, and implant into patients were in place during the early years that the procedures were performed,1,2 but overtime the regulatory requirements evolved and became more clearly defined. The movement to more strictly regulate islets came through a broader effort initiated by the Food and Drug Administration (FDA)

Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas, Volume 2 https://doi.org/10.1016/B978-0-12-814831-0.00003-8

Telemedicine (communications between the operating room and the clinical islet lab)

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Personnel

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Procedures Supplies and reagents Storage Recovery Process and process controls Labeling Product tracking Records Reporting Deviation in processing

62 62 62 63 63 63 63 63 63 64

Inspections Corrective actions and process improvement Outcome analysis

64 64 64

References

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after reports surfaced from the Center for Disease Control (CDC) that HIV and other contaminated tissues were used in patients and unsafe tissues had also been imported from outside of the United States.3–8 After these discoveries, the FDA set about the task to develop a process to ensure safety by standardizing the recovery, preparation and use of human cells, tissues, and tissue-based products intended for clinical use (Table 1). A clear set of industry standards was needed since the previous regulatory framework was inadequate and fragmented. Also, due to the quickening pace of scientific advancement, demand for cellular and tissue-based products was increasing.

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© 2020 Elsevier Inc. All rights reserved.

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3.  Requirements for clinical islet laboratories

TABLE 1  Brief history of the FDA’s regulatory approach to the development of Title 21 of the Code of Federal Regulations, or CFR, section 1271, the “Tissue Rules”8–14 Timeline

History

1990s

Due to reports of HIV transmission through transplantation of human tissue and reports of potentially unsafe tissue for transplant being imported into the United States, the FDA conducted an investigation and determined the need to protect the public from transmission of diseases through the transplant of unsuitable tissue.

December 1993

The FDA published an interim final rule that was implemented immediately under the authority of the US Public Health Service Act, specifically Section 361, that authorized the creation and enforcement of regulations deemed necessary to prevent the introduction, transmission, or spread of communicable diseases.

July 1997

After public comment, a final limited rule, Part 1270, was issued in July 1997, which required certain communicable disease testing, donor screening, and record keeping for human tissue intended for transplantation.

1997

That same year, the FDA presented a consolidated regulatory approach to cover all human cells, tissues and cellular or tissue-based products (HCT/Ps), on tiered and risk-based approach, depending on the inherent risk of the cell-based product.

November 2004

The FDA issued a final rule requiring HCT/P establishments to operate following Current Good Tissue Practice (CGTP) for the collection, Screening, testing, processing, storage, labeling, packaging, and distribution of HCT/Ps to prevent the introduction, transmission, and spread of communicable diseases.

May 2005

The 2004 announcement was followed by rulemaking with public and stakeholder input, and due to its complexity, was implemented in three separate parts or rules. It was then codified under 21 CFR section 1271, and became effective on May 25, 2005.

The regulatory framework that emerged is often referred to as the “Tissue Rules,” which guide how human cells, tissues, and tissue-based products (HCT/ Ps) are manufactured; these products include both allogeneic and autologous islet cells. The overall goal of the regulations is to prevent the transmission of infectious diseases and contamination of human products that may happen during improper recovery, handling, and processing. The rules also standardize operations across institutions that manufacture tissues/cells for human use, in essence creating a common language and actions. While these regulations are essential to ensure patient safety, the resources needed to develop and maintain programs to manufacture cells for transplant, including clinical islet programs, constitute a significant barrier to the broader application of these therapies; few health-care institutions possess the resources, infrastructure, and expertise to prepare tissues/cells suitable for use in humans.

Allogeneic vs autologous islet The focus of this chapter is to outline requirements for a clinical auto islet lab, but a broader understanding of the differences between allogeneic islets for type 1 diabetes and autologous islets for CP is worthwhile since there are substantial overlaps and differences. Few health-care institutions currently process allogeneic islets for human transplant since the procedure is still considered experimental and not reimbursed by insurance providers. However, in anticipation that allogeneic islets

will become a standard of care for type 1 diabetes in the future, the establishment of a clinical auto islet lab can serve as a foundation to expand into manufacturing allogeneic islets for clinical use. The Tissue Rules, which governs both allogeneic and autologous islets are listed with the FDA under Title 21 of the Federal Code of Regulations (CFR), Part  1271, which defines human cells, tissues, and cellular and ­tissue-based products (HTC/P), including islets as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer to a human recipient.”15 These rules provide a detailed explanation of what constitutes safe manufacturing in every aspect of the process. Autologous islets are regulated solely under the Tissue Rules (Section  361 of the FDA’s Public Health Service Act) since the cells are removed from an individual (organ) and implanted into the same individual during the same surgical procedure. While the 21CFR1271 tissue regulations still apply to allogeneic islets, these rules are supplemented by other requirements. Allogeneic islets must meet a higher regulatory threshold before they can be transplanted into a patient, and fall under the more stringent regulations outlined in Section  351 of the FDA’s Public Health Service Act since allo islet cells also meet the definition of a drug. Allogeneic islets require an approved Investigational New Drug Application and Biological License (Table 2).16,17,19,20 The differences in regulations between allogeneic and autologous islets are due to the nature of the diseases and the source tissue from which the islet cells are

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Registration with the FDA

TABLE 2  Comparison of treatment and regulatory structure between allogeneic and autologous islet transplant Allogeneic islets

Autologous islets

DISEASE DIAGNOSIS Type 1 diabetes • Autoimmune disease in which patient’s immune system attacks and destroys its own pancreas • Insulin ceases to be made by patient’s pancreas

Chronic pancreatitis • Gastrointestinal disease marked by unremitting pain and destruction of pancreatic endocrine and exocrine function • No immunologic issues

PROCEDURE • When a deceased donor becomes available, a patient receives an islet transplant • Islets are isolated from each donor pancreas and injected into the recipient’s portal vein • Patient is injected with donor islets

• A patient’s pancreas is removed • Islets are isolated and injected into the portal vein • A patient is given his/her own islet cells

