Manufacturing issues are better than I thought earlier.
My earlier post thinking test method validation was the issue because that's what took down Sandoz and how Coherus got a CRL. But thinking about it a little further, Spectrum already did testing of their samples in the P2 trial; testing issues should have popped up then. Duh! Regarding Sandoz and Coherus, they didn't have to do a P2. They developed their tests somewhat concurrently w their study to prove biosimilarity, and bam, a CRL. I guess they didn’t develop a very good assay
Regarding tech transfer, you want to validate the test methods (ID, critical manufacturing tests), validate 3 manufacturing runs, putting samples from those manufacturing runs on stability (for testing later), storing Retain samples from each batch, validation of shipment of product under controlled conditions etc. That's just a normal part of doing business. Spectrum would want to contract out their manufacture to 2 or 3 contract manufacturing organizations (CMOs) as a good business practice. At this point in time Hanmi is probably the only one making bulk drug substance (i.e. API) but Spectrum will contract out the packaging of product to one or 2 CMOs.
Another biggie, and common occurrence is to get a 483 for lack of manufacturing controls by the owner of the drug (Spectrum). As the owner of the drug they need to be in charge of what goes on between Hanmi (Spectrum’s API manufacturer) and their Packager; in particular it’s the Quality unit that does this. So they need to get the batch Certificate of Analysis from Hanmi, and Spectrum would sign off on that release certificate. Hanmi would then ship the API to Packager and Packager would ship their Certificate of Manufacturer to Spectrum, and Spectrum give the approval/go ahead to release product based on those specs. You could imagine, that some key items might slip under the rug. Who pulls samples for Stability? Is it Hanmi? Spectrum? Or Packager? Probably Hanmi for API and Packager for final product. In order to know who does what, you put together a Technical/Quality Agreement and it’s an addendum to the Supply/Purchase Contract. You need the Technical, Quality and Purchasing peeps from each organization to come together to figure out ‘Who does what’. The Packager that Spectrum brought in would definitely be following Spectrum’s guidance (if I say jump, they want to know how many feet). Ditto w Hanmi following Spectrum guidance but who knows maybe since this was Hanmi’s baby, Spectrum was not exhibiting the level of control that was needed w Hanmi. Or Packager too. Yep, the more I think about it I think this is where the problem w manufacturing was at.
