Page 1727 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 96 Investigational New Drug–Enabling Processes for Cell-Based Therapies 1533

necessary as poor controls of production processes can lead to the In summary, cell therapy products are being used in a variety of
introduction of adventitious agents or other contaminants, or to therapeutic indications and their development for and use in other
inadvertent changes in the safety, potency, purity, or stability of the indications is progressing into the clinic. However, the clinical
biological product that may not be detectable in final product testing, administration of living biologics carries elements of risk. Rigid
which is a keystone of the final product release. 6 control processes to minimize risk need to be implemented. Charac-
terization, although a predictor of efficacy, is not a predictor of safety
or quality. As full characterization is unlikely, it is imperative that
Aseptic Processing manufacturing and aseptic processes be designed and validated to
produce a safe, reliable product. If manufacturing methods change,
As living functional cells are the product, terminal sterilization is as is often the case, essentially a new product is created, and rechar-
not an option, therefore aseptic processing is required, with the acterization and repeat testing will be required to assess the impact
use of closed manufacturing systems to the extent possible. This of those changes on the product.
is considered a critical aspect of the manufacturing process and
should be defined and validated as such, particularly as the risk of
delivering a contaminated product is increased not only because THE REGULATION OF CELL THERAPY PRODUCTS
of the inability to sterilize the product, but also because the time-
lines involved with cell products and product administration may The Center for Biologics Evaluation and Research (CBER) currently
occur before final sterility testing has been completed. The nature regulates cell therapy products considered as HCT/Ps under two
8,9
of the starting material and processes that involve open or closed sections of the Public Health Service (PHS) Act. Section 361
manipulations determine the level of a controlled environment to be includes products that require no IND be filed prior to the initiation
implemented. of clinical studies and are consistent with products defined in 21 CFR
10
1271.10, i.e., minimally manipulated, homologous use, not a
combination product, and either has no cellular or systemic effect,
Target Cell Population or, if it is active on a cellular or systemic basis, is used in an autologous
setting, in an allogeneic setting in first- or second-degree blood rela-
Cells of therapeutic interest are often found in small numbers. tives, or is for reproductive use. Section 351 of the PHS Act 10,11
Therefore an important first step of cell processing can be the initial includes products that require clinical data be collected under an IND
isolation or enrichment of a cell population of interest from the application, and do not meet the definition of exempt products
tissue source. Several commercial fully automated closed systems described above for Section 361 products. Cell therapies that also
are already in use and include the CliniMACS Prodigy system have a device or scaffold associated with them can be regulated by
(Miltenyi Biotec), the Sepax 2 system (Biosafe SA), and the Elutra the Center for Devices and Radiological Health (CDRH) as a con-
system (Terumo BCT). Cell-culturing processes can be specific to sultant to CBER or as the lead center if the scaffold is the primary
a given cell type; for example, cells such as T cells can be grown in mode of action. Table 96.1 summarizes regulation of HCT/Ps as
nonadherent suspension culture where large-scale bioreactors, such as Section 351 and 361 products.
bag-based and traditional stirred-tank vessels, are used. This culturing
system requires a small surface area and can produce high cell yield.
There is a growing interest in ex vivo expansion of adherent cells THE INVESTIGATIONAL NEW DRUG PROCESS
for a variety of clinical applications. Mesenchymal stromal cells are
grown adherently on tissue culture-treated surfaces but require a Presented below is a summary of the basic procedures to file an IND
large surface area to be produced on a large scale. Miltenyi Biotec with the FDA. The regulatory pathway to conduct a clinical trial
culture bags offer a closed-system process along with the CLINI- using a cell therapy product will involve an IND if the product does
cell (MABio). Multilayered flasks have been developed (CellCube not meet the major criteria defining minimally manipulated
and CellSTACK, Corning) to address surface area. Bioreactors products.
(G-Rex, Wilson Wolf Manufacturing and WAVE, GE Healthcare
Life Sciences) and microcarrier-based culturing systems (SoloHill
Engineering) are designed to support cell growth at a variety of IND Sponsor/Investigator
scales. 7
The Sponsor of an IND trial is the individual or organization that
takes legal responsibility for and initiates the clinical investigation.
Autologous Versus Allogeneic Products This may be an individual, an academic institution, the government
(the NIH), or a pharmaceutical company. In contrast, the Investigator
Given their unique donor specificity, autologous products are attrac- is the individual who actually conducts the clinical trial and under
tive because of their decreased risk of immunologic reactions, bioin- whose direction the investigational product is administered. In many
compatibility, and communicable disease transmission. However, small cell-therapy clinical trials, the sponsor may in fact also be the
they are inherently more limited and more variable owing to indi- investigator, so that the trial is conducted under a single individual
vidual patient characteristics and/or disease state. Use of allogeneic who is designated as a Sponsor/Investigator. 12
donors is associated with greater risk than autologous donation
because of the risk of infectious disease transmission from the donor
to the recipient, overall risk of an immune response, and donor-to- Requesting a Meeting
donor variability. However, allogeneic cells have the potential to treat
hundreds of patients from a single manufactured lot of cells and can Product regulatory development almost always begins with meet-
be an “off-the-shelf” product. ings between the sponsor and the FDA. Even with the availability
Methods used in the production of cell products for clinical thera- of various Guidance Documents, sponsors are rarely in a position
pies depend on the nature of the final product and their targeted to submit a successful IND application with a cellular therapeutic
population. Autologous products are patient-specific and are manu- product without direct FDA interactions in order to agree on
factured using a “scaled out” approach. Cells are manufactured in submission details. The agency has designated meeting types to
small-volume batches and each patient constitutes their own “lot” of create a consistent level of support for products under development.
product. Allogeneic product manufacturing can use a scaled-up A meeting request is submitted to the FDA stating the type of
approach with a bulk manufacturing strategy to produce larger- meeting requested with draft questions and suggested dates for the
volume batches to treat multiple patients. meeting.