LONG-TERM CARE • A patient may receive more than one donor pancreas/islet transplant • A patient must take lifetime immunosuppression

• No immunosuppressive drugs are required since islets are from the patient

REGULATORY REQUIREMENTS • • • • •

FDA 21CFR1271 FDA 21 CFR Part 210 and 211 FDA 21 CFR 600, 601, 610 FDA Investigational New Drug Application16–18 FDA Biological License Application19

• FDA 21CFR1271

r­ecovered (allogeneic vs autologous donor). In an allogeneic islet transplant, islets are isolated from the pancreas of a deceased person and transplanted into the patient to treat type 1 diabetes, an autoimmune disease. Allogeneic islet recipients require lifelong immunosuppression, and often multiple islet infusions from several donor pancreases, to restore a basic level of glycemic control. Allogeneic islet transplants have had limited success and are considered experimental by the medical community. In contrast, Autologous islet transplants have been successfully carried out after pancreatectomy for CP for more than 40 years.21 Unlike type 1 diabetes, CP is a gastrointestinal disease in which the removal of the pancreas is sometimes needed to treat the unrelenting pain that is a hallmark of the disease.22–24 Since CP has nothing to do with the patient’s insulin-producing islets and is not an autoimmune disease, a patient’s islets can be re-transplanted after the pancreas is removed, during the same surgical procedure to prevent brittle diabetes. Patients are not immune to their islets, so immunosuppression is never needed. Requirements and regulations to prepare islets for transplant outside of the United States have comparable regulatory bodies. In Canada, the regulatory framework for islet cell transplant is under the purview of the Health Products and Food Branch.25 In Europe, islets are regulated by the EMEA (EU Regulatory Body).26 In Japan, the Japan Ministry of Health, Labor, and Welfare, under the Pharmaceuticals and Medical Device Agency27 govern clinical islet transplantation.

Registration with the FDA In the United States, clinical auto islet programs are required to register as Tissue Establishments with the FDA Center for Biologics Evaluation and Research (CBER), using the FDA form 335628 that can be submitted to the online HCT/P establishment registration system (eHCTERS).29 Registration is as simple as completing an electronic form that requests the necessary organizational information—legal name of the establishment manufacturing islets for transplant, director contact information, the location of the islet establishment and indication of what tissues/cells the establishment plans to manufacture for clinical use (Fig. 1).29 It also requires an indication of what will be done with the tissues/cells— that is, recover, process, store, label, package, distribute, etc. Registration should be submitted within 5 days of beginning clinical program operations.29 Allogeneic islet programs do not complete the Tissue Establishment Registration until they have an approved Investigation New Drug application and Biological License (21 CFR 207 and/or 807).29 Once the Tissue Establishment online registration form has been completed, the FDA assigns the establishment a permanent registration number. Tissue Establishment Registrations must be kept current and amended promptly with any relevant changes. Annual registration updates are also required, regardless of whether any changes were made during the prior reporting year.

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See Instructions for OMB Statement.

DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION

(FDA Establishment Identifier)

ESTABLISHMENT REGISTRATION AND LISTING FOR HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS (HCT/Ps)

FEI:

(See reverse side for instructions)

a. Bone b. Cartilage

A. Islet auto-transplantation

c. Cornea d. Dura Mater

a. PHONE b. c.

e. Embryo

EXT

SATELLITE RECOVERY ESTABLISHMENT (MANUFACTURING ESTABLISHMENT FEI NO._________________ TESTING FOR MICRO-ORGANISMS ONLY

SIP Directed Anonymous

f. Fascia g. Heart Valve

5. ENTER CORRECTIONS TO ITEM 4

h. Ligament

6. MAILING ADDRESS OF REPORTING OFFICIAL (Include institution name if applicable, number and street, city, state, country, and post office code)

i. Oocyte

SIP Directed Anonymous

j. Pericardium k. Peripheral Blood Stem

Autologous Family Related Allogeneic

l. Sclera a. PHONE 7. ENTER CORRECTIONS TO ITEM 6

m. Semen

EXT b. PHONE

n. Skin o. Somatic Cell Therapy Products

8. U.S. AGENT

r. Vascular Graft

a. E-MAIL 9. REPORTING OFFICIAL'S SIGNATURE

s. Autologous Islets t.

a. TYPED NAME

u.

b. E-MAIL

FORM FDA - 3356 (7/17)

Autologous Family Related Allogeneic

p. Tendon q. Umbilical Cord Blood

c. TITLE

SIP Directed Anonymous

d. DATE

v.

Autologous Family Related Allogeneic

Screen

Test

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Distribute

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3.  Requirements for clinical islet laboratories

4. PHYSICAL LOCATION (Include legal name, number and street, city, state, country, and post office code)

Recover

13. HCT/Ps REGULATED AS DRUGS OR BIOLOGICAL DRUGS

NO.

Types of HCT / Ps

12. HCT/Ps REGULATED AS MEDICAL DEVICES

NO.

c. DRUG FDA 2656

INACTIVE

10. ESTABLISHMENT FUNCTIONS AND TYPES OF HCT / Ps Establishment Functions

NO.

b. DEVICES FDA 2891

CHANGE IN INFORMATION

d.

PART II - PRODUCT INFORMATION

3. OTHER FDA REGISTRATIONS a. BLOOD FDA 2830

c.

11. HCT/Ps DESCRIBED IN 21 CFR 1271.10

PART I - ESTABLISHMENT INFORMATION

FORM APPROVED:OMB No.0910-0543. Expiration Date: 6/30/2020

VALIDATION--FOR FDA USE ONLY 2. REASON FOR SUBMISSION VALIDATED BY FDA: DISTRICT: a. INITIAL REGISTRATION / LISTING PRINTED BY FDA: b. ANNUAL REGISTRATION / LISTING

1. REGISTRATION NUMBER

ESTABLISHMENT REGISTRATION AND LISTING FOR HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS (HCT/Ps)

1. REGISTRATION NUMBER

FORM APPROVED:OMB No.0910-0543. Expiration Date: 6/30/2020



See Instructions for OMB Statement.

DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION

2

(FDA Establishment Identifier)

FEI:

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ADDITIONAL INFORMATION:

FORM FDA - 3356 (7/17)

Registration with the FDA

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Proprietary Name(s):

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FIG. 1  FDA HCT/P establishment registration.

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3.  Requirements for clinical islet laboratories

Registration with other regulatory agencies Each state has a regulatory framework that may require a clinical islet program to meet additional conditions before the program can start transplanting patients. For example, in New York, a facility that manufactures clinical autologous islets must register as a state tissue bank30 and complete a more comprehensive regulatory submission than what is required by the FDA. Some states may require the clinical labs that perform auto islets register as a CLIA establishment. Further, each health-care institution that processes auto islets for transplant may require their clinical islet lab to meet specific qualifications, which may include adhering to requirements of the Joint Commissions, an independent, not-for-profit organization tasked with accrediting and certifying health-care institutions within the United States,31 and/or Foundation for the Accreditation of Cellular Therapy.32 It is crucial for each clinical islet lab to understand the federal, state, and local regulations to which they must report and to work closely with their health-care institutions’ leadership and regulatory bodies to ensure buy-in and agreement on the standards to which the clinical auto islet lab must adhere.

General requirements for a clinical auto islet lab The FDA expects that health-care institutions performing clinical auto islet transplants have the regulatory components described in 21CFR1271 (Tissue Rules) in place before transplanting its first patient. Unlike allogeneic islets, in which institutions must demonstrate safety, and in some cases, efficacy, there are no such requirements for auto islet programs when completing the FDA Tissue Establishment Registration. Nor are auto islet programs compelled to ongoing reporting to the FDA as is the case with allogeneic islets operating under an IND. Therefore, it is essential that clinical auto islet labs and the health-care institutions under which they operate police themselves rigorously. The Tissue Rules provides clinical islet labs not only the foundation but also concrete guidelines from which to work safely. The following sections outline the specifics that the Tissue Rules require of labs manufacturing auto islet cells for human use. Adhering to these requirements are necessary to prevent the contamination of the clinical islet prep during the manufacturing process. Requirements include that each clinical auto islet lab has policies that address: • current good tissue practice, • establishment and maintenance of a quality program, • personnel, • procedures, • facilities, • environmental control,

• equipment, • supplies and reagents, • recovery, • processing and process controls, • labeling, • storage, • receipt, predistribution shipment, and distribution of an HCT/P, • records, • tracking, and • complaint file.

Establishment and maintenance of a quality program The development of a quality program33 is essential and should be done before a clinical auto islet lab writes its standard operating procedures (SOPs) describing specific manufacturing processes. A quality program provides the framework for clinical lab management and should include descriptions of how the lab: • establishes and maintain systems to meet core CGTP requirements, • trains personnel involved in activities related to core CGTP requirements, • ensures regulatory compliance, including policy procedure review, approval, and revision, • performs ongoing review and improvement of labs processes, • investigates, evaluates, documents, and reports contamination of the islet product, or relevant deviation to the manufacturing procedure, including how it will take short- and long-term corrective actions, and • perform periodic audits. The health-care institution, under which the islet program is housed, should have a quality program that can be used as the framework for the clinical islet lab. It should be the goal of the clinical lab to coordinate and integrate its efforts as tightly as possible with its healthcare institution to ensure consistency of mission, goals, strategies, and processes. It also makes it easier for clinical auto islet labs since the required periodic audits can be undertaken as part of the health-care institution’s overall efforts.

Facilities and environmental control The vulnerability of islet cells to contamination Islets are particularly vulnerable to contamination for several reasons.

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Facilities and environmental control

First, the starting materials—the excised pancreas, comes from a hospital operating room where aseptic procedures are not under the same strict control as a clean room, due to technical and other environmental limits, which means contamination can be brought into the process from the pancreas itself, and transported to the clinical lab. Second, patients who undergo auto islet transplant often endure multiple pancreatic interventions before the surgery, including previous endoscopic or surgical interventions. The manipulation of the main pancreatic duct that is done during these interventions can randomly transfer bacterial flora from the intestinal tract into the drainage system of the pancreas.34 The presence of microbial contaminants is relatively common in the transport solution in which the excised pancreas is transported for islet processing. Since islet cells are isolated and washed, but not wholly purified during autotransplantation, final transplant solutions can be contaminated. Allotransplantation of contaminated transplant solutions has also been documented in the literature, despite purification of harvested pancreata. Despite the incidence of microbiological contamination, islet transplantation procedures continue to be used to treat CP and diabetes.35–37 It is, therefore, essential to implement a robust microbiology surveillance program. Samples from critical time points—transport solution from the operating room to the clinical lab, reagents used to process cells before contact with the pancreas, and the final transplant prep which is taken back to the operating room (OR) for implant should be collected in sterile containers per manufacturer’s recommendations and sent for microbiological surveillance, testing each of the different samples for up to 14 days postislet infusion.34,38 Finally, some of the larger laboratory equipment— incubators, centrifuges, refrigerators, and microscopes, used in islet cell manufacturing, are not generally designed to undergo automated decontamination cycle, thereby increasing the risk of contamination.

Use of a clean room to manufacture islet cells Given these factors, sterility in islet cell processing represents a challenge from a good tissue practice perspective. It is for these reasons that the majority of clinical auto islet programs process pancreas in a clean room facility, making the control of contaminants easier to manage. It is not an FDA requirement, and autologous islets can be processed in an operating room39 or another facility if needed, but clean room use is recommended since these facilities are constructed specifically to prevent the possible contamination of human tissues and cells. Clean rooms are specially constructed to reduce particulate contamination and control other environmental parameters such as temperature, humidity, and pressure. Monitoring particulates are difficult outside of a clean room environment since contaminants are generated not only by people and the process of isolating tissues but also by the equipment, air, and facility itself. Clean rooms must be maintained and particles continually removed from the air. One of the significant benefits of using a clean room is the positive pressure environment that is managed by an independent air handler and held at the controlled temperature and humidity to ensure that all laboratory equipment is at no risk of contamination. All the air delivered to a clean room passes through high-efficiency particulate air (HEPA) filters, eliminating the introduction of all external particles. Air quality is monitored 24 h a day by an in-house air particle counter. Air pressure monitors are installed and are attached to security alarm systems in the event of low pressure. Clean rooms are classified according to the number and size of the particles permitted per volume of air, designating how clean the air is. In the United States, the number of particles equal to and greater than 0.5 mm is measured in one cubic foot of air, and it is this count that is used to classify the clean room (Table 3).

