Compliance with quality control (QC) standards is a basic requirement for products manufactured under good manufacturing practices (GMP) conditions. In this post we will explore the main compendial QC tests that ensure cell and gene therapies are safe for use in patients, and important considerations for integrating QC testing into the manufacturing process.
Compendial & Non-Compendial Tests
Compendial tests are standardized methods that are basic requirements for manufacturing release. Non-compendial tests are additional analytical methods that may be custom requirements for certain products. In cell and gene therapy manufacturing, non-compendial tests are an important consideration, and often prove to be a technical bottleneck that should be addressed during the product and process development stages.
Three Main Compendial Safety Tests for Cell and Gene Therapy
The following tests make up the minimum safety requirements for release of cell and gene therapy products:
- Mycoplasma Testing: Mycoplasma are bacteria and one of the most common contaminants in cell culture. Mycoplasma can be introduced into cultures through contaminated reagents (e.g. animal sera), infected cells, or by laboratory personnel who are carriers. Mycoplasma contamination may not cause observable changes and will go undetected unless specialized tests are used. The most common, and regulator approved, test is the culture of Mycoplasma growth in broth or agar. This test takes 28 days to complete and presents a significant bottleneck for QC testing in cell and gene therapies.
- Sterility Testing: the “gold standard” test to rule out the presence of viable microorganisms is no growth after 14 days of culture under aerobic and anaerobic conditions. The rich growth media required for culturing human cells for therapies can be an ideal medium for growing bacteria that may be introduced from the environment or operators. Testing for microbial bioburden is essential to providing safe products to patients. However, the long incubation periods required to detect some microbes at low levels can cause significant delays in getting treatments to patients.
- Endotoxin Testing: bacterial endotoxins are pyrogens produced in bacteria that can cause fever. These compounds could come from bacterial contamination during production or through components that are manufactured using bacteria. Therefore, endotoxin contamination in products that will be used in humans is a significant safety concern and efforts should be taken during the manufacturing process to reduce the possibility of introducing endotoxins into therapies.
Planning to Meet QC Requirements for Your Cell and Gene Therapy Product
Cell and gene therapies present unique challenges for QC. In contrast to traditional medicines, cell and gene therapies are often manufactured in small batches limiting the amount of final product available for QC testing. Further, cell and gene therapies are living products with drastically shortened shelf lives compared to conventional pharmaceutical or biopharmaceutical products that can be stored for long periods of time.
Timing is the biggest consideration in planning for QC testing. For instance, the one-month turnaround time for standard, regulator-approved Mycoplasma testing poses problems for many cell and gene therapy products. An alternative, PCR-based method can reduce the turnaround time to one week. Similarly, automated microbial growth systems can reduce the time for sterility testing from two weeks to seven days.
However, there is a drawback to PCR-based Mycoplasma testing and rapid sterility testing: these methods are not yet approved by regulators. Therefore, if a developer chooses to accelerate timelines by using these alternative methods, they must engage in additional discussions with the regulator to secure approval. This is a product-specific decision that should be made pro-actively, early in the development process.
Regulators have recognized the specialized needs of cell and gene therapy products and are engaged in developing new, flexible approaches that will accommodate cell and gene therapies. Further, industry is responding to the need for rapid testing with new innovations in analytics – a topic we will explore in a future post.
Working with experienced QC professionals can help you to understand requirements, budget the appropriate time for QC testing, and make the right decision for your product. CCRM offers QC testing services for products manufactured under GMP conditions. An important part of our process is to educate clients on the time and inputs required for QC testing and develop tailored strategies to mitigate delays.