Given the difficulty of linking the molecular structure of a complex biopharmaceutical to its efficacy and safety, the industry must maintain that “the process is the product”. Any change to the process implies that the product can no longer be assumed to be the same as that for which data was generated during clinical trials.
However, within defined limits, process variability is a fact of bioprocessing life. Here we look at 4 broad sources of bioprocess variation discussing how they occur and highlighting best operating practices to minimize or prevent them.
Biological variations are those derived from the organism and the product expressed and occur because of the use of highly complex living organisms used in biopharmaceutical manufacturing. Selecting the right cell line early in the development process is vitally important but product variability can also be reduced by optimizing process parameters during cell culture.
Automation of an apparently simple sub-operation such as bioreactor feeds can increase process consistency by eliminating variation derived from rates of addition and reducing opportunity for error and failures.
2. Raw Materials and Consumables
Raw materials and consumables used in the production of biopharmaceuticals are direct additions to the process and any variation in these can therefore be a source of variation in the final product. The proliferation of single-use technology has introduced greater variability in processing equipment and it is important the single-use suppliers pay close attention to their own supply chain to prevent this.
For example, when a Parker supplier was providing two distributions of tubing at the upper and lower limits of the diameter specifications, variability resulted in our overmolded manifolds. We worked closely with the supplier to provide a single distribution of tubing which, in turn, ensured consistency in our own product.
Variation in operational input can be caused by the way equipment is put together in house, differences in the way that different teams perform tasks, and differences in how unit steps are conducted when processes are transferred between facilities.
Automation of manual operations can detect and reduce variation within processing parameters. An example of this is a project in which Parker automated a final bulk filtration and dispense operation for a contract manufacturer. The resulting single-use system automated a 10 step process achieving standardization of the filtration and dispense operation between operators, batches and campaigns as well as increasing dispense accuracy and reducing opportunity for human error.
Temperature and contaminations are two potential causes of major environmental variation. Additional temperature control can be implemented through automation if desired and the use of a closed system should effectively control external contamination.
The automated filtration and dispense system described above was able to convert an operations previously performed using a vertical laminar flow hood into a closed process with fully disposable flowpaths. this significantly reduces the risk of environmental contaminations.
This post was contributed by the Parker Bioscience Division, United Kingdom