Biosafety Testing Throughout the Drug Development Cycle
12th September 2018
By: Daniel Cozens - Scientist, Biosafety,
Biosafety Testing from Cell Line Development Through to Lot Release
For the release of biopharmaceutical drugs onto the market, products must be shown to be safe. Regulatory bodies such as the US Food & Drug Administrators (FDA) and the Medicines and Healthcare Regulatory Agency (MHRA) require products are tested for compliance before release. This involves a number of stringent tests to provide proof that a product is free of contamination and does not pose a risk to patient health. Failure to perform comprehensive and effective biosafety testing can result in the recall of products from the market, reduced confidence in products or have an adverse impact upon patient health.
Improving Biologics Safety Guidelines
The importance of biosafety testing can be highlighted by past incidences when there was inadequate testing. For example, prior to the establishment of guidelines in 1962, millions of patients were given adenovirus and poliovirus vaccine contaminated with an adventitious simian virus from the rhesus monkey kidney cell line used to manufacture the product (1). Although dismissed in 2004, it was suspected that this contamination could have led to increased instances of cancer. Another example occurred in the 1970s where thousands of patients with haemophilia and other bleeding disorders were infected with HIV, Hepatitis B and C and other blood-borne viruses after being given treatment using proteins isolated from human plasma pooled from up to 100,000 donors (2).
Despite the introduction of improved manufacturing practices, there are still reports of contamination in the manufacture of biopharmaceutical drugs today. These can be derived from compromised media components, the presence of endogenous viruses in cell lines or from the introduction of adventitious agents during the manufacturing process. Mycoplasma contamination is also regularly detected in cell culture collections. Because of this biosafety testing is still mandatory for the release of all biopharmaceuticals.
Biosafety testing encompasses a number of assays which are used in conjunction to identify agents which could compromize the final product. For example, the incidental introduction of contaminant microorganisms can cause serious clinical consequences to patients. The presence of endotoxin and other impurities in the final product can reduce the efficacy of therapeutic agents and result in adverse, toxic, or immunological reactions. Genomic rearrangements during the culture of cells can alter gene expression, which may have downstream effects on the quality of the final product. These problems must be tested for before lot release of the final product.
Tailor your Biosafety Testing
The extent of testing required is dependent on a number of factors and should be tailored to the individual product. The type of biopharmaceutical and its intended clinical use, the nature of the production process and the pre-existing testing performed on cell banks and culture medium constituents will all affect what biosafety testing is required. The type of testing will also vary depending on the intended geographical market of the biopharmaceuticals.
Here at BioOutsource, we offer a comprehensive package of biologic testing methods which can be tailored to suit your biopharmaceutical product, ensuring the required biosafety testing is carried out at every stage of the drug development process, from master cell bank to bulk harvest, to the final product.
Multiple Assays = Increased Biosafety Coverage
The assays used to confirm the safety of biologics are wide-ranging, and no single approach will establish the safety of a product, therefore it is beneficial to utilize multiple techniques. This provides wider coverage to identify any potential risks to patient health. This rationale can be highlighted in the testing for adventitious viruses. To identify adventitious viruses, the European Medicines Agency (EMA) (3) lists several assays that may be used during the production of biopharmaceutical products. This includes in vitro assays that can be used by inoculating susceptible indicator cell cultures to detect a wide range of human and animal viruses. In vivo assays can supplement in vitro assays to identify the presence of virus that cannot be grown in cell culture. Testing for specific viruses, for example by PCR, is also required, particularly when there is a higher possibly of their presence due to the species of origin of the cell line or the use of animal-derived cell supplements, such as bovine serum.
Retrovirus can be detected by transmission electron microscopy (TEM), direct or indirect infectivity methods, or measurement of reverse transcriptase activity. Although individually these tests do not confirm the safety of a biopharmaceutical, when used in combination these assays can provide confidence that a product is free of adventitious virus.
Expert Support for You
At Sartorius Stedim BioOutsource, we provide expert guidance and support regarding the biosafety testing of your product from the early stages of cell line development through to lot release of final products. We provide tailored packages of assays, performed in cGMP and GLP approved laboratories where assay validation and testing meet the regulatory requirements of the FDA and EMA, to assist in the licensing of your biopharmaceutical product for release to the market.
If you are interested in finding out more about our tailored biosafety testing services, or would like some support, please contact us.