TABLE 3  Clean room airborne particulate cleanliness classes (by cubic meter) Maximum concentration limits (particulates/m3 of air) for particles equal to and larger than the tabulated size

ISO classification number

0.1 μm

0.2 μm

ISO Class 1

10

2

ISO Class 2

100

ISO Class 3

0.3 μm

0.5 μm

24

10

4

1000

237

102

35

8

ISO Class 4

10,000

2370

1020

352

83

ISO Class 5

100,000

23,700

10,200

3520

832

29

ISO Class 6

1000,000

237,000

102,000

35,200

8320

293

ISO Class 7

352,000

83,200

2930

ISO Class 8

3520,000

832,000

29,300

ISO Class 9

35,200,000

8320,000

293,000

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1 μm

5 μm

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3.  Requirements for clinical islet laboratories

Clean room entry and exit Clean rooms are constructed to have an anteroom or antechamber, an area right outside of the clean room where staff gown up before entering the clean room to prevent contaminated air from entering. The anteroom is usually equipped with a sink, cabinets, bench, etc. It can be engineered as an ISO 7 or ISO 8 environment depending on the risk level of the sterile products being prepared in the critical area (Fig. 2). Clean rooms come equipped with self-contained air showers, located between the anteroom and clean room to effectively remove surface-deposited particles from staff prior to entering the clean room (Fig. 3). Pass through window are also used to allow for the transfer of materials in and out of the clean room without contamination (Fig. 4). The clean room, anteroom, air shower, and pass-through windows, should be designed with a closing (interlock) system that allows staff to open only one door (or window) at a time—that is, the anteroom door must be closed before staff can open the door to the air shower, etc.

Training Staff who work in the clean room must undergo training, in addition to regular good tissue practice training on islet isolation processes and contamination control since they enter and exit the clean room through airlocks, gowning rooms, and/or air showers. They must wear distinct clothing designed from materials that would not release particles or fibers into the clean room environment. Garments include coveralls, booties, bouffant caps, face masks, lab coats, gowns, gloves, and sleeves. The entire clean room space (anteroom, air shower, clean room, and pass through window) should be lim-

FIG. 3  AIR SHOWER located between the anteroom and the clean room. The air shower quickly and effectively removes contaminants that would otherwise be carried into the clean room.

ited to authorized personnel only, using biometric or other identification for entry.

Clean room cost The cost for clean room construction can range anywhere from $1 million to several million dollars, making its build out the most cost-prohibitive aspect of developing an autologous islet program (Fig. 5). A less costly modular clean rooms is an option, as is the rental of space, or contracted services, with the local tissue bank, or another bio-manufacturing site with clean room accessibility, or the ability to process tissues under aseptic conditions. These may offer attractive alternatives to a significant outlay of capital since tissue banks, especially, have the infrastructure in place to comply with the federal, state, and tissue bank regulations.

Environment control

FIG.  2  ANTEROOM between the clean room and less clean area outside. Personnel gown up in this area before entering clean room.

Environmental control is a requirement for clinical islet labs since there is a reasonable risk of contamination or cross contamination of the islet cell product.40 As mentioned in the previous section, clean rooms offer

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FIG. 4  Pass through: view from (A) outside and (B) inside of a clean room. The pass through is used for the contamination-free transfer of the pancreas in and out of the classified environment.

FIG. 5  Clean room for islet isolations.

the ideal setting for control of the clinical manufacturing environment. Regardless of whether a clinical islet lab performs its manufacturing in a clean room, operating room, or another laboratory facility, it is required that the lab system has: • temperature and humidity controls; • ventilation and air filtration; • cleaning and disinfecting of rooms and equipment to ensure aseptic processing operations; and • maintenance of equipment used to control conditions necessary for aseptic processing operations. Clinical islet labs are required to inspect their environmental control systems on a periodic basis to make sure that the system and equipment are adequate and functioning properly. As with all aspect of managing a clinical islet lab, environmental monitoring must be documented and records maintained on all procedures. In addition to air quality, equipment such as the biological safety cabinets must be disinfected before and

a­fter use and monitored for air particle counts and growth of microorganisms. Biological safety cabinets and vent filters in the clean room are inspected periodically according to the defined schedules. The storage devices (freezers, refrigerators) for islet products must be monitored continuously by an alarm system for proper temperature, CO2 level, and relative humidity, as applicable.

Equipment Critical equipment is defined as equipment used in the procurement, processing, testing, cryopreservation, storage, transportation, and administration of the islet product.41 It is important to choose equipment appropriate in design for its use. It also must be suitably located within the room where clinical islets will be manufactured so it can be installed and run as specified (Fig. 6). Equipment must be cleaned, sanitized, and maintained according to the established schedules.

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FIG. 6  Imaging and sampling.

Automated, mechanical, electronic, or other equipment used for inspection, measuring, or testing must be capable of producing valid results. All cleaning, calibration, and activities performed on equipment must be documented and records maintained. These records must be displayed on or near each piece of equipment. All critical equipment is required to have a unique identifier and monitored to ensure that cleaning is being performed and that the equipment is functioning correctly and within predetermined specifications. Each islet product, including date and time manufactured, must be included in equipment records. Following these steps minimizes the introduction, transmission, or spread of communicable diseases. The FDA requires that programs establish and maintain procedures to clean and maintain equipment to prevent malfunctions, or other events that could negatively affect the islet cell product, and must routinely calibrate equipment according to the established procedures and schedules. The monitoring of equipment falls into one of three categories: validation, quality control (QC), or preventative maintenance. Validation: Equipment should be validated upon installation, after it is relocated or undergone a repair or an upgrade. QC: QC programs are those processes put in place to ensure ongoing proper cleaning and functioning of equipment. QC records should be reviewed

after each transplant and monthly to monitor the functioning status of equipment. Preventative maintenance: Preventative maintenance and calibration (if needed) should be performed, as required, according to the manufacturer’s recommendations.

