Before proceeding into human clinical trials, manufacturers of biological therapeutics are required by regulatory agencies worldwide to show that their products are free from adventitious agents. These regulatory authorities require a multi-tiered approach to thoroughly demonstrate product biosafety. First, the starting material, such cell line substrate(s), used to manufacture a therapeutic product must be fully characterized. Second, appropriate steps of the product purification process may need to be validated for the ability to remove and/or inactivate potential contaminants such as viruses, mycoplasma, endotoxins, and residual DNA. Third, the final product, as well as the material from appropriate stages of the manufacturing process, must be tested to assure freedom from contamination. AppTec will provide you with the expertise to meet these objectives in a reliable, rapid, and cost-effective manner.
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Designing a Biosafety Testing Program
Start early! Early and systematic attention to biosafety testing can minimize or eliminate costly delays to a project. A dialog with the appropriate regulatory authorities should also be established early in the process.
It is important to emphasize that the regulatory authorities consider each product on a "case-by-case" basis. Factors that influence the extent of testing include source of the starting material, the severity of the disease to be treated, the current availability and efficacy of other treatments, and the stage of the development of the product. We therefore recommend that you consider this section on the design of a biosafety testing program as a framework for discussion with the appropriate regulatory authorities before finalizing a testing program. I. Characterize the Starting Material
The first step in the design of any biosafety testing program is to characterize the starting material. In addition to the cell banks, tissues, blood, etc. from which the product is produced or derived, the starting material includes the raw materials used in the production/purification of the product. These raw materials include bovine serum, porcine trypsin, and other animal-derived cell culture materials.
Characterization of the starting material consists of measuring the property of the material itself, and identifying adventitious agents that may be associated with the material. Tests to characterize the property of the material include species and type identity, growth characteristics, morphology, purity, product expression characteristics, and genetic characterization/stability. Adventitious agent testing generally includes general virus screens (i.e., in vitro and in vivo assays), retrovirus screens, specific virus tests, and assays to detect bacteria, fungi, and mycoplasma. II. Evaluate the Purification Process - Viral Clearance
A critical step in the design of a biosafety testing program is the evaluation of the ability of the purification process to remove or inactivate any adventitious agents (typically viruses, bacteria, or mycoplasma) that may be present in the starting material. The evaluation involves spiking individual process steps with high titer virus, bacteria, or mycoplasma, and measuring the clearance of the agent by each process step using sensitive and validated detection assays. These studies are highly custom and complex. Using the experience gained from the performance of hundreds of these types of studies, we will design and perform a custom clearance study for your specific product and process in accordance with the most current regulatory guidelines. III. Downstream and Final Product Testing
For most biotherapeutics, adventitious agent testing and product characterization needs to be performed at the Unprocessed Bulk Product (UBP), Purified Bulk Product (PBP), and Final Product (FP) stages of production and purification. Every lot of material needs to be tested at these stages. Unprocessed Bulk Product testing usually involves limited virus testing (a general in vitro virus screen and/or a specific virus assay), sterility (including B/F), and mycoplasma testing. Purified Bulk Product testing routinely consists of molecular and analytical characterization studies for product purity and potency, as well as sterility testing. Final Product testing should include sterility and pyrogenicity testing. STABILITY PROGRAMS AND TESTING
AppTec has the expertise and capability to design and implement stability testing of New Drug Substances and Products, meeting International Conference on Harmonization (ICH) Guidelines. These guidelines set forth the stability testing requirements for a Registration Application within the EU, Japan and the U.S.A.
An acceptable stability program should encompass at least three (3) lots, manufactured to a minimum of pilot plant scale, and use a method of manufacture and procedure that simulates the final process to be used on a manufacturing scale. Testing should cover a minimum of 12 months at the time of submission.
The first three (3) production lots of each product manufactured post approval should also be placed on long-term stability studies, using the same stability protocol as in the approved drug application. |