The regulatory agencies have put a much higher premium on characterization and traceability of raw materials used in the manufacture of pharmaceuticals and biopharmaceuticals. The issues with China sourcing for example are well described. Clearly more responsibility for making this assessment has been placed on the drug manufacturer and all other members of the supply chain. I see it as our responsibility as a critical raw material supplier to marketed drugs to actively improve our capabilities in this process. Institution of the Raw Material program is one of several means we are employing to do this.
Additionally, we have seen first hand several examples of raw material problems that resulted in performance issues for our customers in their production systems. Examples include:
1. Carryover of a cleaning agent in a soy hydrolysate from one of the major manufacturers. Interestingly, the change was considered to be non-critical by the hydrolysate manufacturer and no change notification was issued. This particular incident was insidious in nature, as the detergent’s effect on cell culture seemed to be cell line, clone and protein specific. Customers observed a spectrum of effects from nothing to overt toxicity. We instituted a new analytical screening assay for incoming lots of this raw material and put corrective action plan in with vendor.
2. Solubility issues with certain amino acids like cysteine and tyrosine. We have proven to ourselves that not all amino acids are equal. A recent study of tyrosine examining multiple lots from multiple (>5) vendors showed that material from one vendor exhibited significant solubility/toxicity problems. We disqualified this vendor as a provider of this material. Conversely, we’ve also identified alternative forms of both amino acids that have greatly increased solubility properties and are very useful in feeds or concentrates.
3. PVA filterability issues in medium. Again, we’ve observed significant lot specific variance with PVA. This is both vendor to vendor variation as well as lot variation within a single source. We’ve instituted an extensive characterization program to look at physical and chemical properties (e.g. mean particle size, crystalline structure, viscosity of 4% solution, % hydrolysis, MW) of PVA to correlate with filterability characteristics. We’re also examining the use of other grades of PVA as a possible solution.
4. Trace contaminants in hydrolysates, amino acids, etc. Often these can be tied back to the presence of things like trace elements. If these products are being added to cell culture media, this level of variability can result in marked performance issues – growth, productivity, and protein quality.
5. Presence of a manufacturing bioproduct in the biological buffer BisTris. We were able to identify this through analytical testing and to eliminate the problem with a process modification. This was possible for us as we are a primary manufacturer of BisTris even though were not the original manufacturer of the problem material. The assay could then be used to confirm the problem was alleviated.
Other examples could be cited as well but this gives you a flavor.
Our Raw Materials Characterization Program is designed to thoroughly characterize our raw materials, identify risks that could affect performance of our media products and develop strategies to minimize those risks.
The goal/deliverable of the Raw Materials Characterization Program is to develop a best-in-class knowledge base of the raw materials used in our formulations and their impact on performance of our products.
This program will consist of three phases with multiple projects envisioned during each phase. The first phase will develop the support structure needed to successfully perform the studies in the next two phases. The second phase will focus on characterization of individual raw materials while the third phase will evaluate raw material effects in complex media.
Phase I: Initial Support Projects
· Development of a searchable database
· Prioritized list of raw materials
· Development and validation of analytical assays
· Development and validation of biological assays
Phase II: Characterization of Raw Materials
· Characterization of contaminants in raw materials
· Characterization of complex components
· Characterization of simple components
Phase III: Characterization of Raw Materials Effects in Complex Media
· Physical effects
· Biological effects
Next post will discuss projects within the program in more detail.
Posted by Bruce Lehr, Jan 5, 2010