Specific equipment needs for an auto islet lab While equipment budgets can run into seven figure numbers, there is some basic equipment that a clinical auto islet lab needs to manufacture cells for transplant. For the digestion and isolation of cells: (1) a digestion chamber is needed, as is (2) a COBE to purify preps, (3) a self-contained clinical biohazard vacuum and disposal system, and (4) a dedicated enzyme chiller. For the maintenance and culture of islets, a program should have at least three class 2 biological safety cabinets for isolate isolation, recombination, final preparation, packaging, labeling, counting, sampling, and final microbiological surveillance sampling. Other equipment should include: • incubators, • thermo Sorvall RC + refrigerated centrifuges, • low-temperature incubator, • integrated systems to deliver medical-grade compressed oxygen, nitrogen, and carbon dioxide, and • liquid nitrogen delivery system to support freezers.

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For analysis of the islets cells a good microscope with image capture fluorescent (DAPI, Cy2, Cy3) stereoscope equipped with a motorized stage controlled by custom script for automated image capture and stitching, transmitted light, and a ring light, and a fluorescent (DAPI, Cy2, Cy3) stereoscope equipped with a motorized stage controlled by Axiovision for automated image capture and stitching, transmitted light, and a ring light. For reagent and chemical support: • ultrapure water generator, • water baths, • refrigerator and freezers, including: −80°C ultralow freezer, −20°C enzyme freezer, and −30°C enzyme freezer, • medium sterilizer, • table top centrifuges, and • extensive chemical library with basic pH and reagent-making equipment. For imaging capabilities inverted fluorescent microscope (four filter set), and a fluorescent stereoscope (three filter set), microscopes coupled to high-density CCD cameras to take micrographs and visualize the data. Other wet laboratory support equipment fluorescence (full spectrum), luminescence, and absorption automated plate reader with top and bottom plate reading with sipping attachment and computer control, and endotoxin detection system.

Telemedicine (communications between the operating room and the clinical islet lab) While not an FDA requirement, the investment in a good telecommunication system between that allows the clinical islet lab converse with the operating room is a good addition (Fig.  7A and B). The system allows

(A)

for the OR and lab to communicate throughout the process, so the lab is ready to receive the excised pancreas and the OR is ready for the return of the pancreas for implantation.

Personnel Clinical auto islet labs should employ an adequate number of qualified persons to manufacture islet for transplant.42 There are fewer regulatory and programmatic obligations to process auto islets, compared to allo islets, so less staffs are needed. In the auto islet manufacture process, there are no lot release criteria that must be met before release of the islet product for transplant—all preps are transplanted unless some catastrophic event happens to the islet cells during the manufacturing process. Purification is optional. Therefore, three trained staff persons could perform a clinical auto islet isolation. Generally, there is 1-day prep before the transplant, a full day’s work the day of the transplant, and work to clean up and perform assessments following the transplant. The minimum three staffpersons does not include quality personnel, who should be separate from the team who manufactures islet cells. Training should be provided on all tasks employees are expected to perform, using a nontransplant mock isolation environment before participating in an actual clinical isolation. Personnel should first observe a more experienced staff person perform the task, and then complete the task several times under the observation of the trainer. In addition to learning islet processing, all staff, regardless of laboratory experience, should be trained in lab safety and quality issues as defined under the Tissue Rules. These FDA regulations are even more rigorous than general lab safety programs.

(B)

FIG. 7  Telemedicine between (A) operating room and (B) clinical islet lab.

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It is essential that detailed documentation of training is filed in the employee’s personnel folder, along with employee’s job description and resume, since these are documents the FDA and other regulatory agencies would review should there be an audit. It is equally important to demonstrate by evidence (i.e., education, experience, history of manufacturing islets) that staff who train employees are themselves qualified to provide the training.

Procedures Clinical auto islet labs must develop and maintain SOPs that cover core cGTP requirements.43,44 The SOPs fulfill the dual purpose of describing in detail the processes and methods to manufacture islets for transplant as well as the procedures implemented to prevent the risk of introducing, transmitting, or spreading contaminants or diseases to the islet prep. There are specific requirements that each SOP should meet (Table 4). SOPs should be revised as needed and reviewed on a periodic basis, following the guidelines laid forth in the clinical islet lab’s quality program. SOPs should always be available to personnel in the area where the work is performed and available if an audit was conducted.

Supplies and reagents Supplies and reagents used in the islet manufacturing process must be purchased from reliable vendors and include documentation of sterility. Upon receipt, a visual inspection for damage or evidence of contamination should be performed and documented. Supplies, reagents, and chemicals that show any sign of compromise should not be used in the clinical manufacturing process. Records must be maintained that show (a) record of receipt, (b) date of receipt, (c) expiration dates, (d) lot, (e) records from vendor of reagent verification, including tests results where appropriate, and (f) certificate of analysis.45

Storage All areas that house the reagents, chemicals, and other isolation supplies used in the clinical islet manufacturing process must be maintained to prevent mix-ups, contamination, or cross contamination. Supplies must be stored at appropriate temperatures and lighting per the manufacturer’s directions. Critical reagents and supplies should be quarantined 2 weeks before use. Even supplies from reputable vendors should be quarantined for 2  weeks before they are used. No reagents, chemicals, or other supplies can be used after their expiration date and must be removed immediately from the clinical inventory.46

TABLE 4  Standard operating procedure requirements SOP section

Content

Header

The document should have a title, document number, and version. The header should make apparent the activity covered under the SOP.

Revision history

Record the changes made to a procedure and justification of why the procedure was created.

