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General Considerations
One or more product modifications or preparative steps may be required prior to administration of the cell or gene therapy product to the patient. These modifications or steps are frequently performed close to the time of administration; and, therefore, they are performed under conditions not under control of the original manufacturing facility. The nature of these modifications is largely dictated by characteristics of the product in relationship to the particular application. These include thawing, washing, or filtration to remove unwanted cells or substances accumulated during storage, transfer to an infusible solution, or compounding with a vehicle or structural material. In addition, patient considerations, such as the need to dose the product according to patient weight or blood volume, may influence these steps.
All product modifications performed between the time of initial product manufacture and final administration to the patient should be viewed as a part of the overall manufacturing process. The practical implications of this concept are that the process controls must be established for all product storage intervals, transport steps, and modifications, starting with a clear definition of critical control points. Operational requirements for performing any of these steps after initial product manufacture include defined physical space with appropriate environmental controls, trained personnel, detailed standard operating procedures, and a comprehensive quality program.
The unique and irreplaceable nature of many cell and gene therapy products, many of which have originated from an autologous or a selected allogeneic tissue source, creates special considerations for product manufacture, release, and administration. It is critical to both anticipate the need for and to establish policies and procedures to guide product modification or administration steps in cases where predefined release criteria cannot be met. These procedures should include a mechanism to obtain medical consultation to assess risk and benefit considerations for the patient and to provide complete documentation of any decision to modify predefined product specifications.
On-Site Preparation
Prior to administration, on-site preparation of the cell or gene therapy product may involve one or more manipulations. These manipulations include the following:
  1. Change in Final Container—The manufactured product may have been stored or transported in one container but may require transfer to a different container for administration.
  2. Change in Physical State or Temperature—A product may require thawing from the frozen state or warming from the refrigerated state.
  3. Change in Solution or Suspension—A product may have to be dissolved, diluted, or suspended in a liquid.
  4. Addition to Biocompatible Structural Material—A cell or gene therapy product may need to be combined with living, natural, or synthetic structural tissue or matrix. Examples of matrix material include hollow fibers, fibrous sheets, gels, plugs, capsules, sponges, or granules.
  5. Admixture or Compounding with Other Nonstructural Materials—A product may require mixing or compounding with drugs, cytokines, biologics, or other nonstructural materials.
  6. Filtration or Washing—Unwanted materials in the manufactured product, such as particulates, cellular debris, metabolites, or compounds remaining from previous manipulations may require washing or filtration steps.
  7. Sampling—Sampling of the final product immediately prior to administration may be required for certain clinical protocols.
Facility requirements for performing on-site preparative steps or administration of cell and gene therapy products depend on the nature of the products, their applications, and the manipulations required. The most important determinant of facility features is the level of risk for microbial contamination associated with each step. Definition of low-risk and high-risk conditions can be made according to a framework similar to that defined for Low-Risk Level CSPs and High-Risk Level CSPs in the CSP Microbial Contamination Risk Levels section under Pharmaceutical Compounding—Sterile Preparations 797.
Cell and gene therapy products that undergo on-site preparative steps or manipulations must be subjected to appropriate checks or tests to ensure that all quality specifications are met prior to release for patient administration. The nature and extent of manipulations will determine whether release requirements or critical specifications must be added to those required immediately after initial manufacture. Pre-release requirements usually include the following:
  1. physical inspection of the product, which typically includes measures to ensure appropriate product appearance with regard to color, turbidity, particulates or foreign matter, container integrity; product temperature; and accuracy and convenience of labeling;
  2. review of process records; and
  3. for patient-specific products, clerical checking of product labeling or records related to identity of the intended recipient.
In addition, products considered to be high-risk products according to the description under Pharmaceutical Compounding—Sterile Preparations 797 should undergo additional product testing. For all high-risk products, quality assays for the identity, potency, and purity of the active ingredients should be defined and performed. For high-risk products in Category II, sterility and endotoxin testing should be performed.
Administration to Patients
Depending on the specific cell or gene therapy application, steps may need to be taken by trained patient-care staff to prepare the patient for product administration. These steps are aimed at ensuring that the product will provide the intended therapeutic outcome and at minimizing the risk of adverse effects.
