As part of BPI’s “Ask the Expert” series, editorial advisor William G. Whitford (senior technical market manager for GE Healthcare Life Sciences) spoke with editor-in-chief Anne Montgomery and marketing and digital content strategist Leah Rosin on two separate occasions about issues related to culture media and expression titers.

Sourcing Serum-Free Media
Anne discussed cell culture media and process fluids with Bill in March 2014.

Whitford: Things are advancing, and the industry is changing significantly. In general, we are using more structured approaches in management of cell-culture media and process fluids. Pharmaceutical sponsors are demanding that material suppliers provide a consistently available, compliant product that provides robust performance. More than ever, they are requiring that suppliers demonstrate more transparency in their establishment of effective and up-to-date supply-chain management techniques. They are expecting us to design and execute more formal validation strategies to ensure that these materials regularly meet both regulatory and local quality requirements. They expect the use of advanced science and risk- based approaches in general — and well-documented hazard analysis, in particular.

We’ve always been expected to formally troubleshoot exceptions and properly investigate them. But there is a growing expectation to use modern approaches in tracking and reporting and to provide more complete communication of exceptions or notifications. Biomanufacturers are demanding that suppliers are not only basically compliant, but now should be more proactive, resourceful, and responsive than previously understood.

Montgomery: Can you tell me more specifically what suppliers are doing to improve media quality and safety?

Whitford: Well, suppliers in general are improving their quality systems. For example, they are using more formal risk- and hazard-assessment algorithms. At Thermo Fisher Scientific [now GE Healthcare Life Sciences], we are providing better training for our personnel, especially those in testing and reporting areas.

We are developing methods of continued verification and improvement. The materials used in manufacturing chemically defined media not only must be animal-component free, but they also must demonstrate consistency and traceability and have a validated, documented shelf life. They’ve got to be good manufacturing practice (GMP) compliant, they’ve got to have a secure supply, and they should be handled with up-to-date processing technologies: e.g., packaging and storage, transfer, and milling and grinding procedures.

Montgomery: Can you offer some specific examples of the testing theory and methods involved?

Whitford: The type of testing has to be closely determined by particular goals. Very different tests are required to establish such things as a material identity, purity, and potency — especially compared with in-process verification assessment or product status with respect to deliberate fraud/adulteration. For example, hand-held, light-weight, Raman spectroscopy systems are providing a very rugged and robust solution for demonstrating raw-material identity. But they are not valuable for purity assessment, for which you need technologies such as Fourier-transform infrared (FTIR), nuclear magnetic resonance (NMR), or mass spectrometry (MS) analyses.

There are properties you can’t test for at all: e.g., a material’s geographical origin or status as animal-component free. Those characteristics have to be established through vendor qualifications, statements of origin, track-and-trace procedures, and even physical audits of suppliers.

Protein Expression Titers
Over the past decade or so, we’ve watched a “rising tide” of monoclonal antibody (MAb) expression titers from specialized mammalian cell lines, turning the once-respectable 1 g/L goal into a baseline to be doubled, tripled, quadrupled, and even increased into double-digit numbers. But not all protein products have seen such improvements in the same time. In September 2013, Leah asked Bill whether nonantibody proteins will match MAb expression levels.

Whitford: I think the answer is yes, in some particular production modes or platforms at some times in some companies’ hands. The real value of the question is that it raises our awareness of some parameters we may otherwise be taking for granted: “What is special about MAbs compared with ‘other proteins’?” and “What are we really driving at when we ask about these relative levels?”

If we compare the MAb levels being produced today with those from 10 years ago (and for other proteins as well), it becomes a moot point in some respects as to whether one can catch up to the other. We have generally improved rates of expression in the range of 2–8 g/L. But if we consider that in light of newer products with reduced demands — e.g., orphan drugs, personalized medicine, and biosimilars with a dozen different manufacturers — that can influence how we view the question and the importance we place on its answer. In light of that, you might rather consider such other goals as process flexibility, prefabricated facilities, or the new initiative of continuous processing.