Biosafety Considerations for Cell-Based Therapies

Jul 01, 2004

Therapies based on living cells hold great promise as potential cures for life-threatening diseases. These therapies can repair, restore, replace, or regenerate the affected body system in the patient. One example is the use of ex vivo manipulated peripheral-blood or bone marrow progenitor stem cells as immunotherapies. Researchers are trying to create engineered tissues or biohybrid organs by combining cells with various medical-device biomaterials and other biologically active molecules.

A lingering concern is always the very simple question: "Is it safe?" However, answering that question for therapies based on living cells is not simple because biological safety (biosafety) is largely relative; for cellular-based therapies (CBTs) it is perhaps best discussed in terms of biosafety risk. Such risks can be assessed only after considering numerous factors, such as the source of the cells or tissue, preparation methods, the intended recipient, where in the body the cell-based therapy will be implanted, and the method of cell delivery. This article provides an overview of biosafety issues facing cell- and tissue-based products and discusses a systematic, practical approach for addressing them.

Table 1. Types of Biosafety Risks for Cell and Tissue-Based Therapies
ASSESSING RISKS IN LIVING CELLSCBTs are prepared from living sources, which raises clear biosafety concerns regarding the potential presence of infectious disease agents transmitted from the donors. Highly specialized manufacturing processes are often used, commonly necessitating the use of non-FDA approved ancillary materials (for example, media, cytokines, or growth factors) of uncertain safety and quality. Frequently, the final cell-containing product is intended for implantation or delivery into a specific site in the body and interacts with the cellular milieu in a specialized manner to yield the therapeutic effect. This is why biosafety concerns cover the delivery systems used and the post-implantation fate of the cells (Table 1).

Table 2. Unique Aspects of Cell and Tissue-Based Products
Manufacturing procedures for therapies based on living cells or tissues are unique (Table 2). This is important since many physiochemical techniques such as viral inactivation, filtration, and terminal sterilization are incompatible with therapies dependent upon living cells since such methods would render the cells nonviable. Using such techniques to make a CBT safe would eliminate the possibility of it also being efficacious.

Given the inability to completely assess risks that may be lurking in a product derived from living sources and the inability to inactivate or eliminate unknown threats inherent in living cells, it is obvious that providing an absolute assurance of biosafety is not possible. Consequently, a systematic, risk-based approach to biosafety must be employed that considers the unique characteristics of the product in relation to the condition of the recipient.1 Such an approach requires an ongoing biosafety risk assessment throughout all stages of development — before, during, and after administration of the product.

ELEMENTS OF A BIOSAFETY PROGRAMA comprehensive program for assessing, minimizing, and monitoring risks to biosafety includes the following elements, which are also illustrated in Figure 1:

1. Qualification of materials used in product manufacturing

  • Biosafety and qualification of cells and tissues
  • Biosafety and qualification of key ancillary materials

2. Final product release testing

3. Preclinical pharmacology and toxicology

  • General preclinical design
  • Preclinical biosafety animal studies

Figure 1: Biosafety Must Be Assessed At All Stages
4. Delivery system testing

5. Clinical monitoring

6. Pharmacovigilance

Qualification of materials used in product manufacturing

Federal regulations mandate establishment of a quality control unit as part of good manufacturing practices (GMP).2 This is particularly important for cell- and tissue-based products, since the manufacturing process entails the use of source and ancillary materials of differing complexity, variability, and risk for introduction of adventitious agents. FDA has made it clear via conference presentations, mass mailings to IND sponsors and guidance documents that developers of gene therapies and cell- or tissue-based products must have a qualification program in place prior to initiating clinical studies.3-7