Author(s)

Key roles include the Author, Reviewer, Approver, and Quality Reviewer/Approver.

Approval

The approval is generally found on the cover page. Each health-care institution is different, and the SOPs may require more than one approval signatures.

Purpose

The purpose should summarize the intent of the SOP in one or two sentences. It should be detailed enough so users can recognize what the document covers.

Scope

The scope should define to whom or what the particular set of procedures applies.

References

The SOP should include references and related documents that are needed in addition to the SOP to understand and execute the procedure described in the text.

Definitions

The SOP should define terms that may be unfamiliar to users and spell out acronyms and abbreviations used in the document.

Roles and responsibilities

Define the personnel responsible for performing activities written in the procedure.

Procedure

This is the critically important section of the SOP. The FDA wants to ensure that standards meet compliance expectations. It is also equally important to remember that the FDA and other regulatory agencies will hold clinical islet labs to the standards outlined in the written procedures, evaluating whether the standards and practices described have been maintained.

Appendices/attachments

These documents are often blank worksheets and flow charts that serve as an aid in explaining the procedures.

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Procedures

Clinical islet programs should keep inventory receipt logs for all critical supplies and reagents, including manufacturer, lot numbers, and expiration dates. The manufacturer, lot number, and expiration date of critical reagents and supplies used in the manufacture of each cellular therapy products must be documented on the collection and processing worksheets.

Recovery All efforts to recover islets from the excised pancreas must use caution and follow the SOPs to ensure that no contamination or cross contamination is introduced during the manufacturing process.47

Process and process controls Generally, the auto islet manufacturing process validates and approves the process through its SOPs since the product itself is transplanted before microbiological surveillance is completed. Policies, methods, and protocols should be established and designed to avoid contamination of the islet cell product, maintaining the product’s function and integrity, and prevent the introduction, and transmission of infectious disease microorganisms.48 Process monitoring is accomplished using defined procedures for measuring and assaying the islet products. Since autologous islets are transplanted immediately after isolation/collection, cell counts are performed on all products to document islet count and islet equivalents. Each critical manufacturing step in the islet processing procedure is recorded and reviewed by the appropriate staff. Final review and approval for release is accomplished by the director or approved designee before transplant. The manufacturing steps and the results of product viability testing postislet isolation become part of the permanent record for the product, each given a unique identifier. The clinical islet lab uses aseptic methods designed to minimize contamination of the cellular therapy product. Ongoing monitoring of the efficacy of aseptic methods occurs through quarterly internal audits and analyses of the islet product sterility assay data.

Labeling The establishment of procedures to control and label the islet product is part of the requirements under the Tissue Rules.49 Auto islets are rarely if ever, prepared with other cellular products. Nonetheless, preps should be labeled for proper identification, and all samples, assessments, etc. should contain a label that easily references it to the organ from which the islets were isolated and include a distinct identification code affixed to all products, samples, etc. related to the specific islet prep.

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Product tracking For each clinical cellular therapy product, a unique identification number is assigned which allows tracking of the product through the isolation procedure to the final disposition to the patient in the OR.50 For each clinical cellular therapy product, a chain of custody form should follow the product throughout the process and will include names, signatures, and dates for each step in the process. A copy of the chain of custody should reside in the islet processing lab, operating room records system, and patient record.

Records Records management is an essential requirement of programs operating under the Tissue Rules.51 Documents about each particular islet product must be created to facilitate a review of the islet product’s history before taking the tissue to the operating room for implant, and, for follow-up evaluation or investigation as needed. Records must be accurate and legible. It is important for records to identify the person performing the work and the dates, and must be as detailed as necessary to provide a complete history of the work performed on the islet product. Other records pertinent to the manufacture of the islet products (i.e., labeling, equipment logs, equipment cleaning, etc.) must also be maintained and organized under the records management system. Record retention is vital for clinical islet labs as part of the Tissue Rules. Programs must keep records of individual islet products that were manufactured for transplant for at least 10 years.

Reporting Auto islets are not under the same strict FDA oversight as allogeneic islet programs, but clinical labs must adhere to the Tissue Rules when it comes to reporting adverse reactions.13 Since transplants are autologous, and patients are tested for infectious diseases presurgery, it would be extremely rare, if not nearly impossible, for a communicable disease to be transmitted to a patient during the auto islet manufacturing process. However, a clinical islet program must investigate any adverse reaction involving an infectious disease of an autologous islet patient.52 Microbiology results would confirm whether a disease was transmitted during the manufacturing. If this should happen, the event must be reported to the FDA as an adverse reaction, if it is (a) fatal, (b) life threatening, (c) results in permanent impairment of a body function or damage to body structure, or (d) necessitates medical or surgical intervention, including hospitalization. The

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reaction must be submitted to the FDA using the electronic reporting system within 15 calendar days of initial receipt of the information.53

Deviation in processing Deviations in a procedure that poses a threat to the final islet product must be recorded on a deviation form as described in the Tissue Rules.53 Each report must contain a description of the islet product deviation, information relevant to the event and the manufacture of the islet product involved, and information on all follow-up actions that have been or will be taken in response to the deviation. A clinical islet lab must report deviation that relates to a core CGTP requirement on Form FDA 3486 within 45 days of the discovery of the event.54 Planned deviations in manufacturing can be approved by the director or senior staff to ensure that the deviation will not adversely affect the purity, potency, or efficacy of the cellular therapy product, and are documented on the deviation form, along with the rationale for the planned deviation. Planned deviations do not need to be reported.

Inspections Clinical islet labs must permit inspections from the FDA at any reasonable time and manner to determine the lab’s compliance with the Good Tissue Rules.55–57 No advanced notice is required from the FDA, and in most cases, none is given. The FDA is not required to obtain a warrant for permission to inspect a lab before conducting an investigation. Therefore, clinical islet labs should always be prepared for an inspection. The FDA inspectors are entitled to inspect only those areas directly engaged in the processing (preparation, isolation, assessment) of human islets, including the clinical islet lab (clean room, anteroom, air showers, rooms where reagents are stored, sterilized, etc.), equipment, finished and unfinished materials, containers, processes, procedures, labeling, records, files, papers, and other information required to be maintained according to the regulations. The FDA inspectors also have authority to review and copy documents, take samples, and use other appropriate methods to gather information and make observations as deemed necessary. As part of the clinical lab’s quality program and SOPs, the lab should have a designated person(s) to act as the direct communicant with the FDA during the inspection. The health-care institution’s legal counsel should also be notified immediately. However, the FDA inspector may question any of the clinical islet lab personnel as the inspector deems necessary.

