A critical function of a manufacturing quality-assurance and quality-control program (QA/QC) is the development of a qualification
program for the source of cells and tissues that will be used as part of the final product, and all critical reagents, including
ancillary materials such as cytokines and growth factors needed to prepare the final product but are not intended to be part
of the final product.
Table 3. QC/QA Biosafety Program for Product Manufacturing
QA/QC is your first line of defense in evaluating and, where possible, eliminating known risks to biosafety presented by a
source material or key ancillary materials and at key stages in manufacturing as outlined in Table 3. There may be unforeseen
risks to biosafety that only emerge during preclinical safety testing in relevant animal models. Some risks can only be evaluated
when this stage has been reached.
Biosafety and qualification of cells and tissues. A core set of documents available from FDA regarding donor screening as well as direct testing of cells and tissues for pathogens
of concern, is applicable to the diversity of sources of cells and tissues used to create cellular- and tissue-based products
(autologous, allogeneic, xenogeneic, banked vs. non-banked).6-9 For developers of therapies based on human cells and tissues, FDA's draft reviewers' guidance contains helpful information
on testing autologous and allogeneic cell and tissue sources as well as testing of cell banks.6 The guidance also cites key documents, such as those from the International Conference on Harmonization (ICH).
Similarly, for therapies based on animal-derived cells and tissues (xenotransplantation), or cells and tissues that are co-cultured
with animal cells (for example, murine feeder cells), valuable information can be found in FDA's guidance on xenotransplantation.7 It is important to recognize that these guidance documents describe only general expectations for biosafety assessments
and in the case of ICH guidance documents, often specifically exclude CBTs from their scope. However, in the absence of more
specific guidance for cell containing products, the principles described in these documents are applicable.
There are additional biosafety concerns to be addressed for cell-based therapies involving ex vivo genetic modification of cells (regulated as gene therapy). Specific biosafety testing or information to be gathered depends
on the vector system used and can include product testing and long-term patient follow-up.8,10
Biosafety and qualification of key ancillary materials. Often, in order for a cell- or tissue-based therapy to possess the desired therapeutic characteristics, it must undergo a
variety of manufacturing steps involving enzymes, cell selection or depletion with antibodies, and ex vivo culture in serum-containing media with a cocktail of cytokines and growth factors. Typically, these processing materials
are only transient and are not intended to be part of the final product. The biosafety of these ancillary materials must be
assessed since they come in contact with cells that will be subsequently administered to patients. The degree of biosafety
necessary to satisfy regulatory authorities depends largely on its origin (synthetic vs. animal- or human-derived) and whether
the vendor supplied the reagent for "in vitro research only" versus a product previously approved by FDA for human use.11
Regardless of the regulatory status of an ancillary material, the manufacturer of the cell- or tissue-based product is ultimately
responsible for developing procedures to evaluate risks to biosafety and performing additional testing. Demonstrating removal
or absence of an ancillary material from the final product is one example where additional testing is needed regardless of
whether or not the ancillary material is FDA-approved.
Final product release testing
21 CFR 610 requires that the final product is tested prior to release for distribution and administration in patients.12 These release tests include a number of specifications that must be met for microbiological safety, including bacterial and
fungal sterility, pyrogenicity (endotoxin), and mycoplasma (for cultured products). Also included are a number of release
specifications relating to product quality and characterization, such as identity, purity, potency, and cellular viability.
There are many legitimate issues regarding the need for some types of testing, or the length of time it takes to obtain test
results in relation to the limited stability of many CBTs.