Posted on: 15th December 2018

From glove management and cleaning/disinfection to regulator expectations and technology solutions, the operation of isolators has become an increasing concern among members. The question was: how to address these issues?

A new workstream

During 2017, the Phorum looked at what its members were discussing, such as operational issues or the approaches that regulators were asking them to adopt. A common debate was how people were performing aseptic filling using isolators. Two areas were specific talking points and were a great opportunity for collaboration in the new workstream: glove management and the cleaning, disinfection and sterilization of the isolator including their ‘indirect contact parts’, e.g. bowls that hold stoppers for vials inside the isolator.

The new workstream is split into separate glove and the cleaning teams. The workstream consists of 22 members of the wider Fill Finish Phorum, with the most active being members from Eli Lilly, AstraZeneca, Bayer, CSL Behring, Pfizer and BMS.

Deliverables

The workstream’s initial aim is to produce good practice guides for these two areas. It has taken two draft documents from a member company and is adapting these to make them more appropriate for general use in the whole industry. It plans to complete the draft guides by Q2 2019.

A major isolator manufacturer is also producing a good practice document on glove management and the workstream is collaborating with it to compare documents and reference each other’s work, which will strengthen the overall advice to BioPhorum members.

For glove management, the workstream will put forward a common nomenclature for gloves; for instance, if there is a problem with a glove, how would you determine the risk to the product? There will also be good practice around the integrity testing of gloves, the methods that are available to use, their pros and cons, etc.

It also plans to consult with some regulatory authorities on the two guides as members consider that some of the current requirements, particularly from the European Medicines Agency, are counter productive.

For example, the requirement to remove all indirect contact parts for sterilization in an autoclave, before returning them to the isolator to be disinfected. This is both technically difficult, particularly on old isolators, and is not always considered necessary.

Benefits and risks

“The main benefits of the workstream are around making networking connections with other engineers and scientists dealing with the same isolator-related issues. And learning about the approaches used by other companies to address their challenges,” says Dawn Downey, Senior Consultant Engineer from Eli Lilly.

Chris Burns, Aseptic Processing Manager at Bayer, says that collaboration between industry peers is always a benefit of BioPhorum participation. “Being able to create these two reference materials based on the collective successes (and failures) of others can serve to standardize practices and associated rationales across the industry, which has the potential to standardize regulatory expectations. Collaboration also affords us the opportunity to standardize our language as an industry. This is a natural by-product of having such a diverse group of individuals from different companies discussing these common topics, and it helps to eliminate confusion and increase the efficiency of the discussions.”

For glove management, users will have a common language in an easy-to-use format so they can share data about a glove’s lifecycle, potential faults, etc. The standards will also help facilitate investigations when something goes wrong and provide some strong risk management controls.

“The main risks are associated with glove management, which is an area where common practices have not been published much, and the proposed changes associated with Annex 1 around cleaning and disinfection practices for indirect product contact parts,” Downey adds.

For cleaning and disinfection, a key benefit of this work is the focus on the main risks associated with the operation of isolators rather than other sterile filling systems, such as sterile areas or Restricted Access Barrier Systems. This has not fully been done before and will provide a positive, peer-reviewed industry response to some concerns, particularly those raised by the European regulator.

“Industry tends to work in silos, while regulatory agencies do not,” suggests Burns. “Addressing and justifying common issues independently carries the risk of creating shifting agency expectations, as they encounter what they feel should be best practice at one company or facility, which becomes their new standard for assessing others. By discussing and addressing issues together, we collectively decide on and justify best practices, thus creating the standards ourselves.”

Another benefit is that the new standards could potentially save a considerable amount of time in costly equipment redesign and process changes. Clearly, once they are generally accepted across the industry they will become good, common practice.

The forward view

Looking ahead, one area the workstream plans to cover is process simulations in isolators (as opposed to more traditional aseptic filling areas). This will look at, for example, how members would perform simulations and the related good practice.

To date, the workstream has been working on some very important issues, but in a reactive way. Through discussions with the leadership group in the Fill Finish Phorum and the workstream members, it plans to change this emphasis and become more proactive in its work by identifying and agreeing the questions that need answering in the next two to three years. This will be the basis of future effort.

These may cover areas such as how to accommodate smaller batch sizes and how to apply existing technologies to isolators much faster than at present. The workstream has started these conversations and will be discussing the questions in detail at a face-to-face meeting in March 2019. These will be developed in detail through to the end of Q2 2019.

However, the workstream’s immediate focus is delivering its existing plan. Once it has done that, it can start looking at the detail of these other wider topics.

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