The clinical islet lab should verify the identification of the FDA inspector and proactively request information on (a) why the inspection is being conducted, (b) scope of the inspection, and (c) agree on an agenda for the inspection. The lab contact should remain with the FDA investigator at all times and record the inspector’s questions, comments, suggestions, etc. The clinical lab representative should also make duplicate copies of information collected by the FDA—samples, records, and other materials. The FDA inspector must provide the clinical islet lab contact with a written statement of factual observations detailing any condition or practices that may not comply with the new interim regulation. The clinical lab representative should verbally confirm that the inspector was not denied any information to which the inspector was entitled. Within approximately 7 days of the inspection, with the consultation of legal counsel, the clinical islet lab should respond to the FDA in writing to each observation, and include: 1. identification and explanation of inaccuracies, 2. demonstration, where appropriate, that a practice or condition, in fact, complies with applicable regulations, 3. description, where appropriate, proposed corrective actions, and 4. obtain a copy of the Establishment Inspection Report by filing a request under the Freedom of Information Act (FOIA).

Corrective actions and process improvement Even if no FDA inspection takes place, clinical islet labs should continually improve their operations and take immediate and long-term corrective actions or make improvements to process based on information provided by an internal review of processes, audits, individual observations, and deviation occurrence reporting.44 Process improvement activities aimed at the detection, prevention, or correction of problems should be discussed on a regular basis at clinical lab staff meetings.

Outcome analysis The clinical islet lab team should review the isolation data of all autologous transplant recipients after each isolation and conduct more extensive reviews on a quarterly basis. Data from these reviews should be presented at the health-care institution’s quality assurance meetings on an annual basis at a minimum.

References 1. Ricordi  C, Tzakis  AG, Carroll  PB, et  al. Human islet isolation and allotransplantation in 22 consecutive cases. Transplantation. 1992;53(2):407–414.

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2. Carroll  PB, Ricordi  C, Rilo  HR, et  al. Intrahepatic human islet transplantation at the University of Pittsburgh: results in 25 consecutive cases. Transplant Proc. 1992;24(6):3038–3039. 3. Mascola L, Guinan ME. Screening to reduce transmission of sexually transmitted diseases in semen used for artificial insemination. N Engl J Med. 1986;314:1354–1359. 4. Centers for Disease Control. Testing donors of organs, tissues, and semen for antibody to human T-lymphotropic virus type III/ lymphadenopathy-associated virus. MMWR. 1985;34:294. 5. Berry  WR, Gottesfeld  RL, Alter  HJ, Vierling  JM. Transmission of hepatitis B virus by artificial insemination. JAMA. 1987;257:1079–1081. 6. Clarke  JA. HIV transmission and skin grafts (Letter). Lancet. 1987;1:983. 7. Compliance Program Guidance Manual Inspection of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) 7341.002. The Food and Drug Administration; 2005. 8. Erice A, Rhame F, Sullivan C, Dunn D, Jackson B, Balfour Jr. HH. Human immunodeficiency virus (HIV) infection in organ transplant recipients (OTRS). In: IV International Conference on AIDS Book 2 Stockholm, June 12–16; 1988:363. 9. Centers for Disease Control. Human immunodeficiency virus infection transmitted from an organ donor screened for HIV antibody--North Carolina. MMWR. 1987;36:306–308. 10. Kessler  DA, Siegel  JP, Noguchi  PD, Zoon  KC, Feiden  KL, Woodcock  J. Regulation of somatic-cell therapy and gene therapy by the Food and Drug Administration. N Engl J Med. 1993;329(16):1169–1173. 11. Food and Drug Administration. Points to Consider in Human Somatic Cell Therapy and Gene Therapy. Rockville, MD: Center for Biologics Evaluation and Research; 1991. 12. Public Health Service Act, 42 U.S.C. Section 262, Section 351. 13. Code of Federal Regulations. 21 § 1271, 3d. 2006. 14. Department of Health and Human Services, The Food and Drug Administration. Application of current statutory authorities to human somatic cell therapy products and gene products; notice. Fed Regist. 1993;58(197). Thursday, October 14. 15. Food and Drug Administration, ed. Human Cells, Tissues, and Cellular and Tissue-Based Products. Food and Drug Administration; 2017. 21 CFR 1271. 16. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice. Food and Drug Administration; September 2004; 69 FR 59258. 17. US Department of Health and Human Services, Food and Drug Administration. The Code of Federal Regulations. Title 21: Food and Drugs, Parts 210 and 211. 2018 18. US Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice; September 2004. http://www.fda.gov/CbER/gdlns/steraseptic.pdf. 19. Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products. The Food and Drug Administration, Center for Biologics Evaluation and Research; September 2009. 20. Yamamoto T, Horiguchi A, Ito M, et al. Quality control for clinical islet transplantation: organ procurement and preservation, the islet processing facility, isolation, and potency tests. J Hepatobiliary Pancreat Surg. 2009;16(2):131–136. 21. Robertson RP, Lanz KJ, Sutherland DE, Kendall DM. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes. 2001;50(1):47–50. 22. Rodriguez Rilo HL, Ahmad SA, D’Alessio D, et al. Total pancreatectomy and autologous islet cell transplantation as a means to treat severe chronic pancreatitis. J Gastrointest Surg. 2003;7(8): 978–989.

