Lessons Learned for Applying a Holistic Microbial Control Process for Oligonucleotides in Process Control Excursions
Joann Lau, microbiology engineer, Genetech
Oligo Makers Should Consider a Holistic Microbial Control Plan, Says Roche Expert
Microbial control should be a key part of any oligonucleotide drug manufacturing operation, according to a leading Roche researcher, who suggests a holistic strategy is the best way of ensuring products are free of bacterial contamination.
Traditionally, lab-based oligonucleotide synthesis experiments were not carried out in sterile conditions. However, for developers looking to take oligo therapeutics to market microbial control is vital, according to Joann Lau, microbiology engineer at Swiss drug and diagnostics firm Roche, who spoke about the subject at TIDES USA.
“The oligos that were manufactured are for non-sterile drug substances; however, they turn into sterile drug products with the intent of intrathecal administration and also ocular. Therefore, the expectation for controls for bioburden and endotoxin are significantly tighter and how can we achieve this and that is really by having a strong control strategy.
“It is actually also recommended by the EU GMP annex 1 that even non-sterile products have this sort of control strategy,” she added.
Holistic strategy
With this in mind, Lau urged delegates to consider a holistic strategy, which she defined as “a risk assess process, where you identify your process, your equipment, the facility that you’re manufacturing and the source water that you’re using, and pretty much ensure that you can use it to provide a quality product every time.”
Lau cited a plan developed by the European Pharmacopoeia oligonucleotide consortium as a framework for the development of such a strategy.
“First, you assess your process and establish the potential risks. Do you have any open handling steps within your manufacturing? What kind of water are you using? What equipment are you using? The aim is to understand the risks in terms of microbial Ingress.
“Second, you look at how to reduce these risks that you have identified. There are certain steps that you can do to prevent this by either entering some 0.2-micron filters at specific intermediate steps, or maybe having some sort of control over the raw materials that you’re using,” she said.
The next stage is to run the process and gather data to develop controls and establish threshold, Lau said, explaining “You can have alert and action limits that are relevant to your specific process.”
Using the approach, Roche has characterized each part of the synthesis process, assigning unit operations where there is little risk of bacterial contamination as green and those with greater risk as yellow or red.
Lau used the filtration step as an example. “We have deemed the ultrafiltration step as a red or high risk. Here you are really in an environment where it’s quite aquatic; the time that you’re manufacturing is relatively long. So this is where you might see more of an ingress or also a proliferation of your microbes if they were present,” she said.
Roche also takes samples at various points throughout the process to assess it prior to API release and identify any potential contamination issues and take corrective actions.
Lau said, “We perform an investigation that includes root cause analysis, trying to find out where the microbe came from? How did it get in? What are the sources? What is the contributing factor?” adding that, in such circumstances, Roche does not release the batch.
The next step — once the root cause analysis is complete — is to conduct a patient safety assessment to determine the potential impact of the batch under examination, which involves identifying the bacterial species and the number of colonies present.
“A holistic microbial control strategy is ever growing and strengthened with each lesson learned,” Lau said, urging delegates to map processes and put in place action plans for all teams involved — both internal and external partners — should microbial contamination occur.
“This is never really a single man job. It is more time functional, multi-cross team, and even within your different companies, internal and external, you really have to commit to this. And, all of these efforts really put into ensuring that you have a product that is of quality and the safety to patients.
“Your microbial control strategy is only as strong as how up to date it is. So really be proactive, be collaborative, [and] have these questions upfront to see how you can build a strong control strategy,” Lau said.