Raw materials have a wide definition: cell-culture media; excipients; chemical additives; detergents; manufacturing process agents, for example, anti-foam agents or even product contact materials like the plastic used in disposable bags. Small changes can have a significant, measurable effect, and often it is difficult to determine root cause. Not all of the potential sources of variation are investigated or understood at the process development phase. Thousands of possible variables exist, and many have a trivial impact. The critical ones would, ideally, be investigated. In reality, commercial operations will experience the effects of unforeseen variability and will need to act accordingly.
Raw material variability may lead to quality compliance issues, process inconsistency, or bioprocess productivity problems. Many of these issues would be upstream in the cell-culture or fermentation step but could also be downstream in purification. The ‘blackbox’ nature of upstream processes makes things doubly difficult. Common examples would be out of specification for a product critical quality attribute (CQA), slower cell growth, low titer, and evidence of extraneous matter following visual inspection.
Fixing Variability in Raw Materials
Current best practice to fix these compliance issues includes extensive investigation and characterization of the impact, multifaceted statistical analysis (multi-variate analysis), both on the process and of the materials under suspicion. When the probable cause is found, the supplier can be asked to help. Additional testing, batch screening, and lot-to-lot blending are often tactics employed, either at the supplier or in house.
Sometimes the supplier is a big company selling materials to many industries and biopharmaceutical manufacturing is a small part of their overall business. In this case, their willingness to help could be limited. Often a component of the material is a naturally occurring substance maybe derived from a crop or another (preferably non-animal) living substance. In this case, it might be extremely difficult to control variability due to environmental factors. Changing to a chemically defined material would be preferred but is not always possible for legacy products where the license has been submitted with detailed raw material and other bioprocess information.
Despite the courageous work done by the engineers and scientists, there is a rising tide of questions along the lines of ‘surely, there’s a better way?’ These investigations are expensive and energy sapping. Moreover, with increased regulatory expectations, it is difficult to claim ‘we are in control’. Health authorities want to see process understanding, and they want to know that supplier quality is suitably reliable.
A New Approach
A certificate of conformance or certificate of analysis (CoA) is the current way of controlling quality; however, this way won’t do the job going forward. A more sophisticated approach using ranges and tolerances for critical material attributes is needed. The focus of attention needs to be outside the walls of the bioprocess facility (i.e., at the supplier’s plant) as well as in the bioprocess. Raw material supply chains are complex and multi-tiered. Risk management tools are expected and widely used for impact assessments and to focus on the most important issues.
The industry is now developing an additional approach, which seeks to make the external inbound raw material supply chain fit for purpose. At a recent BioPhorum Operations Group meeting, 17 companies pooled their knowledge and committed to a joint program of supply-chain improvement. Taken to its logical end point, the change envisaged is transformational. The following are four principles behind the transformation:
Supply chain transparency is of paramount importance. The players at each stage need to be more open and appreciative of the significance of their role in a patient centered world. The manufacturer needs to have a clear understanding of who the suppliers are, and who are their suppliers, onward and upward as far as is necessary. This understanding would help lead to clarity, for example, where changes have been made to a material or conversion process.
Aligning supplier capabilities to end user and regulatory requirements will increasingly necessitate ‘pharma standard’ attitudes and cGMP operations for second- and third-tier suppliers, whereas only first-tier suppliers might have been in focus before.
End-to-end information flow from suppliers to biopharmaceutical manufacturers including electronic transmission of CoA and other analysis data will become commonplace over the next few years. In return, end users will transmit their cleansed results back to close the loop. Standards will be put in place for how this will be achieved. Quality-by- design approaches to specifying requirements are key and getting to variability true root causes of variability is crucial.
For the manufacturers cross-functional teams covering operations, quality control, quality assurance, purchasing, and manufacturing science are now best practice to ensure all perspectives are taken into account for supply chain improvement.
The biological molecule is often thought of as the value-adding element of drug substance, but unless the variability of each and every material that the cells come into contact during their creation is carefully considered and controls put in place, manufacturers might fall short of the mission.
Simon Chalk is director of the BioPhorum Operations Group, [email protected].