Case study

From paper to practise – a case study in PUPSIT

The context

Committing to a pre-use post-sterilization integrity testing (PUPSIT) strategy is a significant undertaking because, while some regulatory bodies recommend it, it may compromise downstream sterility and its implementation is associated with increased process complexity. This is why PUPSIT continues to generate considerable debate in the biopharmaceutical industry. To help support informed decision-making in this area, the BioPhorum/PDA Sterilizing Filtration Quality Risk Management Consortium has produced a series of articles. One of these is a paper titled Strategy roadmap for the implementation of a risk-based approach to pre-use post-sterilization integrity testing (PUPSIT). This allows companies to use scientific data and risk-based approaches to make and defend decisions related to PUPSIT.
Roche is one of the companies that has used the document to develop an internal position paper on PUPSIT and create its own risk-based approach, which is based on the BioPhorum/PDA PUPSIT strategy.

The story

“We’re a large company with different manufacturing sites and multiple filling lines in each site,” said Marc Steffens, Global Project Manager at Roche. “So it’s always been a challenge to establish harmonized processes, approaches, and strategies across our network. The same has been true for PUPSIT. The internal PUPSIT landscape is very diverse, and we have some sites and filling lines that do PUPSIT, while others don’t. As a result, we didn’t have a fully consistent strategy for how to assess the need for PUPSIT based on scientific considerations.”

Steffens added that the standardization of processes and the harmonization across the networks have always been key topics for Roche, so the BioPhorum/PDA consortium work is highly valued. “Based on this work, we have been able to establish guidelines to ensure that each site and each filling line is assessing this topic in the same manner. This will also improve our position when discussing our strategy with regulators or inspectors. For example, where we received previous observations, while not explicitly related to PUPSIT, inspectors noticed that one site does it one way while another does it differently. This leads to another critical step for us, towards a consistent approach.”

Steffens said that BioPhorum’s paper added value because Roche was looking for a more consistent strategy for PUPSIT as each site had previously created individual assessments. 

These were not necessarily done in the same way and with the same focus. Most of the assessments focused on the risk of using a flawed, non-integral filter, but disregarded the product properties that could lead to clogging of a flawed membrane. But it’s the combination of these two issues that results in a flaw-masking risk, i.e., the only scientific trigger for PUPSIT.

Marc Steffens, Global Project Manager at Roche

The outcomes

Steffens added that a significant change was that Roche was now applying an industry approach to PUPSIT. “This is important as it means we’re speaking as an industry, which helps us to, for example, defend our position in front of regulators.” He also commented that, previously, Roche had already used risk-based assessments but that the BioPhorum work had helped the team incorporate additional risk factors such as the flaw masking risk. Kewei Yang, Principal Scientist/Pharmaceutical Project Leader at Roche, explained this industry approach also helped the global roll-out of the new guidance. “We translated the BioPhorum work into our first internal guidance on this topic, for which we got endorsement and agreement from all our different manufacturing sites. It meant we now have an agreed global internal strategy for interpreting the EMA’s requirements on PUPSIT. Different sites used to interpret the regulatory requirements and prepared their risk assessment in their own way, so the outcomes from each site were different. Now we are aligning our strategy across sites and countries.” Roche has not only started to implement the BioPhorum approach but has already taken the next step. “After creating our internal guidance in 2021,” said Steffens, “we’re now in discussions with the different sites on setting up a risk assessment template to provide end-users with concrete and specific guidance on how to assess the flaw-masking risk. “One outcome of the end-user assessments could be that PUPSIT doesn’t make sense from a scientific perspective and hence may justify the removal of that step. But we’re just at the beginning of the process and the implementation will continue over the next few years. We haven’t had any inspection or audits in the last few months where PUPSIT was challenged, so we haven’t yet had any feedback on the strategy we’re now applying.”

Lessons learned

Steffens said that communication and dialogue, especially with health authorities, were important. “Once the BioPhorum/PDA consortium started these discussions, it soon became clear that we all have the same problems and questions, and that each company is struggling with PUPSIT. So, it’s also essential to be transparent on what we’re doing and what our strategy looks like. As PUPSIT is a compliance-related topic, discussions should include not only technical subject matter experts but also those from the quality department.” Yang explained he had learned a lot from the discussions in the BioPhorum team and that the publication would be valuable to the whole pharmaceutical industry. “It has been a great experience to join the BioPhorum discussions with experts from the other companies. These help us challenge our opinions and share our knowledge and know-how. A lesson learned is the importance of communicating with the different stakeholders; for example, our manufacturing colleagues from the different drug product sites, QA teams, and global functions. Communication is essential as this helped us get an endorsement from the different sides and ultimately establish a company guidance on this topic.”