Ralph Quadflieg, head of Supplier Quality Management at Roche, speaking at an SAFC symposium on supply chain vulnerability in biopharmaceutical manufacturing yesterday, said instances of raw material problems leading to drug recalls and shortages are increasing in number and severity.
This fits with a 2013 report by the International Society for Pharmaceutical Engineering (ISPE), which revealed that “material issues” account for approximately 20% of drug shortages, second only to drug quality problems.
Suppliers and distributors of materials must be more open about their supply chains and provide significantly more thorough characterisation of their materials, Quadflieg said, adding that Roche wants to “change from a transactional relationship” by “building up trust and treating the supplier as an internal department.”
‘We know a lot but not all’
Suppliers provide pharmaceutical manufacturers with either customized materials, made to parameters defined by the client, or commodities with specifications that fit the customers’ needs.
The latter may also be delivered to other manufacturing industries, and the supplier is not necessarily aware of how pharma companies plan to use the batch. The specifications of these off-the-shelf products are not detailed enough to reflect every critical material attribute of the substance.
The result, said Quadflieg, is that changes to the make-up of raw materials, small enough not to affect the official material specification, can go undetected until they cause problems during biomanufacturing.
These differences can happen when suppliers tweak their production process or manufacture across different sites, when buyers purchase from multiple suppliers.
In one case, Roche/Genentech’s supplier of depth filters changed its source for diatomaceous earth. Although the replacement “looked great and seemed a perfect change,” Genentech’s resulting cell culture did not work and cells died, said Quadflieg.
“We found out that a key trace element that had been in that earth before was vital for our cell culture. We always used the same filter from production through to development and commercialisation.
“This was completely unexpected – how should you [foresee] that diatomaceous earth could contribute to your media performance?”
Another example “was not even a change” to the raw material’s components, Roche’s expert told the symposium.
“Our supplier for antifoam produced in a multipurpose facility. The product they produced before was also antifoam – not for cell culture but for something else – and was cytotoxic.”
Although all specifications were met, the effects of the previous manufacturing line carried over into the new product and were critical to Roche’s cell line.
“This shows in our business with cell cultures and biological systems we know a lot but maybe not all. Sometimes I feel the specification is just the tip of the iceberg.”
‘Policeman-type audits’
The solution, said Quadflieg, is to create material that is truly interchangeable between sites or even suppliers, so attributes such as trace elements, leachable substances and other impurities do not vary: “Production shouldn’t notice that there was a technical transfer.”
To achieve this, companies must establish technical transfer teams, involving experts from all sides, “so the supplier understands the key parameter that defines the comparability of the two different materials for us; and the supplier takes over these parameters into their qualification so they really do the technical transfer for us.”
When asked by the audience how Roche achieves these checks, Quadflieg said the company wanted to move away from “a policeman-type audit,” and it came down to “the trust that we establish – we ask the distributor, who is your manufacturer? I’ve said in many instances, ‘If they don’t open up their books, then we are done. We cannot manage them.’”