How You Can Ensure Your Processing Systems are Fit for Now and the Future

Written by: Matthias Mikkelsen, Fill/Finish Systems Specialist, Flexicon Liquid Filling, Watson-Marlow Fluid Technology Solutions.

The pharmaceutical sector has always been at the forefront of innovation, and these rapid changes have continued in recent years. Most noticeable is the transition towards biologic therapies and this shift is expected to continue. Biologic-based therapies such as monoclonal antibodies and cell therapies have totally different processing requirements to traditional small molecule treatments and as such the pharmaceutical processing industry has had to undergo its own transition in order to meet these evolving needs.  

Key requirements of biologics currently in development include gentle processing mechanisms that protect the integrity of sensitive products, and heightened requirements of small batch production.

Regulation is often a step behind innovation, responding to developments rather than guiding innovation. However, recent changes to GMP requirements have attempted to not only regulate for existing processes but also guide future developments to ensure the highest levels of safety are maintained.

So how can you design your processes to be compliant with the new Annex 1 guidelines?

Understanding the Landscape

The Annex 1 revision of Good Manufacturing Practices (GMP) for sterile drug products includes changes in several areas of pharmaceutical manufacturing, including risk management, environmental monitoring, and sterility assurance. It better aligns sterile drug manufacturing principles with those of the World Health Organization (WHO), the Pharmaceutical Inspection Cooperation Scheme (PIC/S) and the US Food and Drug Administration’s (FDA) 2004 guidance.

Prioritising sterility assurance, the regulations emphasise the potential role of human interventions in contamination and how this risk should be minimised through the implementation of a contamination control strategy (CCS). They also emphasise the use of systems that separate the Grade A environment from its surroundings, such as isolators or Restricted Access Barrier Systems (RABS).

In order to design and implement a compliant process, there are many considerations to be aware of. Three key focus areas will be vital to create systems that are not only compliant now but also stand the test of time.

Hygienic by Design

Hygiene is a guiding principle of any pharmaceutical process. Designing systems with remote access so that operations, maintenance and repairs can be performed outside the cleanroom is a clear opportunity to avoid compromising the sterile environment. It is also important to demonstrate compliance to facilitate the regulatory approval process. To support this, a detailed written description of equipment design and monitoring requirements should be available as part of the User Requirement Specification.

Minimise Interventions

Human interventions can be a source of unintentional contamination and error that could result in the loss of an entire batch. Minimising these is therefore important for product quality, patient safety and financial results. So how can you minimise interventions within the aseptic core given that so many of these novel processes were originally developed manually?

Prior to production, the setup of the machine to the different vial sizes has always been a source of mechanical faults. This results in downtime and potential lost batches. By having a recipe driven, automatic set up process, most of the risks can be avoided from the beginning.

The latest fill/finish technologies incorporate extensive automation and integrate systems that ensure any additions to the sterile environment are done so without compromise. This includes sterilisation of the entire system prior to production with vaporised hydrogen peroxide, and the use of no touch transfer when introducing vials in Ready to Use (RTU) trays. Stoppers and caps must be brought in via Rapid Transfer Ports (RTPs).

Fully automated gloveless machines may initially seem like the obvious choice to minimise interventions, however, should an accident or issue occur, they do not allow any possibility of rectification without fully compromising the sterile environment and as such the whole batch. Systems that incorporate gloves allow for the rectification of any accidents without full batch loss. These gloves should be demonstrated to have appropriate mechanical and chemical resistance and the frequency of glove replacement should be clearly defined within the CCS. Generally, glove integrity testing should be performed at a minimum frequency of the beginning and end of each batch.

Consider all Components

Any addition to the sterile environment has the potential to cause contamination, from the equipment itself to the gases used. Each one therefore needs to be carefully considered. The proper materials should be used for equipment so that they can either be easily and repeatedly cleaned, such as stainless steel, or easily replaced with pre-sterilised components. For fully aseptic processes, both direct and indirect product contact parts should be sterilised, including inner packaging. Any gases used should be filtered through a sterilising filter.

The use of peristaltic pumps removes any ‘direct contact’ parts. As the tubing and the nozzles are single use and available pre-sterilised, contamination is prevented.

Fit for the Future

We can’t predict the future of bioprocessing, but by looking at recent trends in the industry it is likely that the focus on biologics and sterility demands will grow as we look to develop treatments for diseases which are currently untreatable. To be as prepared as possible for this progress, we should align with current best practice and, as an industry, work to continually improve automation, sterility and validation. This will ensure that we are delivering efficient processing systems that can be used to bring innovative treatments to patients safely and quickly.