In cases where autologous, selected allogeneic, or xenogeneic tissue is the source of the cell or gene therapy product, determination of patient suitability for the therapy, including the evaluation of histocompatibility between the donor and the recipient, typically occurs prior to the product preparation. However, because of the possibility of changes in clinical status of the patient after the time of tissue collection, such as fever, infection, recurrence or spread of tumors, or organ dysfunction, a thorough re-evaluation of the patient's general condition and suitability for therapy must be performed in close proximity to product administration. This evaluation usually includes a patient history, physical examination, and laboratory studies such as blood counts and chemistries. In addition, baseline physical or functional measurements, laboratory tests, or imaging studies relevant to the specific application may be obtained. Examples include pulmonary function tests for a therapy aimed at improving lung function, measurement of blood levels of an enzyme that is the gene product in a gene therapy application, and nuclear imaging of organs prior to anticancer therapies.
A variety of patient interventions related to route of product administration may be required before product administration. For cellular therapies requiring intravenous administration, patients with poor peripheral venous access may require placement of a central venous catheter. In applications where cells or matrices combined with cells are implanted into the patient, the site of implantation may require preparation in the operating room. This may involve surgically opening the site, removing the degenerated or damaged tissue, trimming of the adjacent tissue to accommodate the implant, and excising the tissue from a second site to be used as an anchor or support for the implant. For instance, in the case of cell products for wound healing, it is critical that the site for grafting be free from infection and that it demonstrates a well-prepared wound bed. In cells intended to repair cartilage defects, the site of damage needs to be prepared so that the cells can be applied to a watertight compartment. For applications involving direct administration of the product into an organ system (for example, bronchioalveolar system) or vascular network (for example, coronary arteries), the patient may require endoscopic or surgical access to these sites.
In all cases, the need for adequate anesthesia and premedication must be carefully evaluated in conjunction with these steps prior to product administration. For example, if it is anticipated that DMSO will remain in a thawed, cryopreserved cellular product, the patient is given an antihistamine prior to administration of the cells to block adverse effects associated with histamine release induced by the DMSO. Pre-administration patient evaluation must also include assessment of concurrent therapies that may interact with the cell or gene therapy product to modify its effects. Some therapies may be considered adjunctive to the cell or gene therapy, such as cytokines that promote proliferation or differentiation of the infused or implanted tissue. Other commonly used drugs such as antibiotics, antineoplastics, anticoagulants, and anti-inflammatory agents must be evaluated for possible effects on the efficacy of the cell or gene therapy product.
Some cell or gene therapy products are patient-specific, in that they are manufactured from a selected tissue source, such as autologous, selected allogeneic, or xenogeneic tissue. Certain patient-specific products have a defined potential for benefit or adverse immunoreactivity. Systems must be in place to prevent administration of such a product to the wrong patient. Recommended systems include procedures similar to those used for administration of human blood products, with special attention given to the correct identification of the patient and patient-specific product by at least two people immediately prior to administration.
Cell and gene therapy products can be administered by a variety of routes. These include the intravenous route, the parenteral routes (subcutaneous, intramuscular, and intra-arterial), and the respiratory or gastrointestinal tract route. Other possibilities include direct application of cell or gene therapy products into regional vasculature, organs, tissues, or body cavities by means of needles or catheters or following surgical exposure of the tissue. While parenteral administration can be accomplished in routine outpatient or inpatient facilities, the other means of administration may require specialized facilities, such as an aseptic operating theater or endoscopic suite. In all cases, standard operating procedures and a quality program must be in place to ensure that the product is administered in the intended manner.
There should be written policies and procedures for monitoring patient outcomes and managing reports of adverse events. Patient-outcome assessment should include indicators that are likely to detect errors or problems related to the entire manufacturing process, with special attention given to manipulations, storage, or transportation after the initial manufacture of the product. Management of adverse reactions should include procedures for ensuring prompt medical evaluation and treatment of patients with suspected adverse effects and a system for reporting and evaluating adverse effects that may point to a potential defect in the administered product. Reporting procedures include providing details required for federal, state, or USP adverse-event reporting programs.
Follow-up and monitoring procedures should be implemented for patients who have received gene therapy vectors or ex vivo gene therapies. To the extent that it is relevant and that it can be assessed, vector or modified cell biodistribution and persistence in vivo should be monitored. With direct administration of vectors, localization to the germ line may be an issue. Although preclinical studies can be used to address this issue, useful information may be gained through patient monitoring. In the case where a retroviral vector has been administered, patients should be monitored for replication-competent retrovirus (RCR) according to the FDA's Draft Guidance for Industry: Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-Up of Patients in Clinical Trials Using Retroviral Vectors (October 2000). This involves active monitoring during the first year and archiving of patient samples thereafter if RCR is not detected initially.
Database systems to collate and track patient-monitoring results are essential to management of this information. National registries or publication of data should be considered for establishing the collective safety of gene therapy.