For any oncolytic virus company I have talked to it has been a major effort to produce the oncolytic virus in suitable quantity and quality for the first clinical trials. In practice, the company has two options for GMP manufacturing: An own GMP facility, or a contract manufacturing organization (CMO).
Building an own GMP facility is often not an option – at least for the first clinical trials – due to time, resources and expertise required for building the facility and running it. There are more than 100 CMOs who claim to have vast experience in the production of biologics. However, as many biotechs have found, the real skill and experience today is low. Some have paid a high price in teaching the selected CMO partner through the process.
So what are the real alternative strategies and how to succeed?
In Phase I trials, the number of patients is typically rather low and thus a small scale production process can be used. Sometimes even lab scale provides with a sufficient virus quantity. Geography may make a big difference: for instance in the USA full GMP may not be required in Phase I, unlike in the EU. Regardless, when full GMP is required, it means not only producing one virus batch in a controlled environment with GMP compliant raw materials, but also establishing a complex production process. For oncolytic viruses this could take 12-24 months:
- First, the basic cultivation process needs to be set up, including selection and banking of a host cell line.
- The Master Cell Bank (MCB) needs to be characterized.
- Using the MCB, the master viral seed stock (MVSS) is prepared and characterized.
- GMP production starts with an engineering batch that verifies the manufacturing and analytical methodology, and provides the detailed information that is required for the preparation of Standard Operating Procedures (SOPs) that are used in the GMP manufacturing.
- Finally the production of GMP batch(es) starts. It is only possible after the previous steps have been successfully completed.
Characterization is a major challenge. As oncolytic viruses are new from regulatory viewpoint there are no established guidelines on how purity testing should be conducted to ensure approval for a clinical study. A special challenge arises from the oncolytic viruses being replication competent: Assays used for the detection of possible adventitious agents are based on cell culture and in vivo studies in which a replication competent oncolytic virus needs to be neutralized prior to the assays.
As a conclusion most oncolytic viruses will be GMP-manufactured by a CMO. There is one key to success: You must have a detailed understanding of everything the CMO will need to do to comply with regulations. If you have no experience, hire suitable people or use highly trusted consultants. Select the CMO carefully – and verify carefully that they really possess the skills and experience that you require. And DO NOT rely on only one opinion from one consultant as there are no well-rounded experts yet on the field. It’s not possible to outsource the key decisions: Eventually you are held responsible.
Dr. Antti Vuolanto is VP Quality and Manufacturing at Oncos Therapeutics with good experience in biologicals manufacturing. He invites you to post your comments and share experiences, either by responding to this blog or
via email directly firstname dot lastname at oncos dot com.