Page 1732 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 97

GRAFT ENGINEERING AND CELL PROCESSING

Adrian P. Gee

Hematopoietic stem cell transplantation (HSCT) originated using and, important for this discussion, minimally manipulated BM for
bone marrow (BM) cells from allogeneic donors. Sources of cells have homologous use and not combined with another article. This there-
subsequently increased to include autologous marrow, growth factor- fore means that traditional HSCTs do not fall under FDA regulations,
mobilized peripheral blood, umbilical cord blood, and placenta. In and that these procedures are currently considered practice of
this chapter, the ex vivo processing of these cells and other cells used medicine.
in the context of HSCT is reviewed. Processing may range from With the exceptions noted, most other cellular therapy and HSCT
simple depletion of ABO-incompatible red blood cells (RBCs) or products fall under IND regulations and are referred to as Type
plasma, to more complex procedures designed to engineer the graft 351 products. These are cells that have been cultured ex vivo and
components to enhance engraftment, prevent graft-versus-host transduced or activated ex vivo, and therefore are more than mini-
disease (GVHD), or to introduce genetic modifications into the cells. mally manipulated. The facility processing these cells is required to
Facilities performing these procedures are often involved in other operate under GMP. These regulations were originally developed for
types of cellular therapies. These include provision of cells for adju- the pharmaceutical industry to ensure that drugs are manufactured
vant therapies in the post-HSCT setting and to support clinical trials under a controlled and auditable process that ensures their safety,
in regenerative medicine. The dramatic growth in these new applica- purity, and potency. The FDA has indicated that the application
tions has attracted the interest of regulatory agencies, which have of GMP to cellular therapy products follows a continuum, such
worked hard to develop an appropriate strategy to address a complex that products that are manufactured for a phase I/II clinical trial
new area of medicine. An understanding of the regulations is therefore under an IND are not expected to be prepared under full GMP. As
essential because they are based on the type of cellular therapy the trial proceeds the expectation is that the application of GMP
product. will become more rigorous, such that a phase III product would be
extensively characterized and manufactured using a fully validated
process.
REGULATORY ISSUES WITH CELL PROCESSING Implementation of Part 1271 regulations has had an impact on
the “routine” laboratory that prepares cells primarily for HSCT.
Regulation of a fast-moving field, such as cellular therapies, has posed Laboratories that use cells other than BM must now register annually
a challenge to the United States Food and Drug Administration with the FDA; ensure that donors meet eligibility requirements (or
(FDA) and other national regulatory authorities. However, in the past document why noneligible donors are used); and manufacture, store,
few years, a risk-based structure has emerged in the United States of and distribute the cells under GTP. If a laboratory has previous
America that has clarified the strategy. In brief, manufacturers of experience manufacturing products under GMP conditions, it already
cellular therapy products need to determine whether they fall under will be familiar with most of the features of GTP. In general, these
Investigational New Drug (IND) regulations, which require manu- cover personnel, procedures, facilities, environmental control and
facturing of the product under good manufacturing practices (GMP); monitoring, equipment, supplies and reagents, recovery, processing
whether they fall under Part 1271 of Title 21 of the Code of Federal and process controls, process changes, process validation, labeling
Regulations (21CFR) Human Cells, Tissues, and Cellular and Tissue- controls, storage, receipt, predistribution shipment and distribution,
Based Products (HCT/Ps), which require manufacturing of the records, tracking, and complaints. Implementation of the compo-
product under good tissue practices (GTP); or whether they are nents of GMP and/or GTP operations is a time-consuming process
exempt from both of these regulations. that requires development, implementation, and maintenance of
GTP regulations, which came into effect in May 2005, were numerous components and generates a considerable volume of docu-
established nominally to prevent the introduction, transmission, and mentation. Professional societies, such as the Foundation for the
spread of communicable diseases by HCT/Ps. This was based on the Accreditation of Cellular Therapy (FACT) and AABB (formerly the
presumption that most posttransplant infections and admissions to American Association of Blood Banks), have developed standards and
intensive care units were attributable to administration of contami- an accreditation process that takes into account GTP/GMP regula-
nated products. The validity of this assumption is open to question. tions and provides a framework around which compliance can be
GTP regulations provide a framework for screening, performing ex built (see Professional Standards section).
vivo processing, storing, and distributing HCT/Ps, and provide the An exception from the products described earlier is cord blood.
FDA with an overview of current activities by requiring an annual In the United States, cord blood is a licensed product and facilities
registration of collection and processing facilities. The Part 1271 that prepare and bank cord blood are required to obtain a Biologics
regulations effectively filled a gap in the law that left unregulated License. This allows the manufacturer to introduce, or deliver for
HCT/Ps that were minimally manipulated (e.g., were not cultured introduction, a biologic product into interstate commerce (21 CFR
ex vivo, genetically modified, or activated ex vivo), were intended for 601.2).
homologous use, or were not combined with another article (e.g., a Central to both GMP and GTP regulations is the establishment
matrix or scaffold) for administration. Minimally manipulated HCT/ and maintenance of a quality program. This must ensure that the
Ps should not exert a systemic effect and should not be dependent appropriate regulations are being followed on an ongoing basis; that
on the metabolic activity of living cells for their function. If this were mechanisms are in place for detecting, reviewing, and remediating
not the case, then the cells should be for autologous use only, for use errors and deviations from regulations, policies, and procedures; and
in a first- or second-degree blood relative, or for reproductive use. that an audit program will be developed, implemented, and main-
Cellular products that fall into this classification are referred to as tained. Activities performed by the quality program must be docu-
Type 361 products. The Part 1271 regulations do not apply to vascu- mented, and the program should be staffed by individuals who are
larized organs for transplantation; whole blood or blood components; not involved in hands-on manufacturing of the products.

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