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23. Clayton  HA, Davies  JE, Pollard  CA, White  SA, Musto  PP, Dennison  AR. Pancreatectomy with islet autotransplantation for the treatment of severe chronic pancreatitis: the first 40 patients at the leicester general hospital. Transplantation. 2003;76(1):92–98. 24. Gruessner  RW, Cercone  R, Galvani  C, et  al. Results of open and robot-assisted pancreatectomies with autologous islet transplantations: treating chronic pancreatitis and preventing surgically induced diabetes. Transplant Proc. 2014;46(6):1978–1979. 25. Health Products and Food Branch, eds. Safety of Human Cells, Tissues and Organs for Transplantation Regulations. Canada: Health Products and Food Branch; 2015. SOR/2007-118. 26. European Medicines Agency. Scientific Recommendation on Classification of Advanced Therapy Medicinal Products. European Medicines Agency; 2018. Article 17. Vol. 1394/20072011. 27. Japan Pharmaceutical Manufacturers Association. Pharmaceutical Administration and Regulations in Japan. 2018. 28. Food and Drug Administration. Electronic Human Cell and Tissue Establishment Registration (eHCTERS). https://www.fda.gov/Biologics BloodVaccines/GuidanceComplianceRegulatoryInformation/ EstablishmentRegistration/TissueEstablishmentRegistration/ ucm147970.htm; 2018. Accessed 16 July 2018. 29. Food and Drug Administration. Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs That Are Regulated Under a Biologics License Application, and Animal Drugs, and the National Drug Code. Food and Drug Administration; 2017. 21 CFR 207. 30. New York State Department of Health. Tissue banks and nontransplant anatomic banks. In: New York Codes Rules and Regulations Part 52. New York State Department of Health; 2007. 31. The Joint Commission. What is Certification? https://www.jointcommission.org/certification/certification_main.aspx; 2018. Accessed 16 July 2018. 32. The Foundation for the Accreditation of Cellular Therapy. http:// www.factwebsite.org; 2018. Accessed 16 July 2018. 33. Code of Federal Regulations, The Food and Drug Administration. Establishment and Maintenance of a Quality Program. April 1, 2017. Sec. 1271.160. 34. Wray CJ, Ahmad SA, Lowy AM, et al. Clinical significance of bacterial cultures from 28 autologous islet cell transplant solution. Pancreatology. 2005;5(6):5562–5569. 35. Colling  KP, Blondet  JJ, Balamurugan  AN, et  al. Positive sterility cultures of transplant solutions during pancreatic islet autotransplantation are associated infrequently with clinical infection. Surg Infect (Larchmt). 2015;16(2):115–123. 36. Berger MG, Majumder K, Hodges JS, et al. Microbial contamination of transplant solutions during pancreatic islet autotransplants is not associated with clinical infection in a pediatric population. Pancreatology. 2016;16(4):555–562. 37. Bucher P, Oberholzer J, Bosco D, et al. Microbial surveillance during human pancreatic islet isolation. Transpl Int. 2005;18(5):584–589. 38. Qi M, Omori K, Mullen Y, et al. Prophylactically decontaminating human islet product for safe clinical application: effective and potent method. Transplant Direct. 2016;2(2):e63. 39. Fan CJ, Hirose K, Walsh CM, et al. Laparoscopic total pancreatectomy with islet autotransplantation and intraoperative islet separation as a treatment for patients with chronic pancreatitis. JAMA Surg. 2017;152(6):550–556. 40. Code of Federal Regulations, The Food and Drug Administration. Environmental Control and Monitoring. April 1, 2017. 21 CFR 1271195. 41. Code of Federal Regulations, The Food and Drug Administration. Equipment. April 1, 2017. 21 CFR 1271.200. 42. Code of Federal Regulations, The Food and Drug Administration. Personnel. April 1, 2017. 21 CFR 1271.170. 43. Code of Federal Regulations, The Food and Drug Administration. Procedures. April 1, 2017. 21 CFR 1271.180.

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44. Code of Federal Regulations, The Food and Drug Administration. Prevention of the Introduction, Transmission, or Spread of Communicable Diseases. April 1, 2017. 21 CFR 1271.145. 45. Code of Federal Regulations, The Food and Drug Administration. Supplies and Reagents. April 1, 2017. 21 CFR 1271.210. 46. Code of Federal Regulations, The Food and Drug Administration. Storage. April 1, 2017. 21 CFR 1271.260. 47. Code of Federal Regulations, The Food and Drug Administration. Recovery. April 1, 2017. 21 CFR 1271.215. 48. Code of Federal Regulations, The Food and Drug Administration. Processing and Process Control. April 1, 2017. 21 CFR 1271.220. 49. Code of Federal Regulations, The Food and Drug Administration. Labeling Controls. April 1, 2017. 21 CFR 1271.250. 50. Code of Federal Regulations, The Food and Drug Administration. Product Tracking. April 1, 2017. 21 CFR 1271.290. 51. Code of Federal Regulations, The Food and Drug Administration. Records. April 1, 2017. 21 CFR 1271.270. 52. Code of Federal Regulations, The Food and Drug Administration. Complaint File. April 1, 2017. 21 CFR 1271.320.

53. The Food and Drug Administration, ed. Human Cells, Tissues, and Cellular and Tissue-Based Products. The Food and Drug Administration; 2017. 21 CFR 1271. 54. The Food and Drug Administration. General Instructions for Completing the Biological Product Deviation Report (BPDR)—Form FDA 3486. https://www.fda.gov/BiologicsBloodVaccines/Safety Availability/ReportaProblem/BiologicalProductDeviations/ ucm129716.htm; 2018. Accessed 16 July 2018. 55. Code of Federal Regulations, The Food and Drug Administration. Inspection and Enforcement of Establishments. Applicability. April 1, 2017. 21 CFR 1271.390. 56. Code of Federal Regulations, The Food and Drug Administration. Inspection and Enforcement of Establishments. Inspections. April 1, 2017. 21 CFR 1271.400. 57. Code of Federal Regulations, The Food and Drug Administration. Inspection and Enforcement of Establishments. Orders of Retention, Recall, Destruction, and Cessation of Manufacturing. April 1, 2017. 21 CFR 1279.440.

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