Industry Insights… with Angela Fuller
Welcome to the latest blog in our Industry Insights series, where we ask our experts to share their in-depth expertise on topics within the pharmaceutical industry. In this instalment, we asked our Microbiology Team Leader, Angela Fuller, to share her knowledge of microbial analysis across all stages of drug development and how it is used to ensure that pharmaceutical products are safe and meet rigorous quality and regulatory specifications.
How does your team support formulation development?
An important part of my role is advising clients on the microbiology aspects of their project and supporting them across the drug development pathway. For formulation development, we often have the most input on projects supplying non-sterile products. For example, if we are working on an aqueous oral solution, the microbiology team will help provide evidence of whether or not it needs to be preserved, and if so, determine the quantity of preservative required as well as define the shelf life of the product.
How does your team support drug product clinical manufacturing?
We work closely with the Drug Product team, providing them with basic training in microbiology alongside assistance with microbial monitoring and simulation tests. This ensures that the Arcinova team as a whole has a good understanding of how to reduce the risk of microbial cross-contamination. We provide advice on appropriate laboratory attire and rigorous cleaning procedures that are required in the manufacturing area, including within isolators and safety cabinets. The area is then continuously monitored to confirm that the environment is fully under control.
Another important part of our work is validating the drug product manufacturing process to make sure that microorganisms are not being introduced through the process. We also develop methods for release testing the drug product after manufacture and often test drug products manufactured at other facilities, along with advising clients on how to manage their own processes.
Is there a difference in how on-site microbiological testing is performed in comparison to the analysis of products made off-site?
There is little difference in our approach to microbiological testing on- and off-site. For clinical materials with a short shelf life that are made by the clinic (e.g. radiolabelled products), we would work with clinics that are geographically close by. The material can be delivered to us, tested, reported back to the clinic and dosed within a short time. In these cases, some of the microbiological data will not be available before it is dosed, so it is vital that we work closely with the clinic for manufacturing process validation to ensure that their process provides a sterile product. Drug products made on site have a longer shelf life supported by a stability programme. There is not the same rush to manufacture and dose within the same week and therfore the product can be fully released prior to dosing and may be dosed over a longer period of time.
Please can you describe the process of microbial analysis for quality control release testing and its implications?
The process for quality control release testing changes depending on whether it is a non-sterile or sterile product. For non-sterile products, the microbiology team will analyse the number of microorganisms within the drug product. This involves taking the product, making it into a suspension or solution and either plating on agar or filtering the solution before transferring the filter membrane onto agar and incubating. This enables us to quantify the microorganisms that have grown. We then have to identify any microorganisms we isolate and determine whether they could cause a problem.
For sterile products, we ensure sterility by filtering the product in an isolator to avoid contamination. The filter is housed in large purpose-made vials of media and incubated.
Bacterial endotoxin testing is another important aspect of quality control release testing to ensure that products are safe for human use. This involves mixing the product with a lysate, extracted from Horseshoe crabs, which reacts with any endotoxin present. We then quantify the amount of endotoxin if present and assess the impact on patient safety. Testing products is an important part of our work, but it is the interpretation of results that is key in microbiology.
Are there any challenges that must be overcome for performing microbial analysis of radiolabelled compounds?
We are at an advantage as we already use aseptic techniques to avoid contamination and we have many of the protocols in place that help us avoid direct contact, which is critically important when handling radiolabelled components and products. The greatest challenge is managing radioactivity – i.e. making sure that radioactive materials are properly disposed of and that areas are cleaned down after contact. At Arcinova, we benefit from having a dedicated radio awareness team on-site and utilising their expertise whenever we have any questions.
Can you describe some common regulatory issues related to pharmaceutical microbial testing?
We are currently assessing what changes, if any, we need to make in response to the soon to be released Annex 1 – the EU regulations associated with sterile product manufacture. There are sometimes situations that are not explicitly covered by the regulations and an important part of our work is assessing the impact of our results and whether they require changes to formulation or manufacturing processes. For example, while the regulation requires that specified microorganisms such as E. coli are tested for, if we isolate other non-listed microorganisms it is the job of the microbiologist to consider the implications of the finding and whether it will cause problems for the patient or reduce the efficacy of the product.
What do you most enjoy about working for Arcinova?
I really enjoy working with my microbiology team and seeing their skills develop over time. Working at Arcinova provides great motivation every day as our end goal is helping patients. We make sure that everyone in the team understands the importance of their contribution to the project at hand, whether that is a new cancer treatment or a novel therapy for a previously incurable disease. Knowing the value of your work is really critical for job satisfaction.
If you would like to find out more about the work of our Microbiology team, please get in touch here